**8. Right-sided operations Right-sided operations:**

**•** Patient's arms are wrapped alongside the body to reduce possibility of shoulder injury and

**•** Pressure points and bony prominences are padded and the body position is secured with

**•** Secure the patient to the table to avoid any shifting with the Trendelenburg position.

**•** Sequential compression devices (Flowtrons) are applied to the legs for DVT prophylaxis.

**•** After positioning, padding, securing and preparing the patient in the supine position, the table is then placed in a Trendelenburg position, whereby the steepness should be adjusted

additional shoulder harness can be placed to support Trendelburg's position

**•** Patient is tilted right side down and adjust the angle during initial exposure

**•** A body warmer (bear hugger) is applied to prevent patient hypothermia.

vacuum-mattress device, especially lateral on the right side.

150 Colorectal Cancer - Surgery, Diagnostics and Treatment

as per exposure needs during the initial exposure step.

**Image 1.** Showing positioning of patient

**Image 2:** showing marking for Right Colonic resections. Insufflation via Veress needle at **Image 2.** Showing marking for Right Colonic resections. Insufflation via Veress needle at LUQ.

#### **PORT PLACEMENTS: 9. Port placements**

LUQ**.**

#### **Preparing for Port Placement: 9.1. Preparing for port placement**


#### **9.2. Instrument port placements for left sided colorectal operations [54]**

**Diagram 1** Showing post placements for left sided colorectal operations


**Image 3.** Showing port placements for left sided colorectal operations

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 153

**Image 3.** Showing port placements for left sided colorectal operations

**9.2. Instrument port placements for left sided colorectal operations [54]**

152 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Diagram 1** Showing post placements for left sided colorectal operations

Distance to symphysis pubis should be ~22-24 cm.

this port.

medial to the right MCL

instrument ports and the camera port.

used for suction/irrigation, ligation and retraction.

**• Robotic camera port, 12 mm (Blue):** Place the port 3-4 cm right and 3-4 cm above umbilicus.

**• Robotic instrument arm port, 8 mm (Yellow):** Place the port a minimum of 8 cm from the camera port, on the right spinoumbilical line (SUL) at the crossing of the mid-clavicular line (MCL). Distance to symphysis pubis should be ~14-16 cm. Linear stapler can be used from

**• Robotic instrument arm port, 8 mm (Green):** Place the port a minimum of 8 cm from the camera port, on the left spinoumbilical line (SUL) at the crossing of the mid-clavicular line

**• Robotic instrument arm port, 8 mm (Red):** Place the port ~ 3 cm sub-xyphoid and ~ 2 cm

**• Robotic instrument arm port, 8 mm (Green-Red):** Place the port 7-8 cm below the left costal margin, slightly medial to the left MCL. Place the port a minimum of 8 cm from the other

**• Assistant port, 5 mm (White):** Place the port 8-10 cm cephalad to the instrument arm port and ~ 4 cm lateral to the right MCL (a minimum of 8 cm from the camera port). This port is

(MCL). The distance to the symphysis pubis should be ~14-16 cm.

**•** Medial to lateral mobilization of sigmoid and descending colon is carried out towards the left sidewall and superiorly towards the spleen. The plane between mesocolon and Gerota's fascia is developed. Left ureter and gonadal vesssels should be identified at this stage.

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 155

**•** Splenic flexure mobilization (SFM) is not mandatory. However, if the anastomosis is likely to be at tension, SFM is strongly recommended. If SFM is needed, IMV is divided high and the plane above the pancreas is developed which can lead the surgeon into the lesser sac.

**•** Rectal dissection and division – Total Mesorectal Excision (TME) is carried out to the pelvic floor for a mid to low rectal cancer or to the peritoneal reflection for an upper rectal cancer.

**•** Anastomosis - Rectal division and anastomosis is performed using surgical staplers. Care should be taken not to damage the pelvic floor at this stage. For rectal division, stapler can be inserted through the assistant port or the R1 can be disabled and undocked and the port changed to a 12 mm port to allow the stapler to pass through. In patients with a very narrow pelvis, a supra-pubic port can be used to divide the rectum anteroposteriorly. We perform a routine flexible sigmoidoscopy to check for anastomotic bleeding, viability of the colon

and rectum and at the same time perform a leak test to check for anastomotic leak.

**•** The patient is positioned in modified Lloyd –Davis position with slight Trendelenberg tilt. The ileocolic and Superior Mesenteric Artery (SMA) pedicles are exposed by retraction of the small bowel and appropriate traction and counter traction on the mesentry. Dissection along the Superior Mesenteric Vein (SMV) will expose the ileocolic vein and artery that are then divided after clipping. Duodenum is identified early and dissection carried out towards

**•** Lateral to medial mobilization allows the right colon to be freed up. Sub ileal dissection completes this dissection allowing the whole specimen to come to the midline. Gastrocolic

**•** Ileocolic anastomosis can be performed intra or extra corporeally depending upon the surgeons preference. Specimen is extracted either through a midline or suprapubic incision.

omental division results in complete mobilization of the heaptic flexure.

**9.7. Post-operative management — (Enhanced Recovery Programme [55])**

**•** Pain management with epidural followed by PCA and then oral/IV/IM analgesia

**•** All patients should have DVT (unless contraindicated) and antibiotic prophylaxis

**•** Post-operatively the patients are transferred to Surgical High Care for close monitoring

**•** Patients encouraged to sit out of bed and encouraged to drink straight after the operation

Gastrocolic omental division from above can complete this step safely.

Great care is taken to avoid injury to the parasympathetic nerves.

**9.6. Operative steps for right sided colonic resections**

the liver to enter the lesser sac.

**Day of operation:**

including 2 protein drinks

#### **9.3. Port placement for right sided colonic resections**

**Image 4.** [74]: showing port placements for right sided colonic resections

#### **9.4. Instrument port placements for right sided colorectal operations**


#### **9.5. Operative steps for left sided colorectal operations**


#### **9.6. Operative steps for right sided colonic resections**


#### **9.7. Post-operative management — (Enhanced Recovery Programme [55])**

#### **Day of operation:**

**9.3. Port placement for right sided colonic resections**

154 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Image 4.** [74]: showing port placements for right sided colonic resections

**•** Camera port 12mm, at left spinoumbilical line (SUL)

**•** Assistant port, 5mm, place at LIF lateral to left MCL

**9.5. Operative steps for left sided colorectal operations**

slipping into the operative area.

division.

**9.4. Instrument port placements for right sided colorectal operations**

**•** Robotic arm port 1, 8mm, at left mid-clavicular line (MCL) 8cms below costal margin

**•** Initial exposure is acquired by cephalad retraction of the omentum to expose the transverse colon and by moving the small bowel out of the pelvis. Loops of small bowel can be stacked in the right upper quadrant to expose the Inferior Mesenteric Vein (IMV). A small swab placed against the small bowel loops can sometimes help by preventing the bowel from

**•** Primary vascular control is achieved by ligating the Inferior Mesenteric Artery (IMA) and IMV earlier in the operation. Disposable locking clips are used to secure these vessels before

**•** Robotic arm port 2, 8mm, is placed in at right SUL 2cms lateral to right MCL **•** Robotic arm port 3, 8mm, is placed in midline 3 cms from pubic symphysis


#### **First post-operative day:**


the console and is able to view infrared images of blood flow in the microvasculature as well as tissue perfusion in real time. This is particularly useful during bowel anastomosis and

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 157

The use of ICG is an attractive method to facilitate visualisation of lymphatic vessels, sentinel

ICG has been used in the recent past to harvest lymphnodes for cutaneous rectal carcinoma

It has also been used in transcutaneous Sentinel Lymph Node detection in vulvar cancer patients [63] and for identification of lymphatic pathway involved in the spreading of prostate

Single incision laparoscopic colectomy (SILC) is well established. SILC is associated with shorter post-operative length of hospital stay and smaller skin incision. There is no difference in operating time or in conversion rate when compared to multiport laparoscopic colorectal operations [65]. The main drawback with SILC is exposure, conflict of instruments, ease of

Robotic single incision laparoscopic surgery may be the answer to some of the problems associated with SILC. The author believes that robotic single incision colectomy will result in less abdominal wall trauma, less pain, needing fewer analgesics, early mobilisation and decreased length of hospital stay. It will have better cosmetic result due to fewer numbers of incisions. There is good evidence to suggest that multiple laparoscopic port incisions can cause

Early experience with robotic SILC performing right hemicolectomy is safe and feasible [69].

**•** Spinioglio G et al mentioned that it took them less time to perform robotic single port

**•** Robotic single-port trans-umbilical total hysterectomy is technically feasible in selected

**•** Hahn Tran et al have successfully performed robotic single-port inguinal hernia repair

**•** The authors believe that robots will also play a role in natural orifice endoscopic surgery

The perfect robotic platform should have a low external profile, which can be deployed through a single access site. It should be able to restore intra-abdominal triangulation while

We need more studies to validate robotic SILC for left sided operations.

laparoscopic cholecystecomies than laparoscopic SILS [70].

and specimen retrieval via the natural orifice in the near future

Other surgical specialties where robotic SILS is gaining interest are listed below:

Lymph nodes harvesting can be a difficult procedure to perform in cancer surgery.

nodes, and metastatic lymph nodes. It was first introduced by Lim and Soter [60].

metastasis [61] and cutaneous Kaposi's sarcoma [62] with successful outcome.

**10.2. Robotic Single Incision Laparoscopic Surgery (SILS) or Colectomy (SILC)**

instrumentation, camera operation and ergonomics [66].

port site hernias even with 5mm ports [67, 68].

patients with gynaecological disease [71].

without any complications [72].

improving patient outcomes [59].

cancer [64].

#### **Second post-operative day:**


#### **Post-operative days 3-5:**


#### **Outpatient follow-up:**


## **10. Future developments**

#### **10.1. Role of ICG in bowel anastomosis and lymph node mapping using da Vinci robot**

Indocyanine green (ICG) is a cyanine fluorescent dye that absorbs near infrared wavelengths of light. It binds to plasma proteins and travels in the vascular system [56]. ICG emits an infrared signal when excited by laser light *in situ*, which can be detected with near-infrared fluorescence camera system (NIRF) [57].

The image from NIRF gives visual assessment of blood vessels, blood flow, and tissue perfusion. ICG has been widely used by the ophthalmologists to visualise retinal blood vessels [58] and the technique has been amalgamated into the da Vinci Si robotic system.

Water soluble ICG can be given intravenously during surgical procedure. The surgeon is able switch into fluorescence imaging modes from normal white light mode by pressing pedals in the console and is able to view infrared images of blood flow in the microvasculature as well as tissue perfusion in real time. This is particularly useful during bowel anastomosis and improving patient outcomes [59].

Lymph nodes harvesting can be a difficult procedure to perform in cancer surgery.

**First post-operative day:**

the physiotherapists

the physiotherapists **Post-operative days 3-5:**

and or opening bowels

**Outpatient follow-up:**

**10. Future developments**

fluorescence camera system (NIRF) [57].

**Second post-operative day:**

**•** The patient will have an epidural and urinary catheter

**•** Will be encouraged to eat normal food

156 Colorectal Cancer - Surgery, Diagnostics and Treatment

**•** Will be encouraged to eat normal food

**•** Pain controlled with oral medications

**•** Follow up at OPD 2-3 weeks post-operatively

**•** Able to mobilize and physiotherapists happy with progress

**•** Will be encouraged to drink 2 litres of fluid and drink 4 high protein drinks

**•** Epidural and urinary catheter removed. Pain management using PCA.

**•** Will be encouraged to drink 2 litres of fluid and drink 4 high protein drinks

**•** Will be encouraged out of bed for 8 hours and take 3 walks of 50 meters each with help from

**•** Will be encouraged out of bed for 8 hours and take 3 walks of 50 meters each with help from

**•** The patient is discharged from the hospital if stable in three to five days i.e. passed flatus

**•** All Cancer patients are discussed at Multidisciplinary Team Meeting, regarding additional

**10.1. Role of ICG in bowel anastomosis and lymph node mapping using da Vinci robot**

Indocyanine green (ICG) is a cyanine fluorescent dye that absorbs near infrared wavelengths of light. It binds to plasma proteins and travels in the vascular system [56]. ICG emits an infrared signal when excited by laser light *in situ*, which can be detected with near-infrared

The image from NIRF gives visual assessment of blood vessels, blood flow, and tissue perfusion. ICG has been widely used by the ophthalmologists to visualise retinal blood vessels

Water soluble ICG can be given intravenously during surgical procedure. The surgeon is able switch into fluorescence imaging modes from normal white light mode by pressing pedals in

[58] and the technique has been amalgamated into the da Vinci Si robotic system.

therapy or adjuvant radiation with or without chemotherapy as indicated.

The use of ICG is an attractive method to facilitate visualisation of lymphatic vessels, sentinel nodes, and metastatic lymph nodes. It was first introduced by Lim and Soter [60].

ICG has been used in the recent past to harvest lymphnodes for cutaneous rectal carcinoma metastasis [61] and cutaneous Kaposi's sarcoma [62] with successful outcome.

It has also been used in transcutaneous Sentinel Lymph Node detection in vulvar cancer patients [63] and for identification of lymphatic pathway involved in the spreading of prostate cancer [64].

#### **10.2. Robotic Single Incision Laparoscopic Surgery (SILS) or Colectomy (SILC)**

Single incision laparoscopic colectomy (SILC) is well established. SILC is associated with shorter post-operative length of hospital stay and smaller skin incision. There is no difference in operating time or in conversion rate when compared to multiport laparoscopic colorectal operations [65]. The main drawback with SILC is exposure, conflict of instruments, ease of instrumentation, camera operation and ergonomics [66].

Robotic single incision laparoscopic surgery may be the answer to some of the problems associated with SILC. The author believes that robotic single incision colectomy will result in less abdominal wall trauma, less pain, needing fewer analgesics, early mobilisation and decreased length of hospital stay. It will have better cosmetic result due to fewer numbers of incisions. There is good evidence to suggest that multiple laparoscopic port incisions can cause port site hernias even with 5mm ports [67, 68].

Early experience with robotic SILC performing right hemicolectomy is safe and feasible [69]. We need more studies to validate robotic SILC for left sided operations.

Other surgical specialties where robotic SILS is gaining interest are listed below:


The perfect robotic platform should have a low external profile, which can be deployed through a single access site. It should be able to restore intra-abdominal triangulation while maintaining the maximum degree of freedom for accurate maneuvers and strength for reliable traction. Several purpose-built robotic prototypes for single-port surgery are being tested [73].

[6] Robot-assisted right colectomy: surgical technique and review of the literature Woj‐ ciech Witkiewicz, Marek Zawadzki, Marek Rząca, Zbigniew Obuszko, Videosurgery

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[7] Kwoh YS, Hou J, Jonckheere EA, Hayati S. A robot with improved absolute position‐ ing accuracy for CT guided stereotactic brain surgery. IEEE Trans Biomed Eng 1988;

[9] McConnell, PI; Schneeberger, EW; Michler, RE (2003). "History and development of

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The author believes that robots will also play a role in natural orifice endoscopic surgery and specimen retrieval via the natural orifice in the near future.

## **11. Summary**

In summary the developments of surgical robotics over the last decade has been very exciting. The technology is improving rapidly. Robots certainly allow the surgeons to perform better operations with improved safety. In colorectal surgery robotics will find its place in pelvic and rectal cancer surgery. The cost of instruments and the system are the biggest barrier to the widespread uptake of robotic surgery by the surgical community. The future applications of this technology may result in further benefits that will offset the cost issue.

## **Author details**

Ray Swayamjyoti, Jim Khan and Amjad Parvaiz

Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Portsmouth, UK

## **References**


maintaining the maximum degree of freedom for accurate maneuvers and strength for reliable traction. Several purpose-built robotic prototypes for single-port surgery are being

The author believes that robots will also play a role in natural orifice endoscopic surgery and

In summary the developments of surgical robotics over the last decade has been very exciting. The technology is improving rapidly. Robots certainly allow the surgeons to perform better operations with improved safety. In colorectal surgery robotics will find its place in pelvic and rectal cancer surgery. The cost of instruments and the system are the biggest barrier to the widespread uptake of robotic surgery by the surgical community. The future applications of

this technology may result in further benefits that will offset the cost issue.

Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Portsmouth, UK

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158 Colorectal Cancer - Surgery, Diagnostics and Treatment

tested [73].

**11. Summary**

**Author details**

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4)

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[69] Spinoglio G, Lenti LM, Maglione V, Lucido FS, Priora F, Bianchi PP, Single-site ro‐ botic cholecystectomy (SSRC) versus single-incision laparoscopic cholecystectomy (SILC): comparison of learning curves. First European experience., Grosso F, Quarati R. Surg Endosc. 2012 Jun;26(6):1648-55. doi: 10.1007/s00464-011-2087-1. Epub 2011

[70] Eun Ji Nam, Sang Wun Kim, Maria Lee, Ga Won Yim et al, Robotic single-port tran‐ sumbilical total hysterectomy: a pilot study, *Gynecol Oncol.* 2011 June 30; 22(2): 120– 126. Published online 2011 June 30. doi: 10.3802/jgo.2011.22.2.120. *PMCID:*

[71] Hanh Tran, Robotic Single-Port Hernia Surgery, F *JSLS.* 2011 Jul-Sep; 15(3): 309–314.

[72] Autorino R, Kaouk JH, Stolzenburg JU, Gill IS, Mottrie A, Tewari A, Cadeddu JA.Current status and future directions of robotic single-site surgery: a systematic re‐ view. *Eur Urol.* 2013 Feb;63(2):266-80. doi: 10.1016/j.eururo.2012.08.028. Epub 2012

doi: 10.4293/108680811X13125733356198. *PMCID:* PMC3183567

Colon Rectum. 2011 Feb;54(2):187-92. doi: 10.1007/DCR.0b013e3181f8d972.

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[62] Crane LMA, Themelis G, Arts HJG, et al. Intraoperative near-infrared fluorescence imaging for sentinel lymph node detection in vulvar cancer: first clinical results. *Gy‐ necologic Oncology*. 2011;120(2):291–295.

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[48] Robotic-assisted Colorectal Surgery in the United States: A Nationwide Analysis of Trends and Outcomes. World Journal of Surgery, 12 2013, vol./is. 37/12(2782-90),

[49] Kim CW, Baik SH, Robotic rectal surgery: what are the benefits?. Minerva Chirurgi‐

[50] Deborah S. Keller, Lobat Hashemi, Minyi Lu, and Conor P. Delaney, Short-Term Outcomes for Robotic Colorectal Surgery by Provider Volume, Journal of the Ameri‐

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[56] Jarmo T. Alander, Ilkka Kaartinen, Aki Laakso, Tommi Pätilä, Thomas Spillmann, Valery V. Tuchin, Maarit Venermo, and Petri Välisuo, A Review of Indocyanine Green Fluorescent Imaging in Surgery. Int J Biomed Imaging. 2012; 2012: 940585.

[57] Flower RW. Injection technique for indocyanine green and sodium fluorescein dye angiography of the eye. Investigative Ophthalmology. 1973;12(12):881–895.

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[73] Mathew R, Kim SH. Robotic right hemicolectomy with D3 lymphadenectomy and complete mesocolic excision: Technical detail. OA Robotic Surgery 2013 Jun 01;1(1):6. http://www.oapublishinglondon.com/article/710,

**Chapter 8**

**Surgical Strategies for Liver Metastases from Colorectal**

Colorectal carcinoma is one of the more common types of cancer around the world. For patients in UICC stage I (i.e., those who have pT1/2 tumors and do not have any lymph node metasta‐ ses), the probability of surviving 5 years is 90% [2]. The prognosis of patients in stages II (pT3/4 tumors without lymph node metastases) and III (tumors with lymph node metastases) has improved steadily in recent years. At present, the 5-year survival in these two groups is 80%

Approximately, 1.2 million cases of CRC occur yearly worldwide, with 412, 900 new cases diagnosed in Western Europe alone and 150, 000 in the United States. [1, 2] Resection of colorectal liver metastases (CRLM) is the only treatment offering the possibility of cure and has been shown to provide clear survival benefits. [3] Unfortunately, only 10% to 20% of patients with CRLM are eligible for this procedure upfront. On the other hand, during the last 10 years, major advances in the management of CRLM have taken place involving principally three different fields: oncology (new and more effective chemotherapeutic agents), interven‐ tional radiology (portal embolization and radiofrequency), and surgery (better instruments and newer techniques). These advances as part of a multidisciplinary team approach have gradually but effectively increased the resectability rate to 20%-30% of cases with a 5-year

Nonetheless, distant metastases eventually arise in about 20% of patients who are stage II or III at the time of diagnosis [3]. About 35% of all patients already have distant metastases when the diagnosis is made. Patients with untreated hepatic metastases have a very poor prognosis.

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nikola Kolev, Valentin Ignatov, Anton Tonev,

Alexander Zlatarov and Krassimir Ivanov

Additional information is available at the end of the chapter

Tanya Kirilova, Georgi Ivanov,

http://dx.doi.org/10.5772/56915

**1. Introduction**

and 60% [1].

survival of 35%-50%. [3]

**Cancer**

## **Surgical Strategies for Liver Metastases from Colorectal Cancer**

[73] Mathew R, Kim SH. Robotic right hemicolectomy with D3 lymphadenectomy and complete mesocolic excision: Technical detail. OA Robotic Surgery 2013 Jun 01;1(1):6.

http://www.oapublishinglondon.com/article/710,

164 Colorectal Cancer - Surgery, Diagnostics and Treatment

Nikola Kolev, Valentin Ignatov, Anton Tonev, Tanya Kirilova, Georgi Ivanov, Alexander Zlatarov and Krassimir Ivanov

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56915

## **1. Introduction**

Colorectal carcinoma is one of the more common types of cancer around the world. For patients in UICC stage I (i.e., those who have pT1/2 tumors and do not have any lymph node metasta‐ ses), the probability of surviving 5 years is 90% [2]. The prognosis of patients in stages II (pT3/4 tumors without lymph node metastases) and III (tumors with lymph node metastases) has improved steadily in recent years. At present, the 5-year survival in these two groups is 80% and 60% [1].

Approximately, 1.2 million cases of CRC occur yearly worldwide, with 412, 900 new cases diagnosed in Western Europe alone and 150, 000 in the United States. [1, 2] Resection of colorectal liver metastases (CRLM) is the only treatment offering the possibility of cure and has been shown to provide clear survival benefits. [3] Unfortunately, only 10% to 20% of patients with CRLM are eligible for this procedure upfront. On the other hand, during the last 10 years, major advances in the management of CRLM have taken place involving principally three different fields: oncology (new and more effective chemotherapeutic agents), interven‐ tional radiology (portal embolization and radiofrequency), and surgery (better instruments and newer techniques). These advances as part of a multidisciplinary team approach have gradually but effectively increased the resectability rate to 20%-30% of cases with a 5-year survival of 35%-50%. [3]

Nonetheless, distant metastases eventually arise in about 20% of patients who are stage II or III at the time of diagnosis [3]. About 35% of all patients already have distant metastases when the diagnosis is made. Patients with untreated hepatic metastases have a very poor prognosis.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In a prospective, observational study carried out on 484 patients from 1980 to 1990, the median time to death was 6.9 months [4]. Adson and colleagues, in the 1970's, were the first to show that patients could be cured by the resection of hepatic metastases [5]. Since then, resection has become established as a standard treatment. For this review, we selectively searched the literature for articles containing the words "colorectal liver metastases, " "chemotherapy, " and "surgery, " paying special attention to studies carried out on larger groups of patients and to randomized clinical trials. [6]

hepatic function can be predicted more precisely with the aid of CT volumetry. This technique enables prediction of the remaining volume of hepatic tissue after surgery to within 10% of

Surgical Strategies for Liver Metastases from Colorectal Cancer

http://dx.doi.org/10.5772/56915

167

Metastases are considered non-resectable or marginally resectable when an R0 resection is not possible. Metastases are also considered marginally resectable in the setting of, for example, extra-hepatic tumor manifestations, technical impediments to surgery, or inadequate expected residual liver mass. For these patients, intensified preoperative chemotherapy can be consid‐ ered. The feasibility of secondary resection should be evaluated at each re-staging under

Today, patients with metastatic CRC should be treated by multidisciplinary teams including surgeons, oncologists and radiologists. Evidence of the benefit of perioperative chemotherapy over surgery alone [22] and the potential benefit of adjuvant chemotherapy (after liver resection) [23] caused a rethink among the experts particularly in terms of the timing of the administration of chemotherapy for CRC patients with initially resectable liver and lung metastases. Poor prognostic factors for patients with liver metastases are multiple metastases, >5 cm in diameter, synchronous presentation, lymph node-positive primary and high tumor marker levels. [17] Thus, even when the metastases are technically resectable (in terms of number, location and size), when facing a patient with more than one of the poor prognostic factors listed above, the current trend is to refer patients for neoadjuvant chemotherapy before surgery. The data from the EORTC study showed quite clearly that nearly all patients were able to tolerate neo-adjuvant chemotherapy. Also, analysis of the PFS curves from the EORTC– EPOC trial shows that the main difference comes after the first 2 months when the curves drop down and then move out in parallel, suggesting that the benefit conferred by perioperative chemotherapy might be a consequence of a reduction in the occurrence of early cancer relapse as a consequence of preoperative chemotherapy. [16] An exception to preoperative chemo‐ therapy is, however, those patients with a single resectable metachronous metastasis who could be directly referred to surgery, [14] with the recognition that this accounts for <10% of patients seen in routine clinical practice. All other patients with resectable metastases should be treated up front with chemotherapy, with the caveats that the patient is able to receive chemotherapy and the position of the lesion is not going to be lost. On the other hand, it has

Metastases are considered resectable when the following criteria are met:

**•** exclusion of a non-resectable extrahepatic tumor manifestation,

**•** <3 hepatic veins and <7 hepatic segments involved,

**•** no hepatic insufficiency, no Child B or C cirrhosis,

the actual value. [9, 11]

chemotherapy. [15]

**•** parenchymal involvement <75%,

**•** no severe accompanying diseases.

**3. New treatment strategies**

Most favorable outcomes were observed in patients with pedicle lymph node involvement (5 year survival rate 25% vs 0% for patients with celiac and/ or para-aortic lymph node metasta‐ ses), and in patients younger than 40 years (5-year survival rate 45% vs 10% for older patients). [7, 8] In relation to our results and those reported by others, we recommend combining hepatectomy with lymphadenectomy only for young CLM patients presenting with pedicle lymph node involvement, in the absence of disease progression after preoperative chemo‐ therapy. On the other hand, patients presenting with celiac or para-aortic lymph node involvement should not be subjected to this oncosurgical treatment strategy. Even concomitant pulmonary metastases should not be considered a contraindication to surgery. Patients with only pulmonary metastases as a site of extrahepatic disease have a particularly good outcome after complete metastasectomy of both liver and lung disease. Five-year survival rates ranged from 22% to 50% in patients with metastases limited to the lungs. [8] Also, selected patients with complex multiorgan metastases have been associated with prolonged survival after a multimodality treatment. Patients with simultaneous hepatic and extrahepatic disease (EHD) do, however, need to be selected for surgery. Elias et al stated that EHD, when resectable, is no longer a contraindication to hepatectomy. [18] More importantly, the total number of metastases, whatever their location, has a strong prognostic effect than the site of the meta‐ stases. In addition, a study conducted at our centre demonstrated that patients with concom‐ itant EHD who were resected experienced a lower 5-year survival than those without EHD (28% vs 55%, *P*<.001). Five poor prognostic factors were identified with multivariate analysis: EHD location other than lung metastases, EHD concomitant to colorectal liver metastases recurrence, CEA-level>10 ng/ml, >6 colorectal liver metastases and right colon cancer. The fiveyear survival ranged from 64% (0 factors) to 0% (>3factors). [19]

We aim to report the new trends in strategies about surgical treatment of colorectal liver metastases and our experience according to surgical and oncological outcome in patients, operated for IV stage colorectal cancer.

## **2. Criteria for resectability**

Currently available data have led to a change in the indications for resecting hepatic metastases of colorectal carcinoma. Previously, the indication was based on tumor-biological and clinical characteristics. The new criterion is the feasibility of complete resection of both intra- and extrahepatic disease. R0-resectable hepatic metastases, in patients without any extrahepatic metastases, should be resected. [12] As the determination of resectability is becoming ever more complex, all patients with hepatic metastases of colorectal carcinoma should be presented to an experienced hepatobiliary surgeon before the beginning of treatment. Postoperative hepatic function can be predicted more precisely with the aid of CT volumetry. This technique enables prediction of the remaining volume of hepatic tissue after surgery to within 10% of the actual value. [9, 11]

Metastases are considered resectable when the following criteria are met:


In a prospective, observational study carried out on 484 patients from 1980 to 1990, the median time to death was 6.9 months [4]. Adson and colleagues, in the 1970's, were the first to show that patients could be cured by the resection of hepatic metastases [5]. Since then, resection has become established as a standard treatment. For this review, we selectively searched the literature for articles containing the words "colorectal liver metastases, " "chemotherapy, " and "surgery, " paying special attention to studies carried out on larger groups of patients and

Most favorable outcomes were observed in patients with pedicle lymph node involvement (5 year survival rate 25% vs 0% for patients with celiac and/ or para-aortic lymph node metasta‐ ses), and in patients younger than 40 years (5-year survival rate 45% vs 10% for older patients). [7, 8] In relation to our results and those reported by others, we recommend combining hepatectomy with lymphadenectomy only for young CLM patients presenting with pedicle lymph node involvement, in the absence of disease progression after preoperative chemo‐ therapy. On the other hand, patients presenting with celiac or para-aortic lymph node involvement should not be subjected to this oncosurgical treatment strategy. Even concomitant pulmonary metastases should not be considered a contraindication to surgery. Patients with only pulmonary metastases as a site of extrahepatic disease have a particularly good outcome after complete metastasectomy of both liver and lung disease. Five-year survival rates ranged from 22% to 50% in patients with metastases limited to the lungs. [8] Also, selected patients with complex multiorgan metastases have been associated with prolonged survival after a multimodality treatment. Patients with simultaneous hepatic and extrahepatic disease (EHD) do, however, need to be selected for surgery. Elias et al stated that EHD, when resectable, is no longer a contraindication to hepatectomy. [18] More importantly, the total number of metastases, whatever their location, has a strong prognostic effect than the site of the meta‐ stases. In addition, a study conducted at our centre demonstrated that patients with concom‐ itant EHD who were resected experienced a lower 5-year survival than those without EHD (28% vs 55%, *P*<.001). Five poor prognostic factors were identified with multivariate analysis: EHD location other than lung metastases, EHD concomitant to colorectal liver metastases recurrence, CEA-level>10 ng/ml, >6 colorectal liver metastases and right colon cancer. The five-

We aim to report the new trends in strategies about surgical treatment of colorectal liver metastases and our experience according to surgical and oncological outcome in patients,

Currently available data have led to a change in the indications for resecting hepatic metastases of colorectal carcinoma. Previously, the indication was based on tumor-biological and clinical characteristics. The new criterion is the feasibility of complete resection of both intra- and extrahepatic disease. R0-resectable hepatic metastases, in patients without any extrahepatic metastases, should be resected. [12] As the determination of resectability is becoming ever more complex, all patients with hepatic metastases of colorectal carcinoma should be presented to an experienced hepatobiliary surgeon before the beginning of treatment. Postoperative

year survival ranged from 64% (0 factors) to 0% (>3factors). [19]

operated for IV stage colorectal cancer.

**2. Criteria for resectability**

to randomized clinical trials. [6]

166 Colorectal Cancer - Surgery, Diagnostics and Treatment


Metastases are considered non-resectable or marginally resectable when an R0 resection is not possible. Metastases are also considered marginally resectable in the setting of, for example, extra-hepatic tumor manifestations, technical impediments to surgery, or inadequate expected residual liver mass. For these patients, intensified preoperative chemotherapy can be consid‐ ered. The feasibility of secondary resection should be evaluated at each re-staging under chemotherapy. [15]

#### **3. New treatment strategies**

Today, patients with metastatic CRC should be treated by multidisciplinary teams including surgeons, oncologists and radiologists. Evidence of the benefit of perioperative chemotherapy over surgery alone [22] and the potential benefit of adjuvant chemotherapy (after liver resection) [23] caused a rethink among the experts particularly in terms of the timing of the administration of chemotherapy for CRC patients with initially resectable liver and lung metastases. Poor prognostic factors for patients with liver metastases are multiple metastases, >5 cm in diameter, synchronous presentation, lymph node-positive primary and high tumor marker levels. [17] Thus, even when the metastases are technically resectable (in terms of number, location and size), when facing a patient with more than one of the poor prognostic factors listed above, the current trend is to refer patients for neoadjuvant chemotherapy before surgery. The data from the EORTC study showed quite clearly that nearly all patients were able to tolerate neo-adjuvant chemotherapy. Also, analysis of the PFS curves from the EORTC– EPOC trial shows that the main difference comes after the first 2 months when the curves drop down and then move out in parallel, suggesting that the benefit conferred by perioperative chemotherapy might be a consequence of a reduction in the occurrence of early cancer relapse as a consequence of preoperative chemotherapy. [16] An exception to preoperative chemo‐ therapy is, however, those patients with a single resectable metachronous metastasis who could be directly referred to surgery, [14] with the recognition that this accounts for <10% of patients seen in routine clinical practice. All other patients with resectable metastases should be treated up front with chemotherapy, with the caveats that the patient is able to receive chemotherapy and the position of the lesion is not going to be lost. On the other hand, it has also become a standard strategy to give postoperative adjuvant chemotherapy to all resected patients (if possible) based on the data for the resected patients in the EORTC–EPOC trial. [22] For patients who are non-responders, there are two treatment strategies available: 1) change to a new chemotherapy protocol or 2) liver resection before the metastatic disease becomes unresectable. At this point it is important to mention that, the decision to perform either treatment strategy should always be decided by a multidisciplinary. Currently, it has become mandatory to select the systemic therapy regimen based on biological predictive factors, such as KRAS mutation status. This strategy has had a double impact: first of all, it has helped to optimize the choice of first-line treatment, in turn decreasing the risk of immediate disease progression; secondly, it has also helped to better select the second-line 'rescue' treatment strategies with the possibility of resection. [27] However, considering that surgery is still the only treatment that has curative potential per se, in some situations this can be the treatment of choice, even if resistance to medical treatment generally means that the patient has a unfavorable tumor biology. The situation is much simpler for patients whose metastases are initially unresectable, where systemic therapy is administered until an adequate response has been achieved. [24]

Right and retro-hepatic mobilization Hepatic vein division

Total vascular exclusion of the liver – supra-hepatic Total vascular exclusion of the liver – infra-hepatic

Right hepatectomy

**Figure 1.** Different types of liver resections

Left hepatectomy Postoperative CT scan – left lobe hypertrophy

Mesohepatectomy

Surgical Strategies for Liver Metastases from Colorectal Cancer

http://dx.doi.org/10.5772/56915

169

#### **4. Primarily resectable hepatic metastases**

For operable hepatic metastases, hepatic resection is the treatment of choice. The reported 5 year-survival rates that have been achieved after the resection of isolated hepatic metastases with curative intent range from 25% to 50% [1–4, 6–8]. Hepatic metastases, however, are primarily resectable in only about 20% of patients [4]. For the remaining 80%, resection is contraindicated by the presence of diffuse hepatic metastases, non-resectable extra-hepatic disease, or impaired liver function. It is now generally accepted that the contraindications for hepatic resection that were defined in the 1980's are no longer applicable. At that time, the presence of 4 or more tumor nodules, metastases exceeding 5 cm in size, extra-hepatic disease, or a tumor-free resection margin of less than 1 cm [9] was held to contraindicate hepatic resection. Many subsequent studies have confirmed that these are, indeed, relevant prognostic factors for survival after the resection of hepatic metastases of colorectal carcinoma, yet longterm survival is still possible when hepatic resection is performed despite the presence of these supposed contraindications. There have also been technical improvements in the treatment of hepatic metastases of colorectal carcinoma. Diagnostic assessment has become markedly more sensitive through the use of modern types of CT and MRI scanners and the introduction of PET-CT (5, 10–14]. Furthermore, surgical dissecting techniques and the development of potent systemic chemotherapy protocols have been optimized [15–18]. As a result, 5-year survival rates after the resection of hepatic metastases of colorectal carcinoma have improved markedly. [6] Today, even patients with more than three metastases or with metastases larger than 5 cm in diameter can be cured with appropriate surgical treatment, as found in a recent analysis [7]. One hundred and two patients were tumor-free 10 years after the resection of hepatic meta‐ stases of colorectal carcinoma, and only one patient among them developed a recurrent tumor thereafter.

also become a standard strategy to give postoperative adjuvant chemotherapy to all resected patients (if possible) based on the data for the resected patients in the EORTC–EPOC trial. [22] For patients who are non-responders, there are two treatment strategies available: 1) change to a new chemotherapy protocol or 2) liver resection before the metastatic disease becomes unresectable. At this point it is important to mention that, the decision to perform either treatment strategy should always be decided by a multidisciplinary. Currently, it has become mandatory to select the systemic therapy regimen based on biological predictive factors, such as KRAS mutation status. This strategy has had a double impact: first of all, it has helped to optimize the choice of first-line treatment, in turn decreasing the risk of immediate disease progression; secondly, it has also helped to better select the second-line 'rescue' treatment strategies with the possibility of resection. [27] However, considering that surgery is still the only treatment that has curative potential per se, in some situations this can be the treatment of choice, even if resistance to medical treatment generally means that the patient has a unfavorable tumor biology. The situation is much simpler for patients whose metastases are initially unresectable, where systemic therapy is administered until an adequate response has

For operable hepatic metastases, hepatic resection is the treatment of choice. The reported 5 year-survival rates that have been achieved after the resection of isolated hepatic metastases with curative intent range from 25% to 50% [1–4, 6–8]. Hepatic metastases, however, are primarily resectable in only about 20% of patients [4]. For the remaining 80%, resection is contraindicated by the presence of diffuse hepatic metastases, non-resectable extra-hepatic disease, or impaired liver function. It is now generally accepted that the contraindications for hepatic resection that were defined in the 1980's are no longer applicable. At that time, the presence of 4 or more tumor nodules, metastases exceeding 5 cm in size, extra-hepatic disease, or a tumor-free resection margin of less than 1 cm [9] was held to contraindicate hepatic resection. Many subsequent studies have confirmed that these are, indeed, relevant prognostic factors for survival after the resection of hepatic metastases of colorectal carcinoma, yet longterm survival is still possible when hepatic resection is performed despite the presence of these supposed contraindications. There have also been technical improvements in the treatment of hepatic metastases of colorectal carcinoma. Diagnostic assessment has become markedly more sensitive through the use of modern types of CT and MRI scanners and the introduction of PET-CT (5, 10–14]. Furthermore, surgical dissecting techniques and the development of potent systemic chemotherapy protocols have been optimized [15–18]. As a result, 5-year survival rates after the resection of hepatic metastases of colorectal carcinoma have improved markedly. [6] Today, even patients with more than three metastases or with metastases larger than 5 cm in diameter can be cured with appropriate surgical treatment, as found in a recent analysis [7]. One hundred and two patients were tumor-free 10 years after the resection of hepatic meta‐ stases of colorectal carcinoma, and only one patient among them developed a recurrent tumor

been achieved. [24]

thereafter.

**4. Primarily resectable hepatic metastases**

168 Colorectal Cancer - Surgery, Diagnostics and Treatment

Right and retro-hepatic mobilization Hepatic vein division

Total vascular exclusion of the liver – supra-hepatic Total vascular exclusion of the liver – infra-hepatic

Right hepatectomy

**Figure 1.** Different types of liver resections

Mesohepatectomy

Left hepatectomy Postoperative CT scan – left lobe hypertrophy

### **5. Perioperative complications**

Hepatic resections can now be performed safely and effectively. The mortality of hepatic resection was about 5% as late as 1990, while recent articles on the subject generally document figures between 1% and 2%. This reduction of mortality has been achieved even though the resections themselves have become ever more extensive. [3]

**9. Neoadjuvant chemotherapy in patients with resectable CRLM**

however, the trial was insufficiently powered to evaluate overall survival. [33]

At present, only 10% to 20% of patients with hepatic metastases of colorectal carcinoma can be considered candidates for resective surgery. Opportunities for resection are often limited

**10. Strategies for improving resectability**

Despite major survival improvements achieved with successful primary hepatectomy for CRLM, [7-13, 20] many of these patients experience disease recurrence. Data indicate that pre or post-operative chemotherapy may provide a meaningful benefit, although controlled trials are needed. Tanaka et al [21] reported a retrospective analysis of patients with multiple CRLMs, wherein use of neoadjuvant chemotherapy was an independent predictor of survival by multivariate analysis. In 71 patients undergoing hepatectomy for more than five bilobar liver tumors, 3- and 5-year survival rates were superior (*P*<.05, log-rank) in the neoadjuvant chemotherapy group (n=48; 67.0% and 38.9%) than in the hepatectomy-alone group (n=23; 51.8% and 20.7%). Furthermore, neoadjuvant treatment reduced the need for extended (>4 segments) hepatectomies (39 of 48 neoadjuvant vs 23 of 23 control patients). Data from the LiverMetSurvey [5] also indicate a survival improvement with neoadjuvant treatment. In 207 patients with more than five metastases resected, 5-year survival was better with neoadjuvant treatment, although not significantly (20% vs 15%) and among 1, 045 patients who had only one liver metastasis resected, 5-year survival rates were 49% and 57% with and without neoadjuvant chemotherapy, respectively. Similar results were reported in a metanalysis by Mitry et al, [22] which showed a strong trend toward better diseasefree survival with adjuvant 5-FU treatment (HR 0.76, *P*=5.8), and a trend toward favorable overall survival (HR 0.76, *P*=9.8). In addition, a phase III randomized study (The EORTC Intergroup) examined perioperative FOLFOX4 (5-fluorouracil (5-FU), leucovorin, oxaliplatin) chemotherapy for patients with potentially resectable CRLM.23 A total of 364 patients with up to four CRLM were randomized between perioperative FOLFOX4 (oxaliplatin 85 mg/mІ and LV5FU2), six cycles before and six cycles after surgery (CT), vs surgery alone (S). Eleven of 182 patients were ineligible in each arm, mostly due to more advanced disease; 31 and 30 patients in the CT and S arms, respec‐ tively, could not undergo resection. At a median follow-up of 3.9 years, progression-free survival (PFS) was significantly better with CT in the group of resected patients, although the trial was formally not positive in the intentionto- treat (ITT) analysis (HR 0.79, *P*=.058). In terms of postoperative chemotherapy in resectable patients with CRLM data from United States and Europe show better survival in patients receiving adjuvant chemotherapy after resection of CRC liver metastases. [24] Use of adjuvant or neoadjuvant systemic treatment is widely recognized as standard of care in cases of liver resection, and was the focus of single-center studies with XELOX/FOLFOX25 and XELOX plus bevacizumab.26 So far, only one study has as yet shown a clear benefit. [27] In this randomized trial, 109 patients (75 assessable) with one to three hepatic lesions received hepatic arterial floxuridine plus intravenous 5-FU (n=30) or no further therapy (n=45) after hepatectomy. The 4-year recurrence-free rates (46% vs 25%) and 4-year liver recurrence-free rates (67% vs 43%) were significantly better in the adjuvant therapy group. Median survival differences were not statistically significant (64% vs 49%),

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171

### **6. Long-term results after hepatic resection**

More than 40% of appropriately selected patients with colorectal carcinoma who undergo the resection of hepatic metastases survive for at least 5 years thereafter [5, 6, 8, 9]. This is partic‐ ularly true of patients whose surgery was performed more recently. As many as two-thirds of patients later develop a recurrent tumor, and half of them have a recurrent tumor in the liver [23]. In one of the largest studies performed to date, which included 1001 patients, showed that the benefit of surgery extends not just to patients who have undergone an R0 resection (5 year survival: 37%), but also to those who have undergone an R1 resection, i.e., a resection with positive margins, up to 20% of whom are still alive 5 years after surgery. [31]

#### **7. Prognostic parameters**

Many different prognostic scores are used to predict the patient's risk of recurrence and chances of long-term survival on the basis of preoperatively measured parameters. The three most commonly used scoring systems in hepatic surgery are those of Nordlinger, Fong, and Iwatsuki [2, 9, 24]. Although these scoring systems differ with respect to certain individual parameters, they share the common feature that a low score (i.e., the presence of no more than a few risk factors) is correlated with a low risk of recurrence, while the chance of long-term survival is less than 10% when all risk factors are present. No preoperatively measurable prognostic parameter can identify with any certainty the patients who will not benefit from surgical treatment. The most important prognostic factor, according to all studies, is a tumorfree resection margin [10, 11, 25, 26].

### **8. Expanded application of resection for CRLM**

Liver resection is the current preferred treatment for CRLM patients and should be undertaken whenever feasible and potentially curative (R0), regardless of prognostic factors and presence of extra hepatic metastases. The main limiting factors to perform curative resection of CRLM are: presence of bilobar or bulky disease and presence of extra hepatic disease. Resection in patients with multiple or bulky lesions may result in insufficient residual hepatic tissue (i.e., less than 30% functional parenchyma). [19]

## **9. Neoadjuvant chemotherapy in patients with resectable CRLM**

**5. Perioperative complications**

170 Colorectal Cancer - Surgery, Diagnostics and Treatment

**7. Prognostic parameters**

free resection margin [10, 11, 25, 26].

less than 30% functional parenchyma). [19]

**8. Expanded application of resection for CRLM**

resections themselves have become ever more extensive. [3]

**6. Long-term results after hepatic resection**

Hepatic resections can now be performed safely and effectively. The mortality of hepatic resection was about 5% as late as 1990, while recent articles on the subject generally document figures between 1% and 2%. This reduction of mortality has been achieved even though the

More than 40% of appropriately selected patients with colorectal carcinoma who undergo the resection of hepatic metastases survive for at least 5 years thereafter [5, 6, 8, 9]. This is partic‐ ularly true of patients whose surgery was performed more recently. As many as two-thirds of patients later develop a recurrent tumor, and half of them have a recurrent tumor in the liver [23]. In one of the largest studies performed to date, which included 1001 patients, showed that the benefit of surgery extends not just to patients who have undergone an R0 resection (5 year survival: 37%), but also to those who have undergone an R1 resection, i.e., a resection

Many different prognostic scores are used to predict the patient's risk of recurrence and chances of long-term survival on the basis of preoperatively measured parameters. The three most commonly used scoring systems in hepatic surgery are those of Nordlinger, Fong, and Iwatsuki [2, 9, 24]. Although these scoring systems differ with respect to certain individual parameters, they share the common feature that a low score (i.e., the presence of no more than a few risk factors) is correlated with a low risk of recurrence, while the chance of long-term survival is less than 10% when all risk factors are present. No preoperatively measurable prognostic parameter can identify with any certainty the patients who will not benefit from surgical treatment. The most important prognostic factor, according to all studies, is a tumor-

Liver resection is the current preferred treatment for CRLM patients and should be undertaken whenever feasible and potentially curative (R0), regardless of prognostic factors and presence of extra hepatic metastases. The main limiting factors to perform curative resection of CRLM are: presence of bilobar or bulky disease and presence of extra hepatic disease. Resection in patients with multiple or bulky lesions may result in insufficient residual hepatic tissue (i.e.,

with positive margins, up to 20% of whom are still alive 5 years after surgery. [31]

Despite major survival improvements achieved with successful primary hepatectomy for CRLM, [7-13, 20] many of these patients experience disease recurrence. Data indicate that pre or post-operative chemotherapy may provide a meaningful benefit, although controlled trials are needed. Tanaka et al [21] reported a retrospective analysis of patients with multiple CRLMs, wherein use of neoadjuvant chemotherapy was an independent predictor of survival by multivariate analysis. In 71 patients undergoing hepatectomy for more than five bilobar liver tumors, 3- and 5-year survival rates were superior (*P*<.05, log-rank) in the neoadjuvant chemotherapy group (n=48; 67.0% and 38.9%) than in the hepatectomy-alone group (n=23; 51.8% and 20.7%). Furthermore, neoadjuvant treatment reduced the need for extended (>4 segments) hepatectomies (39 of 48 neoadjuvant vs 23 of 23 control patients). Data from the LiverMetSurvey [5] also indicate a survival improvement with neoadjuvant treatment. In 207 patients with more than five metastases resected, 5-year survival was better with neoadjuvant treatment, although not significantly (20% vs 15%) and among 1, 045 patients who had only one liver metastasis resected, 5-year survival rates were 49% and 57% with and without neoadjuvant chemotherapy, respectively. Similar results were reported in a metanalysis by Mitry et al, [22] which showed a strong trend toward better diseasefree survival with adjuvant 5-FU treatment (HR 0.76, *P*=5.8), and a trend toward favorable overall survival (HR 0.76, *P*=9.8). In addition, a phase III randomized study (The EORTC Intergroup) examined perioperative FOLFOX4 (5-fluorouracil (5-FU), leucovorin, oxaliplatin) chemotherapy for patients with potentially resectable CRLM.23 A total of 364 patients with up to four CRLM were randomized between perioperative FOLFOX4 (oxaliplatin 85 mg/mІ and LV5FU2), six cycles before and six cycles after surgery (CT), vs surgery alone (S). Eleven of 182 patients were ineligible in each arm, mostly due to more advanced disease; 31 and 30 patients in the CT and S arms, respec‐ tively, could not undergo resection. At a median follow-up of 3.9 years, progression-free survival (PFS) was significantly better with CT in the group of resected patients, although the trial was formally not positive in the intentionto- treat (ITT) analysis (HR 0.79, *P*=.058). In terms of postoperative chemotherapy in resectable patients with CRLM data from United States and Europe show better survival in patients receiving adjuvant chemotherapy after resection of CRC liver metastases. [24] Use of adjuvant or neoadjuvant systemic treatment is widely recognized as standard of care in cases of liver resection, and was the focus of single-center studies with XELOX/FOLFOX25 and XELOX plus bevacizumab.26 So far, only one study has as yet shown a clear benefit. [27] In this randomized trial, 109 patients (75 assessable) with one to three hepatic lesions received hepatic arterial floxuridine plus intravenous 5-FU (n=30) or no further therapy (n=45) after hepatectomy. The 4-year recurrence-free rates (46% vs 25%) and 4-year liver recurrence-free rates (67% vs 43%) were significantly better in the adjuvant therapy group. Median survival differences were not statistically significant (64% vs 49%), however, the trial was insufficiently powered to evaluate overall survival. [33]

#### **10. Strategies for improving resectability**

At present, only 10% to 20% of patients with hepatic metastases of colorectal carcinoma can be considered candidates for resective surgery. Opportunities for resection are often limited by an unfavorable anatomical site of the metastasis (-es), poor function of the remaining hepatic parenchyma, and/or the patient's poor general condition. Multiple strategies have been developed in order to increase the percentage of patients whose metastases are resectable.

more frequent perioperative complications. Vauthey et al. found that steatohepatitis after

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173

Systemic chemotherapy is currently the main treatment approach for non-resectable CRLM. Incorporation of drugs such as oxaliplatin and irinotecan have led to an improvement of median survival as well as response rates compared with those achieved previously with 5 fluoracil (5-FU)/leucovorin-based regimens. Development of oral fluoropyrimidines has also improved treatment options in these patients. Median survival duration after systemic chemotherapy alone is approximately 20 months, [28, 29] however, only 1% to 2% of such patients remain alive at 5 years. [3, 30] On the other hand, the improved efficacy of newer

There is no longer any doubt that patients benefit from hepatic resections that are performed with curative intent. The current discussion concerns the question whether they also benefit from accompanying adjuvant or neo-adjuvant chemotherapy. The first encouraging data on adjuvant chemotherapy after hepatic resection were published by Kemeny et al., who com‐ pared local intra-arterial therapy combined with systemic 5-FU chemotherapy to adjuvant treatment with 5-FU alone. A trend was found toward improved progression-free survival in the group that additionally received regional therapy (37.4 versus 17.2 months, p = 0.06) [20, 44]. Nonetheless, the overall survival was no better in this group. This finding could not be replicated in a German study of intraarterial chemotherapy administered in the hepatic artery [21]. There are currently two further options for systemic chemotherapy: neo-adjuvant and adjuvant postoperative chemotherapy. For adjuvant chemotherapy, data are only available on 5-FU based treatment. Portier et al., in the AURC 9002 trial, describe an improved 5-year tumorfree survival of 33.5% among patients receiving adjuvant 5-FU bolus therapy, compared to 26.7% treated with resection alone [22]. These 5-FU patients' overall survival was no better than that of their counterparts without 5-FU, but the study size was, in any case, inadequate to detect a moderate benefit. An unplanned subgroup analysis revealed that patients with a greater tumor burden (diameter >5cm, or 3 or more tumor nodules) survived longer if they received adjuvant chemotherapy. Likewise, a pooled analysis of a number of studies, including the FFCD study, found a trend toward a benefit from adjuvant 5-FU treatment, in terms of both progression-free survival and overall survival [23]. These data appear promising, especially because there have been further improvements in chemotherapeutic regimens since they were published. Further evidence that adjuvant 5-FU treatment confers a survival benefit after the resection of hepatic metastases of colorectal carcinoma comes from a cohort study of 792 patients by Parks et al. [24]: The median survival time was 47 months, compared with 36 months without 5-FU. This year (2010), Nordlinger et al. have published the results of the

irinotecan use is associated with a significantly higher 90-day mortality [15].

regimens in down staging tumors is rendering more patients resectable. [14]

**13. Accompanying chemotherapy**

**12. Systemic chemotherapy in patients with non-resectable CRLM**

Liver surgery has progressed in parallel to the improvements in chemotherapy and interven‐ tional radiology. Bad-located tumors (situated deeply or close to critical vascular or biliary structures) can now be safely resected thanks to the availability of sophisticated instru‐ ments such as the ultrasonic dissector, argon gas diathermy and new techniques such as the one of low-central venous pressure anaesthesia that allows an almost bloodless field. With the routine use of intraoperative ultrasound examination precise localization of liver lesions and planning of the resection is done aiming at removing all possible lesions with a clear margin and at the same time preserve the maximum of liver parenchyma. This improve‐ ment in surgical planning and techniques has been directly responsible for the low hospital mortality. The risk of liver resection for CRLM has decreased in specialized hepatobiliary centres probably below the figures observed after colorectal surgery. The mortality of elective liver resection on non-cirrhotic livers is estimated to be around 1% [35, 36] at a time when patients' age and disease complexity are increasing, in addition to the associated changes of SOS and CASH often present in chemotherapy patients undergoing surgery. The experi‐ ence of the centre has a major impact on outcome: the mortality and morbidity of liver resections decreased inversely to the number of cases performed in the institution. [37] It has been shown in US that patients resected at high volume centres (>25 cases/year) for liver cancer have not only a better perioperative outcome, but also a better long-term survival, [38] and similar results concerning the correlation between high volume surgery and specializa‐ tion and outcome were observed in Europe. [39]

## **11. Preoperative chemotherapy ("down-staging")**

When hepatic metastases of colorectal carcinoma are unresectable, systemic chemotherapy is indicated. About 20% of metastases respond to treatment with 5-fluorouracil (5-FU) and folic acid [4]. When these are used in combination with newer drugs, such as oxaliplatin or irinotecan (CPT-11), the response rate rises as high as 60% [29]. Folprecht et al. reviewed the available studies on the "down-staging" of hepatic metastases of colorectal carcinoma and found that resectionrates are correlated with response rates [4]. The first major clinical series of this type was published in 1996 by Bismuth et al. [13] and updated in the years thereafter [14, 30]. The 5-year-survival was 40% (95% confidence interval: 33% to 68%) and was thus comparable to that of patients with primarily resectable hepatic metastases. A major bias in the studies of neoadjuvant chemotherapy published to date arises from patient selection. In the available prospective studies of patients with "isolated" hepatic metastases (i.e., no extrahepatic metastases), the criteria for nonresectability differ from one study to another and are often poorly defined. The hepatotoxicity of all currently used chemotherapeutic drugs argues against their use as neoadjuvant treatment for patients with primarily resectable hepatic metastases. Oxaliplatin can cause sinusoidal obstruction ("blue liver"), while irinotecan can induce fatty liver or steatohepatitis [31–34]. These changes are associated with significantly more frequent perioperative complications. Vauthey et al. found that steatohepatitis after irinotecan use is associated with a significantly higher 90-day mortality [15].

## **12. Systemic chemotherapy in patients with non-resectable CRLM**

Systemic chemotherapy is currently the main treatment approach for non-resectable CRLM. Incorporation of drugs such as oxaliplatin and irinotecan have led to an improvement of median survival as well as response rates compared with those achieved previously with 5 fluoracil (5-FU)/leucovorin-based regimens. Development of oral fluoropyrimidines has also improved treatment options in these patients. Median survival duration after systemic chemotherapy alone is approximately 20 months, [28, 29] however, only 1% to 2% of such patients remain alive at 5 years. [3, 30] On the other hand, the improved efficacy of newer regimens in down staging tumors is rendering more patients resectable. [14]

### **13. Accompanying chemotherapy**

by an unfavorable anatomical site of the metastasis (-es), poor function of the remaining hepatic parenchyma, and/or the patient's poor general condition. Multiple strategies have been developed in order to increase the percentage of patients whose metastases are resectable. Liver surgery has progressed in parallel to the improvements in chemotherapy and interven‐ tional radiology. Bad-located tumors (situated deeply or close to critical vascular or biliary structures) can now be safely resected thanks to the availability of sophisticated instru‐ ments such as the ultrasonic dissector, argon gas diathermy and new techniques such as the one of low-central venous pressure anaesthesia that allows an almost bloodless field. With the routine use of intraoperative ultrasound examination precise localization of liver lesions and planning of the resection is done aiming at removing all possible lesions with a clear margin and at the same time preserve the maximum of liver parenchyma. This improve‐ ment in surgical planning and techniques has been directly responsible for the low hospital mortality. The risk of liver resection for CRLM has decreased in specialized hepatobiliary centres probably below the figures observed after colorectal surgery. The mortality of elective liver resection on non-cirrhotic livers is estimated to be around 1% [35, 36] at a time when patients' age and disease complexity are increasing, in addition to the associated changes of SOS and CASH often present in chemotherapy patients undergoing surgery. The experi‐ ence of the centre has a major impact on outcome: the mortality and morbidity of liver resections decreased inversely to the number of cases performed in the institution. [37] It has been shown in US that patients resected at high volume centres (>25 cases/year) for liver cancer have not only a better perioperative outcome, but also a better long-term survival, [38] and similar results concerning the correlation between high volume surgery and specializa‐

tion and outcome were observed in Europe. [39]

172 Colorectal Cancer - Surgery, Diagnostics and Treatment

**11. Preoperative chemotherapy ("down-staging")**

When hepatic metastases of colorectal carcinoma are unresectable, systemic chemotherapy is indicated. About 20% of metastases respond to treatment with 5-fluorouracil (5-FU) and folic acid [4]. When these are used in combination with newer drugs, such as oxaliplatin or irinotecan (CPT-11), the response rate rises as high as 60% [29]. Folprecht et al. reviewed the available studies on the "down-staging" of hepatic metastases of colorectal carcinoma and found that resectionrates are correlated with response rates [4]. The first major clinical series of this type was published in 1996 by Bismuth et al. [13] and updated in the years thereafter [14, 30]. The 5-year-survival was 40% (95% confidence interval: 33% to 68%) and was thus comparable to that of patients with primarily resectable hepatic metastases. A major bias in the studies of neoadjuvant chemotherapy published to date arises from patient selection. In the available prospective studies of patients with "isolated" hepatic metastases (i.e., no extrahepatic metastases), the criteria for nonresectability differ from one study to another and are often poorly defined. The hepatotoxicity of all currently used chemotherapeutic drugs argues against their use as neoadjuvant treatment for patients with primarily resectable hepatic metastases. Oxaliplatin can cause sinusoidal obstruction ("blue liver"), while irinotecan can induce fatty liver or steatohepatitis [31–34]. These changes are associated with significantly

There is no longer any doubt that patients benefit from hepatic resections that are performed with curative intent. The current discussion concerns the question whether they also benefit from accompanying adjuvant or neo-adjuvant chemotherapy. The first encouraging data on adjuvant chemotherapy after hepatic resection were published by Kemeny et al., who com‐ pared local intra-arterial therapy combined with systemic 5-FU chemotherapy to adjuvant treatment with 5-FU alone. A trend was found toward improved progression-free survival in the group that additionally received regional therapy (37.4 versus 17.2 months, p = 0.06) [20, 44]. Nonetheless, the overall survival was no better in this group. This finding could not be replicated in a German study of intraarterial chemotherapy administered in the hepatic artery [21]. There are currently two further options for systemic chemotherapy: neo-adjuvant and adjuvant postoperative chemotherapy. For adjuvant chemotherapy, data are only available on 5-FU based treatment. Portier et al., in the AURC 9002 trial, describe an improved 5-year tumorfree survival of 33.5% among patients receiving adjuvant 5-FU bolus therapy, compared to 26.7% treated with resection alone [22]. These 5-FU patients' overall survival was no better than that of their counterparts without 5-FU, but the study size was, in any case, inadequate to detect a moderate benefit. An unplanned subgroup analysis revealed that patients with a greater tumor burden (diameter >5cm, or 3 or more tumor nodules) survived longer if they received adjuvant chemotherapy. Likewise, a pooled analysis of a number of studies, including the FFCD study, found a trend toward a benefit from adjuvant 5-FU treatment, in terms of both progression-free survival and overall survival [23]. These data appear promising, especially because there have been further improvements in chemotherapeutic regimens since they were published. Further evidence that adjuvant 5-FU treatment confers a survival benefit after the resection of hepatic metastases of colorectal carcinoma comes from a cohort study of 792 patients by Parks et al. [24]: The median survival time was 47 months, compared with 36 months without 5-FU. This year (2010), Nordlinger et al. have published the results of the EORTC 40 983 trial, in which neoadjuvant therapy with FOLFOX (folic acid, 5-FU, and oxaliplatin) before and after hepatic resection was compared with resection alone. There were 182 patients in each of the study's two groups (with and without neoadjuvant therapy). The declared study endpoint of a significantly improved progression-free 3-year survival was not met in the intent-to-treat analysis. Tumor-free survival was 28.1% after surgery alone and 35.4% in the FOLFOX group [25]. The study did, however, show a significantly improved tumor-free 3-year survival when all patients whose data could be completely evaluated were taken into account (as opposed to the intent-to-treat analysis). Data on overall survival are currently unavailable. It should also be mentioned that the chemotherapy group had a higher rate of postoperative complications, but their postoperative mortality was no higher. Thus, in our view, preoperative chemotherapy should remain reserved, at least for now, to patients whose hepatic metastases are marginally resectable. This group includes patients whose tumor burden is high because of multiple hepatic metastases and extrahepatic tumor manifestations. Our view is founded on the documented survival benefit that can be achieved in patients who have a large burden of initially unresectable hepatic metastases by down-staging their tumors with chemotherapy, in order to render them resectable. [29]

resection. Patients with Tumors that Developed in Normal Underlying Liver Parenchyma PVE is recommended when the FRL-to-total liver ratio is 25 to 30 [7, 10, 11]. The indication of PVE can be extended to a 40% FLR ratio in patients having received chemotherapy or showing abnormal indocyanine green test results (or other abnormal liver function tests) [10, 12, 13]. Portal-vein embolization should always be considered when the residual hepatic volume without it would be less than 30% of the normal size of the liver, and when at least two contiguous hepatic segments are free of metastases. For technical surgical reasons, the left lateral segments 2 and 3 are particularly suitable for this approach. As long as the liver is not cirrhotic, portal-vein embolization results in a 40% to 60% hypertrophy of the contralateral hepatic lobe. It remains unclear at present whether the stimulus to hypertrophy that portalvein embolization provides might also accelerate the growth of tumor nodules [16, 35]. In any case, the data regarding morbidity, mortality, and long-term survival are comparable to those

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175

Patients with Tumors that Develop in Chronic Liver Disease and Cirrhosis States

Patients with Tumors Invading the Biliary Tree Associated with Cholestasis

**2.** Portal hypertension (blocked to free hepatic veinpressure gradient[12 mmHg)

a minimum of 3-week delay between TACE and PVE is recommended.

PVE is contraindicated in the following types of patients:

**3.** Coagulation disorders (PT\60%, platelet count\50 G/l)

In such cases, the decision is based either on liver volume or on liver volume plus estimation of overall liver function by indocyanin green retention rate at 15 min. An FRLR of 40% is recommended when the ICCG 15 is between 10% and 20%. When the ICCG 15 is[20%, an FRLR

Because biliary obstruction has impaired liver regeneration and hypertrophy, the biliary tree of the FRL must be drained first, and PVE can be performed secondarily. The indication is an

**4.** Even if previous transarterial chemoembolization (TACE) may improve PVE results [16],

Patients should be informed that this procedure is not an antitumoral treatment but a treatment made to increase safety or to enable a surgical procedure. Minor complications are encountered in 20% to 25% of cases and are mainly associated with slight fever and abdominal discomfort and pain. Major complications are infrequent and mainly include infection and subcapsular hematoma, hemobilia, and portal vein thrombosis 9\2% of cases). Mortality due to PVE has not been reported. When tumors (usually small nodules) are present in the nonembolized lobe, it must be explained to the patient that those lesions might increase in size more quickly due to PVE [17]. Patients must also be told that the efficacy of the procedure can be estimated

of standard hepatic resections [16, 36–39].

of 50% is recommended [12–14].

Contraindication for PVE [11]

approximately 4 weeks after

**1.** Tumors invading the portal vein

FRLR\40% [15].

## **14. Portal-vein embolization**

In some cases, the resection of one or more hepatic metastases is technically feasible, yet cannot be performed because the amount of liver tissue remaining after resection would be too small. To minimize the risk of postoperative hepatic insufficiency, ipsilateral hepatic atrophy and contralateral hepatic hypertrophy can be induced preoperatively by selective embolization of the hepatic portal vein, or else by ligation of the branch of the portal vein that leads to the hepatic lobe containing the metastasis.

#### **14.1. Definitions**

Future liver remnant (FLR) is the liver that will be left in place after surgery and that was not targeted by embolization. The FLR must hypertrophy after portal vein embolization (PVE). Most teams wait 4 weeks before surgery. FLR hypertrophy must be measured by way of computed axial tomography (CAT) examination after injection of iodine with volumetric measurements of the FLR segments, with the results compared with the measurements performed before PVE using the same technique. Hypertrophy can be quantified as FLR hypertrophy, which is defined as the difference between FLR after a waiting period from 3 to 6 weeks after PVE minus FLR before PVE divided by FLR before PVE. The waiting period must be long enough to allow hypertrophy and as short as possible to avoid tumor growth, which precludes surgery. Hypertrophy can also be quantified by increased FLR ratio. The FLR ratio is defined as (FLR volume—tumor in the FLR)/ (total liver volume—total tumor volume) [8]. Technical success of PVE is defined by a complete occlusion of portal branches feeding the future resected liver segments. Branches of the FLR must be patent with hepatopetal flow. In the late phase of control portography, parenchymography must be visible only in the FLR. Clinical success is considered to occur when the patient reaches the volumetric criteria for liver resection. Patients with Tumors that Developed in Normal Underlying Liver Parenchyma PVE is recommended when the FRL-to-total liver ratio is 25 to 30 [7, 10, 11]. The indication of PVE can be extended to a 40% FLR ratio in patients having received chemotherapy or showing abnormal indocyanine green test results (or other abnormal liver function tests) [10, 12, 13]. Portal-vein embolization should always be considered when the residual hepatic volume without it would be less than 30% of the normal size of the liver, and when at least two contiguous hepatic segments are free of metastases. For technical surgical reasons, the left lateral segments 2 and 3 are particularly suitable for this approach. As long as the liver is not cirrhotic, portal-vein embolization results in a 40% to 60% hypertrophy of the contralateral hepatic lobe. It remains unclear at present whether the stimulus to hypertrophy that portalvein embolization provides might also accelerate the growth of tumor nodules [16, 35]. In any case, the data regarding morbidity, mortality, and long-term survival are comparable to those of standard hepatic resections [16, 36–39].

Patients with Tumors that Develop in Chronic Liver Disease and Cirrhosis States

In such cases, the decision is based either on liver volume or on liver volume plus estimation of overall liver function by indocyanin green retention rate at 15 min. An FRLR of 40% is recommended when the ICCG 15 is between 10% and 20%. When the ICCG 15 is[20%, an FRLR of 50% is recommended [12–14].

Patients with Tumors Invading the Biliary Tree Associated with Cholestasis

Because biliary obstruction has impaired liver regeneration and hypertrophy, the biliary tree of the FRL must be drained first, and PVE can be performed secondarily. The indication is an FRLR\40% [15].

Contraindication for PVE [11]

EORTC 40 983 trial, in which neoadjuvant therapy with FOLFOX (folic acid, 5-FU, and oxaliplatin) before and after hepatic resection was compared with resection alone. There were 182 patients in each of the study's two groups (with and without neoadjuvant therapy). The declared study endpoint of a significantly improved progression-free 3-year survival was not met in the intent-to-treat analysis. Tumor-free survival was 28.1% after surgery alone and 35.4% in the FOLFOX group [25]. The study did, however, show a significantly improved tumor-free 3-year survival when all patients whose data could be completely evaluated were taken into account (as opposed to the intent-to-treat analysis). Data on overall survival are currently unavailable. It should also be mentioned that the chemotherapy group had a higher rate of postoperative complications, but their postoperative mortality was no higher. Thus, in our view, preoperative chemotherapy should remain reserved, at least for now, to patients whose hepatic metastases are marginally resectable. This group includes patients whose tumor burden is high because of multiple hepatic metastases and extrahepatic tumor manifestations. Our view is founded on the documented survival benefit that can be achieved in patients who have a large burden of initially unresectable hepatic metastases by down-staging their tumors

In some cases, the resection of one or more hepatic metastases is technically feasible, yet cannot be performed because the amount of liver tissue remaining after resection would be too small. To minimize the risk of postoperative hepatic insufficiency, ipsilateral hepatic atrophy and contralateral hepatic hypertrophy can be induced preoperatively by selective embolization of the hepatic portal vein, or else by ligation of the branch of the portal vein that leads to the

Future liver remnant (FLR) is the liver that will be left in place after surgery and that was not targeted by embolization. The FLR must hypertrophy after portal vein embolization (PVE). Most teams wait 4 weeks before surgery. FLR hypertrophy must be measured by way of computed axial tomography (CAT) examination after injection of iodine with volumetric measurements of the FLR segments, with the results compared with the measurements performed before PVE using the same technique. Hypertrophy can be quantified as FLR hypertrophy, which is defined as the difference between FLR after a waiting period from 3 to 6 weeks after PVE minus FLR before PVE divided by FLR before PVE. The waiting period must be long enough to allow hypertrophy and as short as possible to avoid tumor growth, which precludes surgery. Hypertrophy can also be quantified by increased FLR ratio. The FLR ratio is defined as (FLR volume—tumor in the FLR)/ (total liver volume—total tumor volume) [8]. Technical success of PVE is defined by a complete occlusion of portal branches feeding the future resected liver segments. Branches of the FLR must be patent with hepatopetal flow. In the late phase of control portography, parenchymography must be visible only in the FLR. Clinical success is considered to occur when the patient reaches the volumetric criteria for liver

with chemotherapy, in order to render them resectable. [29]

**14. Portal-vein embolization**

174 Colorectal Cancer - Surgery, Diagnostics and Treatment

hepatic lobe containing the metastasis.

**14.1. Definitions**

PVE is contraindicated in the following types of patients:


Patients should be informed that this procedure is not an antitumoral treatment but a treatment made to increase safety or to enable a surgical procedure. Minor complications are encountered in 20% to 25% of cases and are mainly associated with slight fever and abdominal discomfort and pain. Major complications are infrequent and mainly include infection and subcapsular hematoma, hemobilia, and portal vein thrombosis 9\2% of cases). Mortality due to PVE has not been reported. When tumors (usually small nodules) are present in the nonembolized lobe, it must be explained to the patient that those lesions might increase in size more quickly due to PVE [17]. Patients must also be told that the efficacy of the procedure can be estimated approximately 4 weeks after

PVE by way of CAT with injection of contrast media and liver volumetry.

### **14.2. Embolization method**

Access to the portal system should be done under ultrasound guidance to puncture a periph‐ eral branch [8]. Access can be obtained by way of controlateral approach (i.e., puncture of the left portal branch and embolization of theright portal branches) or ispsilateral approach (puncture of the right portal branch to embolize right portal branches. The advantage of the controlateral approach is easier catheterization, but there is a risk of damage to the FLR. Five-French materials (catheter or introductory sheath) are usually recommended. The catheter should be placed at the splenomesenteric confluence to perform a portography to visualize portal anatomy, including its variations, and to localize segment IV branches. Measurement of portal pressure is not routinely performed in patients with normal liver. In cirrhotic patients, measuring the portal and central venous pressures is useful to determine whether the patient has a portostemic gradient[12 mmHg in, which case the patient is at major risk of perisurgical complications [18, 19]. These patients are not eligible for PVE. The aim of embolization is complete obstruction of the targeted branches and redistribution of flow to the FLR branches only. Final portography is mandatory to verify this objective. A final pressure measurement should be obtained at the end of the procedure in patients with chronic liver disease to document portal pressure increase, which is usually approximately 3 mmHg. Embolization of segment IV branches is recommended in patients with tumors who are undergoing extended right hepatectomy. However, if embolization of that segment causes risk of reflux into the portal branch of the FRL, such embolization must not be performed because any major reflux into FRL portal branches might preclude surgery.

## **15. Two-stage hepatic resection**

A further way of enabling curative resection of patients with extensive bilobar hepatic metastases of colorectal carcinoma is so-called two-stage hepatic resection [17]. This technique is suitable for patients with bilateral hepatic metastases who can undergo neither complete tumor resection, nor tumor resection combined with a local ablative procedure, because of the risk of postoperative hepatic insufficiency. Most, but not all, of the tumor burden is resected in a first operation, and then the remaining tumor nodules are resected in a second one, after liver tissue has regenerated. The decision whether to operate in one or two stages depends on the quantity and quality of the extratumoral hepatic tissue*.* The second operation is usually performed three to four weeks after the first, to allow time for the residual liver tissue to become adequately hypertrophic. [40]

the present time this clinical situation is no longer considered as contraindication due to the experience gained with total vascular exclusion (TVE) of the liver combined with vascular reconstruction. These techniques have made the surgery possible even for this group of patients, without exposing them to the risk of massive intraoperative blood loss and gas embolism. TVE consists on hepatic inflow and outflow occlusion. [46-48] This can be achieved by clamping the portal vein/ hepatic artery as well as the supra and infra hepatic vena cava. Alternatively, the hepatic veins are isolated and clamped in addition to the vascular portal structures. The latter technique is more advantageous as it can preserve the caval flow, however, in cases of caval infiltration by metastatic lesion/s this technique is not feasible. On the other hand, if hemodynamic instability is encountered while the vena cava is clamped, a veno-venous bypass should be installed to overcome this complication. Although, it is believed that the hepatic blood flow can be interrupted safely up to 60 minutes, when vascular resection/ reconstruction is necessary, a 60 minute duration of ischemia may be not sufficient. [47] Hence, hypothermic perfusion of the liver should be instituted. The combination of TVE with in situ hypothermic perfusion was evaluated in our center. [68] It is found that this combination was

(a) Portal hypertension (blocked to free hepatic veinpressure gradient[12 mmHg)

must not be performed because any major reflux into FRL portal branches might preclude surgery.

four weeks after the first, to allow time for the residual liver tissue to become adequately hypertrophic.(40)

*CT-scan of the liver in the same day after portal vein embolsiation with Lipiodol.*

*The same patient – hypertrophy of the left liver, 8 weeks later* 

**Figure 2.** Portal vein embolization and liver hypertrophy.

(a) Even if previous transarterial chemoembolization (TACE) may improve PVE results (16), a minimum of 3-week delay between TACE and PVE is recommended.

Patients should be informed that this procedure is not an antitumoral treatment but a treatment made to increase safety or to enable a surgical procedure. Minor complications are encountered in 20% to 25% of cases and are mainly associated with slight fever and abdominal discomfort and pain. Major complications are infrequent and mainly include infection and subcapsular hematoma, hemobilia, and portal vein thrombosis (\2% of cases). Mortality due to PVE has not been reported. When tumors (usually small nodules) are present in the nonembolized lobe, it must be explained to the patient that those lesions might increase in size more quickly due to PVE (17). Patients must also be told that the efficacy of the procedure can

Access to the portal system should be done under ultrasound guidance to puncture a peripheral branch (8). Access can be obtained by way of controlateral approach (i.e., puncture of the left portal branch and embolization of theright portal branches) or ispsilateral approach (puncture of the right portal branch to embolize right portal branches. The advantage of the

A further way of enabling curative resection of patients with extensive bilobar hepatic metastases of colorectal carcinoma is so-called two-stage hepatic resection (17). This technique is suitable for patients with bilateral hepatic metastases who can undergo neither complete tumor resection, nor tumor resection combined with a local ablative procedure, because of the risk of postoperative hepatic insufficiency. Most, but not all, of the tumor burden is resected in a first operation, and then the remaining tumor nodules are resected in a second one, after liver tissue has regenerated. The decision whether to operate in one or two stages depends on the quantity and quality of the extratumoral hepatic tissue*.* The second operation is usually performed three to

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Surgical Strategies for Liver Metastases from Colorectal Cancer

catheterization, but there is a risk of damage to the FLR. Five-French materials (catheter or introductory sheath) are usually recommended. The catheter should be placed at the splenomesenteric confluence to perform a portography to visualize portal anatomy, including its variations, and to localize segment IV branches. Measurement of portal pressure is not routinely performed in patients with normal liver. In cirrhotic patients, measuring the portal and central venous pressures is useful to determine whether the patient has a portostemic gradient[12 mmHg in, which case the patient is at major risk of perisurgical complications (18, 19). These patients are not eligible for PVE. The aim of embolization is complete obstruction of the targeted branches and redistribution of flow to the FLR branches only. Final portography is mandatory to verify this objective. A final pressure measurement should be obtained at the end of the procedure in patients with chronic liver disease to document portal pressure increase, which is usually approximately 3 mmHg. Embolization of segment IV branches is recommended in patients with tumors who are undergoing extended right hepatectomy. However, if embolization of that segment causes risk of reflux into the portal branch of the FRL, such embolization

2. Coagulation disorders (PT\60%, platelet count\50 G/l)

PVE by way of CAT with injection of contrast media and liver volumetry.

**TWO-STAGE HEPATIC RESECTION** 

be estimated approximately 4 weeks after

Embolization Method

controlateral approach is easier

## **16. Extreme liver surgery**

Involvement of major vascular structures (vena cava or hepatic veins) by liver metastases has been considered as a contraindication to surgery for colorectal liver metastases. However, at (a) Even if previous transarterial chemoembolization (TACE) may improve PVE results (16), a minimum of 3-week delay between TACE and PVE is recommended.

Patients should be informed that this procedure is not an antitumoral treatment but a treatment made to increase safety or to enable a surgical procedure. Minor complications are encountered in 20% to 25% of cases and are mainly associated with slight fever and abdominal discomfort and pain. Major complications are infrequent and mainly include infection and subcapsular hematoma, hemobilia, and portal vein thrombosis (\2% of cases). Mortality due to PVE has not been reported. When tumors (usually small nodules) are present in the nonembolized lobe, it must be explained to the patient that those lesions might increase in size more quickly due to PVE (17). Patients must also be told that the efficacy of the procedure can

Access to the portal system should be done under ultrasound guidance to puncture a peripheral branch (8). Access can be obtained by way of controlateral approach (i.e., puncture of the left portal branch and embolization of theright portal branches) or ispsilateral approach (puncture of the right portal branch to embolize right portal branches. The advantage of the

catheterization, but there is a risk of damage to the FLR. Five-French materials (catheter or introductory sheath) are usually recommended. The catheter should be placed at the splenomesenteric confluence to perform a portography to visualize portal anatomy, including its variations, and to localize segment IV branches. Measurement of portal pressure is not routinely performed in patients with normal liver. In cirrhotic patients, measuring the portal and central venous pressures is useful to determine whether the patient has a portostemic gradient[12 mmHg in, which case the patient is at major risk of perisurgical complications (18, 19). These patients are not eligible for PVE. The aim of embolization is complete obstruction of the targeted branches and redistribution of flow to the FLR branches only. Final portography is mandatory to verify this objective. A final pressure measurement should be obtained at the end of the procedure in patients with chronic liver disease to document portal pressure increase, which is usually approximately 3 mmHg. Embolization of segment IV branches is recommended in patients with tumors who are undergoing extended right hepatectomy. However, if embolization of that segment causes risk of reflux into the portal branch of the FRL, such embolization

(a) Portal hypertension (blocked to free hepatic veinpressure gradient[12 mmHg)

must not be performed because any major reflux into FRL portal branches might preclude surgery.

four weeks after the first, to allow time for the residual liver tissue to become adequately hypertrophic.(40)

2. Coagulation disorders (PT\60%, platelet count\50 G/l)

PVE by way of CAT with injection of contrast media and liver volumetry.

**TWO-STAGE HEPATIC RESECTION** 

be estimated approximately 4 weeks after

Embolization Method

controlateral approach is easier

*The same patient – hypertrophy of the left liver, 8 weeks later* 

PVE by way of CAT with injection of contrast media and liver volumetry.

Access to the portal system should be done under ultrasound guidance to puncture a periph‐ eral branch [8]. Access can be obtained by way of controlateral approach (i.e., puncture of the left portal branch and embolization of theright portal branches) or ispsilateral approach (puncture of the right portal branch to embolize right portal branches. The advantage of the controlateral approach is easier catheterization, but there is a risk of damage to the FLR. Five-French materials (catheter or introductory sheath) are usually recommended. The catheter should be placed at the splenomesenteric confluence to perform a portography to visualize portal anatomy, including its variations, and to localize segment IV branches. Measurement of portal pressure is not routinely performed in patients with normal liver. In cirrhotic patients, measuring the portal and central venous pressures is useful to determine whether the patient has a portostemic gradient[12 mmHg in, which case the patient is at major risk of perisurgical complications [18, 19]. These patients are not eligible for PVE. The aim of embolization is complete obstruction of the targeted branches and redistribution of flow to the FLR branches only. Final portography is mandatory to verify this objective. A final pressure measurement should be obtained at the end of the procedure in patients with chronic liver disease to document portal pressure increase, which is usually approximately 3 mmHg. Embolization of segment IV branches is recommended in patients with tumors who are undergoing extended right hepatectomy. However, if embolization of that segment causes risk of reflux into the portal branch of the FRL, such embolization must not be performed because any major reflux

A further way of enabling curative resection of patients with extensive bilobar hepatic metastases of colorectal carcinoma is so-called two-stage hepatic resection [17]. This technique is suitable for patients with bilateral hepatic metastases who can undergo neither complete tumor resection, nor tumor resection combined with a local ablative procedure, because of the risk of postoperative hepatic insufficiency. Most, but not all, of the tumor burden is resected in a first operation, and then the remaining tumor nodules are resected in a second one, after liver tissue has regenerated. The decision whether to operate in one or two stages depends on the quantity and quality of the extratumoral hepatic tissue*.* The second operation is usually performed three to four weeks after the first, to allow time for the residual liver tissue to become

Involvement of major vascular structures (vena cava or hepatic veins) by liver metastases has been considered as a contraindication to surgery for colorectal liver metastases. However, at

**14.2. Embolization method**

176 Colorectal Cancer - Surgery, Diagnostics and Treatment

into FRL portal branches might preclude surgery.

**15. Two-stage hepatic resection**

adequately hypertrophic. [40]

**16. Extreme liver surgery**

the present time this clinical situation is no longer considered as contraindication due to the experience gained with total vascular exclusion (TVE) of the liver combined with vascular reconstruction. These techniques have made the surgery possible even for this group of patients, without exposing them to the risk of massive intraoperative blood loss and gas embolism. TVE consists on hepatic inflow and outflow occlusion. [46-48] This can be achieved by clamping the portal vein/ hepatic artery as well as the supra and infra hepatic vena cava. Alternatively, the hepatic veins are isolated and clamped in addition to the vascular portal structures. The latter technique is more advantageous as it can preserve the caval flow, however, in cases of caval infiltration by metastatic lesion/s this technique is not feasible. On the other hand, if hemodynamic instability is encountered while the vena cava is clamped, a veno-venous bypass should be installed to overcome this complication. Although, it is believed that the hepatic blood flow can be interrupted safely up to 60 minutes, when vascular resection/ reconstruction is necessary, a 60 minute duration of ischemia may be not sufficient. [47] Hence, hypothermic perfusion of the liver should be instituted. The combination of TVE with in situ hypothermic perfusion was evaluated in our center. [68] It is found that this combination was

**Figure 3.** Two stage hepatectomy.

associated with a better liver tolerance to ischemia, a better liver function, and a significantly lower rate of complications compared to standard TVE >60 min. In some cases, a combined liver and vascular resection may be required. An experience with such cases (combined liver and vena cava resection) has shown that a 5-year survival of 38.3% can be obtained even for this group of patients. [49] In conclusion, using TVE and vascular reconstruction techniques, surgery in cases with involvement of the vena cava or hepatic veins is not necessarily contra‐ indicated. However, a very careful evaluation and selection of the cases should be done,

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Optimal duration chemotherapy and timing of liver surgery in responding patients have not been definitively established. For patients not considered resectable, in the clinical setting, most surgeons perform liver resection as soon as metastases become operable. Similarly, there is still debate, whether chemotherapy should precede resection when metastases are synchro‐ nous, particularly when the primary tumor is in place and the surgery involves the resection of the primary tumor as well as a simultaneous major liver resection. At the present, many surgeons believe that the chemotherapy is a better choice for patients with synchronous liver metastases, although these conclusions come from retrospective or surgical series from a single center. Capussotti and colleagues have published several papers on this topic. [40-43] There is only one randomized study [23] which has evaluated the results of preoperative chemotherapy and demonstrating an absolute difference in favor of chemotherapy. However, this study has a drawback as it was not possible to separate the benefits of preoperative chemotherapy from those of adjuvant postoperative chemotherapy. Another issue is the impact which the disease progression while on chemotherapy has on the timing of surgery. Disease progression during neoadjuvant chemotherapy indicates a poor prognosis. In a cohort of 131 patients undergoing rescue hepatectomy, 5-year survival rates were 8% if disease progressed during preoperative chemotherapy, 30% if disease was stable, and 37% in responders. [14] These findings suggest that hepatectomy for CRC metastases should be undertaken as soon as technically feasible and underscore the importance of collaboration between medical oncologists and surgeons in achieving that goal. Medical oncologists should be referring patients for surgery before tumor progression, and surgeons need to consider tumor evolution in addition to resectability. Thus, patients with biologically aggressive tumors unlikely to benefit from resection may be spared surgery upfront and can instead consult with the medical oncologist for a better regimen likely

making sure that the risks involved do not counterbalance the desired benefits. [42]

**17. Timing of surgery**

to induce tumor response or stabilization. [44]

**18. Local tumor destruction and hybrid techniques**

In recent years, local ablative methods such as cryotherapy and radiofrequency ablation (RFA) have come into more common use for the *in situ* destruction of hepatic metastases. Among these methods, RFA has been studied the best. It can be performed percutaneously, laparos‐ associated with a better liver tolerance to ischemia, a better liver function, and a significantly lower rate of complications compared to standard TVE >60 min. In some cases, a combined liver and vascular resection may be required. An experience with such cases (combined liver and vena cava resection) has shown that a 5-year survival of 38.3% can be obtained even for this group of patients. [49] In conclusion, using TVE and vascular reconstruction techniques, surgery in cases with involvement of the vena cava or hepatic veins is not necessarily contra‐ indicated. However, a very careful evaluation and selection of the cases should be done, making sure that the risks involved do not counterbalance the desired benefits. [42]

## **17. Timing of surgery**

Preoperative imaging – bilateral 7 liver mets **(A)**

178 Colorectal Cancer - Surgery, Diagnostics and Treatment

Preoperative imaging – bilateral 7 liver mets **(C)**

**Figure 3.** Two stage hepatectomy.

Preoperative imaging – bilateral 7 liver mets **(E)** First stage liver resection

Second stage liver resection Postoperative imaging

Preoperative imaging – bilateral 7 liver mets **(D)**

Preoperative imaging – bilateral 7 liver mets **(B)**

Optimal duration chemotherapy and timing of liver surgery in responding patients have not been definitively established. For patients not considered resectable, in the clinical setting, most surgeons perform liver resection as soon as metastases become operable. Similarly, there is still debate, whether chemotherapy should precede resection when metastases are synchro‐ nous, particularly when the primary tumor is in place and the surgery involves the resection of the primary tumor as well as a simultaneous major liver resection. At the present, many surgeons believe that the chemotherapy is a better choice for patients with synchronous liver metastases, although these conclusions come from retrospective or surgical series from a single center. Capussotti and colleagues have published several papers on this topic. [40-43] There is only one randomized study [23] which has evaluated the results of preoperative chemotherapy and demonstrating an absolute difference in favor of chemotherapy. However, this study has a drawback as it was not possible to separate the benefits of preoperative chemotherapy from those of adjuvant postoperative chemotherapy. Another issue is the impact which the disease progression while on chemotherapy has on the timing of surgery. Disease progression during neoadjuvant chemotherapy indicates a poor prognosis. In a cohort of 131 patients undergoing rescue hepatectomy, 5-year survival rates were 8% if disease progressed during preoperative chemotherapy, 30% if disease was stable, and 37% in responders. [14] These findings suggest that hepatectomy for CRC metastases should be undertaken as soon as technically feasible and underscore the importance of collaboration between medical oncologists and surgeons in achieving that goal. Medical oncologists should be referring patients for surgery before tumor progression, and surgeons need to consider tumor evolution in addition to resectability. Thus, patients with biologically aggressive tumors unlikely to benefit from resection may be spared surgery upfront and can instead consult with the medical oncologist for a better regimen likely to induce tumor response or stabilization. [44]

## **18. Local tumor destruction and hybrid techniques**

In recent years, local ablative methods such as cryotherapy and radiofrequency ablation (RFA) have come into more common use for the *in situ* destruction of hepatic metastases. Among these methods, RFA has been studied the best. It can be performed percutaneously, laparos‐ copically, or at open surgery and is currently used for tumors up to 5 cm in diameter. Lencioni et al. recently reported a multicenter study of 423 patients with a total of 615 metachronous metas - tases of colorectal carcinoma who were treated with RFA. The average tumor size was 2.7 cm [18]. In this patient group, 25% had local tumor progression, and the 1-, 3-, and 5-year survival rates were 86%, 47%, and 24%. These figures correspond to those of Abdalla et al., who found that tumor progression is more probable after RFA than after surgical resection [19, 43]. In general, RFA is associated with low morbidity and mortality. As no prospective data are yet available for a comparison of local ablative techniques to hepatic resection with curative intent, the procedure cannot be recommended as an alternative to hepatic resection, though it does play a role as an additional, complementary method of achieving complete tumor destruction in patients whose lesions are not otherwise R0-resectable.

**19.1. Frequency of complications**

A total of 21 deaths were reported in 11 series, [41] with overall mortality varying from 0% to 5.2%. Four deaths were related to cirrhosis. Eleven occurred in patients undergoing resections, eight of which were major hepatectomies. Eight deaths were related to liver failure, four of which were subsequent to major hepatectomy with IRFA on the remnant liver for bilobar disease. Five deaths were caused by myocardial infarct; one of these related to a carcinoid crisis and another to a haemorrhage. Four deaths resulted from portal thrombosis, three of which occurred in cirrhotic patients. One of these patients had been treated by IRFA alone. Four deaths were related to septic complications; two of these referred to pulmonary infections, one to infection of the ascites and one to multiple deep abscesses. Lastly, three deaths were reported after postoperative haemorrhaging; one was caused by liver failure after an intrahepatic haematoma in a cirrhotic setting, one resulted from myocardial infarction following a hae‐ morrhage in a large metastasis treated by IRFA, and one patient was treated by major hepa‐ tectomy and two IRFA sessions and died of cardiac arrest after postoperative bleeding.31

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Abdominal infections were reported in 49 patients in 21 series. [41] Diagnosis of infection was delayed by up to 5 months. Seventeen liver abscesses were reported, of which one was fatal and were related to IRFA. Only one case of biliary digestive anastomosis was observed. Ten cases of perihepatic abscesses at resection sites were reported. Twelve were following digestive system-associated procedures. These abscesses were treated by percutaneous drainage and antibiotics. One patient needed re-operation and died from septic shock. Seven cases of wound infection were reported; two were re-operated. Lastly, one case of peritonitis after infection of

Twenty-five early (30 postoperative days) and 14 delayed (sometimes for >4 months18) biliary complications [42] were reported in 10 series. Twelve biliary leakages occurred, 10 of which were early. Six occurred in resection combined with IRFA. One early leakage was caused by a prophylactic cholecystectomy, but two delayed leakages were associated with a biliary stenosis. Fifteen intrahepatic bile collections were described, one of which induced duodenal compression. One article gave details of the treatment of eight biliomas: all eight were drained percutaneously and two recurred after drain clamping. Two were related to biliary stenoses and were treated by intrahepatic stenting; the other six patients under‐ went endoscopic sphincterotomy. Eleven biliary stenoses associated with jaundice and biliary dilatation were reported, of which five were early. These were complicated by biliomas, biliary leakage and cholangitis. In their prospective study, some authors [43] did not observe a correlation between central or peripheric localization of the tumour and the

*19.1.1. Mortality*

*19.1.2. Infections*

the ascites was reported and was fatal.

frequency of biliary complications.

*19.1.3. Biliary complications*

## **19. Radiofrequency thermal ablation (RFA)**

RFA is the most widely used technique for local destruction of CRLM and has gained popu‐ larity because of its relative easy usage, and its effectiveness as an adjuvant treatment.48 For the treatment of CRLM, RFA can be used as: 1) a definitive treatment per se; 2) a complemen‐ tary procedure to surgery, or 3) in the treatment of recurrent metastatic disease after surgery. Results so far show that RFA must be restricted to cases in which the size of the dominant lesion is less than 3 cm or when a maximum of three tumours are present.49 In a study on percutaneous RFA for CRLM, local control was achieved in 78% of tumours <2.6 cm, but only in 47% of tumours 2.6-4.0 cm and 32% of tumours >4.0 cm.42 The anatomic location of a metastasis is an additional limitation of RFA. In the vicinity of a large hepatic vessel, the heat sink effect significantly increases the risk of incomplete ablation. Also, the risk of thermal injury is increased when nodules are close to main biliary structures or to extrahepatic organs. In these cases, new RFA techniques or additional procedures, such as hepatic inflow occlusion or intraductal cooling, have to be considered. [50, 51] Because of the high local recurrence rates, and of the anatomical limitations described above, there is still no place for RFA in patients with resectable colorectal metastases. Surgical RFA for small resectable CRLM could only be acceptable in a randomized trial comparing resection with surgical RFA, [52] and it was shown that hepatic resection is still the treatment of choice for CRLM and that RFA alone provides survival only slightly superior to non-surgical treatment. [53] This is the case also for patients with solitary liver metastases who are treated with RFA (higher LR rate and shorter recurrence free and overall survival). [54] Radiofrequency ablation has been proposed to treat a limited number of small metastases, simultaneously with right PVE. [46, 47] Although this strategy is theoretically appealing because it limits the number of surgical operations, its effectiveness compared to two-step hepatectomies is doubtful. The place of RFA in the treatment of CRM is limited: it is most useful for early recurrences detected as small lesions after resection, because it is not mandatory to stop the chemotherapy, except for the use of bevacizumab, and because RFA allows a ''test of time'' that helps to select out patients with very aggressive/ disseminated disease that would not benefit from repeated surgery.

#### **19.1. Frequency of complications**

#### *19.1.1. Mortality*

copically, or at open surgery and is currently used for tumors up to 5 cm in diameter. Lencioni et al. recently reported a multicenter study of 423 patients with a total of 615 metachronous metas - tases of colorectal carcinoma who were treated with RFA. The average tumor size was 2.7 cm [18]. In this patient group, 25% had local tumor progression, and the 1-, 3-, and 5-year survival rates were 86%, 47%, and 24%. These figures correspond to those of Abdalla et al., who found that tumor progression is more probable after RFA than after surgical resection [19, 43]. In general, RFA is associated with low morbidity and mortality. As no prospective data are yet available for a comparison of local ablative techniques to hepatic resection with curative intent, the procedure cannot be recommended as an alternative to hepatic resection, though it does play a role as an additional, complementary method of achieving complete tumor

RFA is the most widely used technique for local destruction of CRLM and has gained popu‐ larity because of its relative easy usage, and its effectiveness as an adjuvant treatment.48 For the treatment of CRLM, RFA can be used as: 1) a definitive treatment per se; 2) a complemen‐ tary procedure to surgery, or 3) in the treatment of recurrent metastatic disease after surgery. Results so far show that RFA must be restricted to cases in which the size of the dominant lesion is less than 3 cm or when a maximum of three tumours are present.49 In a study on percutaneous RFA for CRLM, local control was achieved in 78% of tumours <2.6 cm, but only in 47% of tumours 2.6-4.0 cm and 32% of tumours >4.0 cm.42 The anatomic location of a metastasis is an additional limitation of RFA. In the vicinity of a large hepatic vessel, the heat sink effect significantly increases the risk of incomplete ablation. Also, the risk of thermal injury is increased when nodules are close to main biliary structures or to extrahepatic organs. In these cases, new RFA techniques or additional procedures, such as hepatic inflow occlusion or intraductal cooling, have to be considered. [50, 51] Because of the high local recurrence rates, and of the anatomical limitations described above, there is still no place for RFA in patients with resectable colorectal metastases. Surgical RFA for small resectable CRLM could only be acceptable in a randomized trial comparing resection with surgical RFA, [52] and it was shown that hepatic resection is still the treatment of choice for CRLM and that RFA alone provides survival only slightly superior to non-surgical treatment. [53] This is the case also for patients with solitary liver metastases who are treated with RFA (higher LR rate and shorter recurrence free and overall survival). [54] Radiofrequency ablation has been proposed to treat a limited number of small metastases, simultaneously with right PVE. [46, 47] Although this strategy is theoretically appealing because it limits the number of surgical operations, its effectiveness compared to two-step hepatectomies is doubtful. The place of RFA in the treatment of CRM is limited: it is most useful for early recurrences detected as small lesions after resection, because it is not mandatory to stop the chemotherapy, except for the use of bevacizumab, and because RFA allows a ''test of time'' that helps to select out patients with very aggressive/

destruction in patients whose lesions are not otherwise R0-resectable.

disseminated disease that would not benefit from repeated surgery.

**19. Radiofrequency thermal ablation (RFA)**

180 Colorectal Cancer - Surgery, Diagnostics and Treatment

A total of 21 deaths were reported in 11 series, [41] with overall mortality varying from 0% to 5.2%. Four deaths were related to cirrhosis. Eleven occurred in patients undergoing resections, eight of which were major hepatectomies. Eight deaths were related to liver failure, four of which were subsequent to major hepatectomy with IRFA on the remnant liver for bilobar disease. Five deaths were caused by myocardial infarct; one of these related to a carcinoid crisis and another to a haemorrhage. Four deaths resulted from portal thrombosis, three of which occurred in cirrhotic patients. One of these patients had been treated by IRFA alone. Four deaths were related to septic complications; two of these referred to pulmonary infections, one to infection of the ascites and one to multiple deep abscesses. Lastly, three deaths were reported after postoperative haemorrhaging; one was caused by liver failure after an intrahepatic haematoma in a cirrhotic setting, one resulted from myocardial infarction following a hae‐ morrhage in a large metastasis treated by IRFA, and one patient was treated by major hepa‐ tectomy and two IRFA sessions and died of cardiac arrest after postoperative bleeding.31

#### *19.1.2. Infections*

Abdominal infections were reported in 49 patients in 21 series. [41] Diagnosis of infection was delayed by up to 5 months. Seventeen liver abscesses were reported, of which one was fatal and were related to IRFA. Only one case of biliary digestive anastomosis was observed. Ten cases of perihepatic abscesses at resection sites were reported. Twelve were following digestive system-associated procedures. These abscesses were treated by percutaneous drainage and antibiotics. One patient needed re-operation and died from septic shock. Seven cases of wound infection were reported; two were re-operated. Lastly, one case of peritonitis after infection of the ascites was reported and was fatal.

#### *19.1.3. Biliary complications*

Twenty-five early (30 postoperative days) and 14 delayed (sometimes for >4 months18) biliary complications [42] were reported in 10 series. Twelve biliary leakages occurred, 10 of which were early. Six occurred in resection combined with IRFA. One early leakage was caused by a prophylactic cholecystectomy, but two delayed leakages were associated with a biliary stenosis. Fifteen intrahepatic bile collections were described, one of which induced duodenal compression. One article gave details of the treatment of eight biliomas: all eight were drained percutaneously and two recurred after drain clamping. Two were related to biliary stenoses and were treated by intrahepatic stenting; the other six patients under‐ went endoscopic sphincterotomy. Eleven biliary stenoses associated with jaundice and biliary dilatation were reported, of which five were early. These were complicated by biliomas, biliary leakage and cholangitis. In their prospective study, some authors [43] did not observe a correlation between central or peripheric localization of the tumour and the frequency of biliary complications.

#### *19.1.4. Liver failure*

Liver failure was reported in 24 patients in 11 articles [41] and was fatal in eight patients. Fourteen liver failures occurred after IRFA combined with major resection. Six liver failures occurred in cirrhotic patients; three of these failures occurred after IRFA alone. Two liver failures were subsequent to portal thrombosis.

resection and IRFA combined with hepatic resection are comparable, even if IRFA is indicated

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The past 10 years have represented a period of learning for surgeons who deal with liverme‐ tastases with the aim of treating more patients by combining IRFA with resection. The benefit: risk ratio is now well known and surgeons have access to the knowledge they need to make more informed choices about whether to resect, ablate or renounce treatment on a lesion-bylesion basis. Surgeons who are skilled in intraoperative ultrasound diagnosis and guidance are now not only able to choose whether or not to perform surgery, but are also able to perform IRFA and do not need to involve a radiologist. Specific complications related to IRFA are rare, especially if the lesion is <35 mm in diameter and is located far from a main biliary duct and no additional septic procedures are used. The surgeon can decide to ablate a lesion in a more difficult situation, but this carries greater risk. Combining resection with IRFA leads to higher morbidity, especially in difficult patients with numerous bilateral lesions, but this may be

The resection of hepatic metastases of colorectal carcinoma is followed by tumor recurrence in up to two thirds of cases, and about half of these recurrences are found in the liver [12, 23, 27, 28]. In general, whenever there is a chance of a curative resection, resection should be considered for recurrent tumors as well. The operative morbidity and mortality of hepatic reresection in experienced centers are no greater than those of primary resection. In a study on second operations in 94 patients with recurrent hepatic metastases of colorectal carcinoma, 38% of the patients were alive 5 years after surgery [12]. Thus, whenever complete resection of the tumor is possible, surgery is indicated even for patients with recurrent hepatic meta‐

The results of surgical treatment of metastatic colorectal carcinoma have improved markedly in recent years. The reasons for this include developments in medical imaging, in perioperative and surgical treatment, and in chemotherapy, with the introduction of potent new protocols. Clinicopathological factors such as tumor size, number of tumor nodules, and extrahepatic tumor manifestations no longer contraindicate hepatic resection. The main consideration at present is the need to achieve a complete R0 resection. Accompanying chemotherapy should be considered, especially for patients with an unfavorable risk profile. Neoadjuvant chemo‐ therapy is reserved for patients with marginally resectable metastases. The resectability or nonresectability of hepatic metastases is a matter that must be evaluated by a surgeon who is experienced in the treatment of hepatic metastases. Hepatic resection of colorectal liver metastases after downsizing by chemotherapy provides the only chance of long term survival

in tumours unresectable by hepatectomy alone. [48]

necessary to achieve R0 (microscopically negative) resection margins.

**20. Hepatic re-resection in case of recurrent tumor**

stases.

**21. Conclusion**

#### *19.1.5. Vascular complications*

Different types of vascular complication were described in in a total of 22 patients. Associated procedures such as cholecystectomy or colectomy induced six haemorrhages, two of which were fatal and one required re-operation after prophylactic cholecystectomy. Three haemor‐ rhages from the needle track were treated during surgery by compression. In three cirrhotic patients, haemorrhage occurred in the necrosis induced by the IRFA; one patient died as a result. [25]

Treatment of two juxta-portal lesions induced haemorrhages from arterial injuries. 25, 26 In one patient, an arterio-portal fistula appeared in an area of necrosis 6 weeks later and was treated by a transfemoral embolization. [18] Similarly, a false aneurysm occurred in one patient 6 months after IRFA and led to a haemorrhage. Five portal thromboses were reported, [19, 25, 34] four of which were complete and fatal. Three of these occurred in cirrhotic patients treated with Pringle vascular occlusion.

#### *19.1.6. Skin burns*

Eight dispersive pad skin burns were reported in four articles. Skin burns occurred when RFA ran for >30 min on high power and within large and multiple skin pads. One skin burn occurred in a patient with bilateral hip prostheses.30 One third-degree skin burn required surgical treatment. [38]

#### *19.1.7. Visceral damage*

Two instances of thermal gastric damage [41] and one of acute cholecystitis near the gallblad‐ der were observed after IRFA during surgery and were treated immediately.

#### *19.1.8. Comparison with hepatectomy*

The morbidity of hepatectomy depends on the extent and complexity of the hepatic resection. Intraoperative RFA as a standalone treatment is indicated for unresectable tumours in patients in whom major hepatectomy would leave a low level of functional hepatic reserve. Mortality and morbidity rates in major hepatic resection are 0–5% and 20–50%, respectively. [45] Rates of liver failure after major hepatectomy preceded by portal embolization are 4–10% vs.2.6% after IRFA [46, 47] combined with hepatic resection. There is reported mortality of 2.3% and morbidity of 19.8% in patients treated by resection and combined IRFA, and estimates their results to be comparable with those of resection alone. [31] Morbidity rates after major hepatic resection and IRFA combined with hepatic resection are comparable, even if IRFA is indicated in tumours unresectable by hepatectomy alone. [48]

The past 10 years have represented a period of learning for surgeons who deal with liverme‐ tastases with the aim of treating more patients by combining IRFA with resection. The benefit: risk ratio is now well known and surgeons have access to the knowledge they need to make more informed choices about whether to resect, ablate or renounce treatment on a lesion-bylesion basis. Surgeons who are skilled in intraoperative ultrasound diagnosis and guidance are now not only able to choose whether or not to perform surgery, but are also able to perform IRFA and do not need to involve a radiologist. Specific complications related to IRFA are rare, especially if the lesion is <35 mm in diameter and is located far from a main biliary duct and no additional septic procedures are used. The surgeon can decide to ablate a lesion in a more difficult situation, but this carries greater risk. Combining resection with IRFA leads to higher morbidity, especially in difficult patients with numerous bilateral lesions, but this may be necessary to achieve R0 (microscopically negative) resection margins.

## **20. Hepatic re-resection in case of recurrent tumor**

The resection of hepatic metastases of colorectal carcinoma is followed by tumor recurrence in up to two thirds of cases, and about half of these recurrences are found in the liver [12, 23, 27, 28]. In general, whenever there is a chance of a curative resection, resection should be considered for recurrent tumors as well. The operative morbidity and mortality of hepatic reresection in experienced centers are no greater than those of primary resection. In a study on second operations in 94 patients with recurrent hepatic metastases of colorectal carcinoma, 38% of the patients were alive 5 years after surgery [12]. Thus, whenever complete resection of the tumor is possible, surgery is indicated even for patients with recurrent hepatic meta‐ stases.

## **21. Conclusion**

*19.1.4. Liver failure*

result. [25]

*19.1.6. Skin burns*

treatment. [38]

*19.1.7. Visceral damage*

*19.1.8. Comparison with hepatectomy*

*19.1.5. Vascular complications*

with Pringle vascular occlusion.

failures were subsequent to portal thrombosis.

182 Colorectal Cancer - Surgery, Diagnostics and Treatment

Liver failure was reported in 24 patients in 11 articles [41] and was fatal in eight patients. Fourteen liver failures occurred after IRFA combined with major resection. Six liver failures occurred in cirrhotic patients; three of these failures occurred after IRFA alone. Two liver

Different types of vascular complication were described in in a total of 22 patients. Associated procedures such as cholecystectomy or colectomy induced six haemorrhages, two of which were fatal and one required re-operation after prophylactic cholecystectomy. Three haemor‐ rhages from the needle track were treated during surgery by compression. In three cirrhotic patients, haemorrhage occurred in the necrosis induced by the IRFA; one patient died as a

Treatment of two juxta-portal lesions induced haemorrhages from arterial injuries. 25, 26 In one patient, an arterio-portal fistula appeared in an area of necrosis 6 weeks later and was treated by a transfemoral embolization. [18] Similarly, a false aneurysm occurred in one patient 6 months after IRFA and led to a haemorrhage. Five portal thromboses were reported, [19, 25, 34] four of which were complete and fatal. Three of these occurred in cirrhotic patients treated

Eight dispersive pad skin burns were reported in four articles. Skin burns occurred when RFA ran for >30 min on high power and within large and multiple skin pads. One skin burn occurred in a patient with bilateral hip prostheses.30 One third-degree skin burn required surgical

Two instances of thermal gastric damage [41] and one of acute cholecystitis near the gallblad‐

The morbidity of hepatectomy depends on the extent and complexity of the hepatic resection. Intraoperative RFA as a standalone treatment is indicated for unresectable tumours in patients in whom major hepatectomy would leave a low level of functional hepatic reserve. Mortality and morbidity rates in major hepatic resection are 0–5% and 20–50%, respectively. [45] Rates of liver failure after major hepatectomy preceded by portal embolization are 4–10% vs.2.6% after IRFA [46, 47] combined with hepatic resection. There is reported mortality of 2.3% and morbidity of 19.8% in patients treated by resection and combined IRFA, and estimates their results to be comparable with those of resection alone. [31] Morbidity rates after major hepatic

der were observed after IRFA during surgery and were treated immediately.

The results of surgical treatment of metastatic colorectal carcinoma have improved markedly in recent years. The reasons for this include developments in medical imaging, in perioperative and surgical treatment, and in chemotherapy, with the introduction of potent new protocols. Clinicopathological factors such as tumor size, number of tumor nodules, and extrahepatic tumor manifestations no longer contraindicate hepatic resection. The main consideration at present is the need to achieve a complete R0 resection. Accompanying chemotherapy should be considered, especially for patients with an unfavorable risk profile. Neoadjuvant chemo‐ therapy is reserved for patients with marginally resectable metastases. The resectability or nonresectability of hepatic metastases is a matter that must be evaluated by a surgeon who is experienced in the treatment of hepatic metastases. Hepatic resection of colorectal liver metastases after downsizing by chemotherapy provides the only chance of long term survival

for patients with initially unresectable colorectal liver metastases. Additional surgical techni‐ ques can be combined to chemotherapy to further improve resectability. The only absolute contraindication for resection is the inability to completely resect all metastases, avoiding postoperative liver failure by leaving enough functional liver parenchyma. The presence of poor prognostic factors no longer limits the indications for resection. Neoadjuvant treatment with chemotherapeutic agents such as irinotecan and oxaliplatin, hepatic artery infusion combined with systemic therapy and biologic agents (bevacizumab, cetuximab) play an important role in increasing the number of patients eligible to secondary resection. However, with the progressive use of neoadjuvant chemotherapy further studies are necessary to answer questions such as the risk: benefit ratio in maximizing response rates versus vascular changes in the liver (current opinion still divided concerning their importance). These questions remain challenging and should not be underestimated. The perfecting of surgical techniques together with safer procedures, as well as the improvement in chemotherapy regimens have allowed doctors to offer patients with liver metastasis the possibility of curative treatment or longterm survival. Factors that were previously considered contraindications for the surgery, such as number of metastases, synchronous metastases and even the presence of extrahepatic disease, must be considered only as prognostic factors and must not prevent the patient from having the opportunity of being treated.

[4] Mentha G, Majno P, Terraz S, Rubbia-Brandt L, Gervaz P, Andres A, et al. Treatment strategies for the management of advanced colorectal liver metastases detected syn‐

Surgical Strategies for Liver Metastases from Colorectal Cancer

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185

[5] Livermetsurvey. International registry of liver metastases of colorectal cancer. [Ac‐

[6] Choti M, Sitzmann J, Tiburi M, Sumetchotimetha W, Rangsin R, Schulick RD, et al. Trends in long term survival following liver resection for hepatic colorectal metasta‐

[7] Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, et al. Recurrence and outcomesfollowing hepatic resection, radiofrequency ablation, and combined re‐

[8] Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001

[9] Nordlinger B, Jaeck D, editors. Traitment de metastases hépatiques as cancers color‐

[10] Gayowski TJ, Iwatsuki S, Madariaga JR, Selby R, Todo S, Irish W, et al. Experience in hepatic resection of colorectal cancer − analysis of clinical and pathological risk fac‐

[11] Minagawa M, Maltuuchi M, Torzilli G, Takayama T, Kawasaki S, Kosuge T, et al. Ex‐ tension of the frontiers metastases from colorectal cancer: Long-term results. Ann

[12] Ercolani G, Grazi GL, Ravaioli M, Cescon M, Gardini A, Varotti G, et al. Liver resec‐ tion for multiple colorectal metastases: influence of parenchymal involvement and total tumor volume versus number or location on long term survival. Arch Surg.

[13] Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carci‐ noma: impact of surgical resection on the natural history. Br J Surg. 1990;77:1241-6.

[14] Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue sur‐ gery for unresectable colorectal liver metastases downstaged by chemotherapy: a

[15] Rodgers M, Mccall J. Surgery for colorectal liver metastases with hepatic lymph node

[16] Adam R, De Haas RJ, Wicherts DA, Aloia TA, Delvart V, Azoulay D, et al. Is hepatic resection justified after chemothera- py in patients with colorectal liver metastases

model to predict longterm survival. Ann Surg. 2004;240:644-58.

involvement: A Systematic review. Br J Surg. 2000;87:1142-55.

and lymph node involvement? J Clin Oncol. 2008;26:3672-80.

section/ablation for colorectal liver metastases. Ann Surg. 2004;239:818-27.

chronously with the primary tumour. EJSO. 2007;33:76-83.

cessed 2010 Mar].

ses. Ann Surg. 2002;235:759-66.

consecutive cases. Ann Surg. 1999;230:309-18.

ectaus. Paris: Springer-Verlag; 1992.

tors. Surgery. 1994;116:703-71.

Surg. 2000;231: 487-99.

2002;137:1187-92.

### **Author details**

Nikola Kolev1 , Valentin Ignatov1 , Anton Tonev1 , Tanya Kirilova2 , Georgi Ivanov1 , Alexander Zlatarov1 and Krassimir Ivanov1

1 Department of General and Operative Surgery, University Hospital "St. Marina", Varna, Bulgaria

2 Department of Gastroenterology, University Hospital "St. Marina", Varna, Bulgaria

#### **References**


[4] Mentha G, Majno P, Terraz S, Rubbia-Brandt L, Gervaz P, Andres A, et al. Treatment strategies for the management of advanced colorectal liver metastases detected syn‐ chronously with the primary tumour. EJSO. 2007;33:76-83.

for patients with initially unresectable colorectal liver metastases. Additional surgical techni‐ ques can be combined to chemotherapy to further improve resectability. The only absolute contraindication for resection is the inability to completely resect all metastases, avoiding postoperative liver failure by leaving enough functional liver parenchyma. The presence of poor prognostic factors no longer limits the indications for resection. Neoadjuvant treatment with chemotherapeutic agents such as irinotecan and oxaliplatin, hepatic artery infusion combined with systemic therapy and biologic agents (bevacizumab, cetuximab) play an important role in increasing the number of patients eligible to secondary resection. However, with the progressive use of neoadjuvant chemotherapy further studies are necessary to answer questions such as the risk: benefit ratio in maximizing response rates versus vascular changes in the liver (current opinion still divided concerning their importance). These questions remain challenging and should not be underestimated. The perfecting of surgical techniques together with safer procedures, as well as the improvement in chemotherapy regimens have allowed doctors to offer patients with liver metastasis the possibility of curative treatment or longterm survival. Factors that were previously considered contraindications for the surgery, such as number of metastases, synchronous metastases and even the presence of extrahepatic disease, must be considered only as prognostic factors and must not prevent the patient from having

the opportunity of being treated.

184 Colorectal Cancer - Surgery, Diagnostics and Treatment

, Valentin Ignatov1

Cancer J Clin. 2005;55:10-30.

and Krassimir Ivanov1

Nov 16]. Available from: http:// www-dep.iarc.fr

, Anton Tonev1

1 Department of General and Operative Surgery, University Hospital "St. Marina", Varna,

[1] Jemal A, Murray T, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2005. CA

[2] International Agency for research on cancer: GLOBOCAN 2002 data. [Accessed 2006

[3] Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing thena‐

tural history of colorectal liver metastases. Lancet. 1994;343:1405-10.

2 Department of Gastroenterology, University Hospital "St. Marina", Varna, Bulgaria

, Tanya Kirilova2

, Georgi Ivanov1

,

**Author details**

Alexander Zlatarov1

Nikola Kolev1

Bulgaria

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188 Colorectal Cancer - Surgery, Diagnostics and Treatment


**Chapter 9**

**Management of Non-Hepatic Metastatic Disease in**

Colorectal cancer is one of the most frequent malignant tumors and a leading cause of cancerrelated death. One third of the patients develop a metastasis during the course of the disease. Because of that, it is very important to know about the evolution of the illness, how to make a quick diagnosis and how to provide an appropriate treatment depending on the tumor and

Management of patients with colorectal metastases without the intervention of a multidisci‐ plinary team specialized in the liver can lead to patients being denied potentially curative

**•** Laboratory test: The serum carcinoembryonic antigen (CEA) level is a valuable marker in patients with recurrent colorectal cancer. It must be remembered that about 25% of tumors

**•** Imaging: Radiologic imaging is a critical component of the preoperative research on a patient with colorectal liver metastasis. In fact, it is often used to determine whether the

**•** Surgical indications: the patient must be in acceptable health to tolerate the physiologic consequences of the surgery. Next, the primary colorectal cancer must be resected and the

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

It´s necessary to have a protocol before the treatment of metastatic disease:

patient should be further considered for resection.

**Colorectal Cancer**

http://dx.doi.org/10.5772/57487

the location of the metastases.

**1.1. Metastatic disease**

**•** Physical examination

do not secrete CEA.

**1. Introduction**

treatments.

C. Alberto Blanco, R. Sánchez, F. Piniella,

D. Pescador, G. Borobio, A. García and C. Cano

Additional information is available at the end of the chapter

## **Management of Non-Hepatic Metastatic Disease in Colorectal Cancer**

C. Alberto Blanco, R. Sánchez, F. Piniella, D. Pescador, G. Borobio, A. García and C. Cano

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57487

## **1. Introduction**

Colorectal cancer is one of the most frequent malignant tumors and a leading cause of cancerrelated death. One third of the patients develop a metastasis during the course of the disease. Because of that, it is very important to know about the evolution of the illness, how to make a quick diagnosis and how to provide an appropriate treatment depending on the tumor and the location of the metastases.

Management of patients with colorectal metastases without the intervention of a multidisci‐ plinary team specialized in the liver can lead to patients being denied potentially curative treatments.

#### **1.1. Metastatic disease**

It´s necessary to have a protocol before the treatment of metastatic disease:


presence of other extrahepatic disease must be ruled out. Preoperative workup should include a recent colonoscopy, chest X-ray and chest CT.

reserve compared with patients who only require wedge resections (Villeneuve and Sundar‐ esan 2009). The key for a successful surgical resection of pulmonary metastases is an adequate selection of the patient through a preoperative evaluation and a precise surgical planning. To

Management of Non-Hepatic Metastatic Disease in Colorectal Cancer

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193

**High-resolution helical CAT scan** is a basic tool which detects approximately 20-25% more nodes that standard CT, and the detection is reliable in nodes of 2-3 mm (Remy-Jardin et al.

**PET** – An examination with Positron Emission Tomography (PET-FDG) is recommended to optimize the selection of patients who are candidates for pulmonary metastasectomy. How‐ ever, we have to take into account the fact that PET has a limited sensitivity for lesions <1 cm in size (Reinhardt et al. 2006). It is very useful to assess the intra-thoracic node involvement (hilar or mediastinal), local hidden recurrence of the primary tumor or in other locations such

The main value of PET is its high sensitivity to detect an extra-thoracic disease. In general terms, metastasectomy must not be performed unless all the deposits or foci of the disease are treatable (except when the patient is included in a specific protocol such as a clinical trial for a vaccine or symptomatic lesions that cannot be treated otherwise). In any case, a positive extrathoracic result in a PET examination is not enough evidence to rule a patient out from surgery for pulmonary metastases. All suspicious extra-thoracic FDG-highlighted areas must be

**Preoperative biopsy** – In patients with highly suspicious lesions in imaging tests, the final diagnosis is often achieved after the surgical removal of the metastases. However, in many cases, a preoperative biopsy with CT-guided fine needle aspiration is a useful and less invasive method to obtain a pathological diagnosis, particularly if the diagnosis of the metastatic disease is not clear, if the patient is not a good candidate for surgery or if the patient has a primary tumor (such as testicular germ-cell cancer or lymphoma) for which surgery may not be

**Bronchoscopy** (with or without endobronchial ultrasound) is indicated as part of the evalua‐ tion in cases of lesions that are centrally located in the CT scan, patients with symptoms of involvement of the respiratory tract and some types of tumors prone to endobronchial involvement, such as breast cancer, colon cancer and renal cell carcinoma [36]. Bronchoscopy

The presence of pathological mediastinal adenopathies requires a **biopsy** with a mediastino‐ scopy or ultrasound-guided endobronchial needle **aspiration cytology**. Most authors consider

Management of patients with pulmonary metastases, according to the guidelines of the National Comprehensive Cancer Network (NCCN) will depend on the form of presentation along time and on whether the metastases can be resected or not. Synchronous resectable

is performed before surgery, when a positive result may contraindicate an operation.

mediastinal node involvement (N2) as a contraindication for resection.

do so, we can use the following diagnostic tests:

as the abdomen or the pelvis (Villeneuve and Sundaresan 2009).

1993; Collie et al. 1994).

biopsied before surgery.

required.

*2.1.1.3.Treatment*


## **2. Non hepatic disease in colorectal cancer**

#### **2.1. Lung metastases**

#### *2.1.1. Lung metastases in CRC*

Colon cancer is a systemic disease in 19% of the patients, and the liver and lungs are the most common locations for a metastasis. Colorectal adenocarcinoma is the most common cancer leading to pulmonary metastasectomy

#### *2.1.1.1. Symptoms*

Most pulmonary metastases are asymptomatic and they are detected incidentally during the initial diagnostic staging study for a primary tumor or in the monitoring imaging studies afterwards, generally during a thoracic CT scan. Symptoms such as coughing, pain or hemoptysis mainly appear in patients with hilar involvement.

#### *2.1.1.2. Preoperative evaluation*

A solitary pulmonary nodule in a patient with a previous cancer can be bening or malignant (primary or secondary); although in most cases will be malignant (Mery et al. 2004). When there are multiple nodules, the probability of metastatic disease increases significantly.

There are no pathognomonic radiological features that distinguish the metastasis of primary tumors, even though metastasis is generally well circumscribed, spherical with smooth margins and are mainly subpleurales or periferics. However, primary lung cancers are single lesions, with irregular edges, asociated linear densities and are often more central.

Although the background and radiographic features of a lesion can provide clues as to whether an individual lesion is bening or malignant, it is not posible to distinguish reliably a metastasis from a primary lung cancer. The resection of the nodule is the most reliable method to establish the diagnosis.

The presence of pulmonary metastasis makes it necessary to carry out a complete staging. The extent of the required pulmonary resection will guide the preoperative evaluation of the patients: patients who require a pneumonectomy will need a higher level of cardiopulmonary reserve compared with patients who only require wedge resections (Villeneuve and Sundar‐ esan 2009). The key for a successful surgical resection of pulmonary metastases is an adequate selection of the patient through a preoperative evaluation and a precise surgical planning. To do so, we can use the following diagnostic tests:

**High-resolution helical CAT scan** is a basic tool which detects approximately 20-25% more nodes that standard CT, and the detection is reliable in nodes of 2-3 mm (Remy-Jardin et al. 1993; Collie et al. 1994).

**PET** – An examination with Positron Emission Tomography (PET-FDG) is recommended to optimize the selection of patients who are candidates for pulmonary metastasectomy. How‐ ever, we have to take into account the fact that PET has a limited sensitivity for lesions <1 cm in size (Reinhardt et al. 2006). It is very useful to assess the intra-thoracic node involvement (hilar or mediastinal), local hidden recurrence of the primary tumor or in other locations such as the abdomen or the pelvis (Villeneuve and Sundaresan 2009).

The main value of PET is its high sensitivity to detect an extra-thoracic disease. In general terms, metastasectomy must not be performed unless all the deposits or foci of the disease are treatable (except when the patient is included in a specific protocol such as a clinical trial for a vaccine or symptomatic lesions that cannot be treated otherwise). In any case, a positive extrathoracic result in a PET examination is not enough evidence to rule a patient out from surgery for pulmonary metastases. All suspicious extra-thoracic FDG-highlighted areas must be biopsied before surgery.

**Preoperative biopsy** – In patients with highly suspicious lesions in imaging tests, the final diagnosis is often achieved after the surgical removal of the metastases. However, in many cases, a preoperative biopsy with CT-guided fine needle aspiration is a useful and less invasive method to obtain a pathological diagnosis, particularly if the diagnosis of the metastatic disease is not clear, if the patient is not a good candidate for surgery or if the patient has a primary tumor (such as testicular germ-cell cancer or lymphoma) for which surgery may not be required.

**Bronchoscopy** (with or without endobronchial ultrasound) is indicated as part of the evalua‐ tion in cases of lesions that are centrally located in the CT scan, patients with symptoms of involvement of the respiratory tract and some types of tumors prone to endobronchial involvement, such as breast cancer, colon cancer and renal cell carcinoma [36]. Bronchoscopy is performed before surgery, when a positive result may contraindicate an operation.

The presence of pathological mediastinal adenopathies requires a **biopsy** with a mediastino‐ scopy or ultrasound-guided endobronchial needle **aspiration cytology**. Most authors consider mediastinal node involvement (N2) as a contraindication for resection.

#### *2.1.1.3.Treatment*

presence of other extrahepatic disease must be ruled out. Preoperative workup should

**•** Complications: Successful outcome in hepatic surgery depends largely upon minimizing intraoperative blood loss. Excessive blood loss is not only associated with increased perioperative morbidity but also with a shorter time to recurrence and decreased survival

Colon cancer is a systemic disease in 19% of the patients, and the liver and lungs are the most common locations for a metastasis. Colorectal adenocarcinoma is the most common cancer

Most pulmonary metastases are asymptomatic and they are detected incidentally during the initial diagnostic staging study for a primary tumor or in the monitoring imaging studies afterwards, generally during a thoracic CT scan. Symptoms such as coughing, pain or

A solitary pulmonary nodule in a patient with a previous cancer can be bening or malignant (primary or secondary); although in most cases will be malignant (Mery et al. 2004). When there are multiple nodules, the probability of metastatic disease increases significantly.

There are no pathognomonic radiological features that distinguish the metastasis of primary tumors, even though metastasis is generally well circumscribed, spherical with smooth margins and are mainly subpleurales or periferics. However, primary lung cancers are single

Although the background and radiographic features of a lesion can provide clues as to whether an individual lesion is bening or malignant, it is not posible to distinguish reliably a metastasis from a primary lung cancer. The resection of the nodule is the most reliable method to establish

The presence of pulmonary metastasis makes it necessary to carry out a complete staging. The extent of the required pulmonary resection will guide the preoperative evaluation of the patients: patients who require a pneumonectomy will need a higher level of cardiopulmonary

lesions, with irregular edges, asociated linear densities and are often more central.

include a recent colonoscopy, chest X-ray and chest CT.

rates after resection of colorectal liver metastases.

**2. Non hepatic disease in colorectal cancer**

hemoptysis mainly appear in patients with hilar involvement.

**•** Survival

**2.1. Lung metastases**

*2.1.1.1. Symptoms*

the diagnosis.

*2.1.1. Lung metastases in CRC*

*2.1.1.2. Preoperative evaluation*

leading to pulmonary metastasectomy

192 Colorectal Cancer - Surgery, Diagnostics and Treatment

Management of patients with pulmonary metastases, according to the guidelines of the National Comprehensive Cancer Network (NCCN) will depend on the form of presentation along time and on whether the metastases can be resected or not. Synchronous resectable metastases are treated with chemotherapy with or without later resection; and if they cannot be resected, then chemotherapy is indicated. Metachronous resectable metastases can be resected with or without neoadjuvant chemotherapy, and chemotherapy is indicated when they cannot be resected. The evaluation of patients in treatment with chemotherapy that can be transferred to surgery is carried out every 2 months in the selected cases (2013).

approach using thoracotomy (Saisho et al. 2009). There are no randomised trials comparing results between open resections and thoracoscopic surgery, although retrospectively patients treated by VATS have similar results to patients treated by conventional open thoracotomy

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Concerning the number of metastasis, it is clear that technically the fewer there is, the better. Although there is no general consensus, ideally from technical and oncologic point of view, it would be less than five (Hellman and Weichselbaum 1995; Weichselbaum and Hellman 2011) however it is true that in the majority of cases, unique pulmonary metastasectomies are conducted and in these patients there is a greater survival advantage (Fiorentino et al. 2010).

For some patients with metastatic CRC, repeated pulmonary metastasectomy offers an excellent opportunity for long-term survival, and it is associated with a low operative mortality rate. Patients with more than 2 metastatic nodes and a maximum diameter of the metastatic pulmonary node of more than 3 cm present a significantly lower survival rate (Hendriks et al.

In the case of patients who do not meet the criteria for a metastasectomy, there are alternative ablative techniques to locally control the lesion, such as **stereotactic radiothera‐ py** and **radiofrequency ablation** or **cryoablation**. The experience with these ablation techniques is limited, but the initial results look promising (Pennathur, Abbas et al. 2009). The role of **chemotherapy** is not yet defined for pulmonary metastases with a colorectal origin, because traditionally, these lesions do not show a good response to adjuvant treatments. Currently, chemotherapy has shown very good responses in primary CRC with regimens such as FOLFOX (fluorouracil, leucovorin and oxaliplatin) and FOLFIRI (fluorour‐ acil, leucovorin and irinotecan), with or without the addition of biological agents such as bevacizumab (anti-vascular endothelial growth factor, VEGF), cetuximab and panitumu‐ mab (anti-epidermal growth factor, EGFR). These therapies have not yet been systematical‐ ly studied, and they may become the most effective treatment for pulmonary metastases. As a last resort, patients whose functional state is poor are candidates for palliative

External radiotherapy can be an option in very specific cases or in clinical trials, provided that

There are many factors that have an influence on survival after a metastasectomy. The presence of one or more factors for poor prognosis does not represent an absolute contraindication for a metastasectomy (Quiros and Scott 2008). Unfavourable prognostic factors include number and size of the metastasis, inability to completely resect the entire metastatic disease, a short disease-free interval after treatment for the primary tumor and thoracic node involvement. For

Metastases in both lungs are not a contraindication for surgery.

treatment only (Villeneuve & Sundaresan 2009).

its part, the histology of the tumor also influences the results.

the tumors are not potentially resectable.

*2.1.2. Prognostic factors*

(Carballo et al. 2009)

2001; Salah et al. 2013).

Although the quality of the currently available evidence on pulmonary **metastasectomy** in cases of colorectal cancer is not enough to draw conclusions on the effectiveness of this kind of surgery (Pfannschmidt et al. 2007; Fiorentino et al. 2010; Pfannschmidt et al. 2010; Salah et al. 2012; Gonzalez et al. 2013), pulmonary metastasectomy in cases of selected patients with metastatic colorectal cancer is a general practice and it is included in the clinical guidelines (Poston et al. 2011). The objective is to limit surgery only for patients who have the highest chances to benefit from it, either with longer survival rates or symptom relief, and to optimize the time of the operation.

The **resectability criteria** admitted by the main groups are the following (Ehrenhaft et al. 1958; Martini and McCormack 1998; Greelish and Friedberg 2000; Jaklitsch et al. 2001; Pfannschmidt et al. 2003; Kondo et al. 2005):


The resection of one or more pulmonary lesions may also be indicated in a patient with a known malignant tumor when:


The approach depends on the number, size, location and estability during the time in TC. In general, Video-assisted thoracoscopic surgery (VATS) is ideal for peripheral metastases single or few, stable and smaller than 3 cm. The central lesions are likely to require a segmentectomy or lobectomy and is best addressed by open thoracotomy.

Video-assisted thoracoscopic surgery has the advantage that it is less painful, postoperative recovery is faster, hospitalization is shorter and lower long-term morbidity, especially intrathoracic recurrences (Saisho et al. 2009). Recurrence rates appear to be similar to the approach using thoracotomy (Saisho et al. 2009). There are no randomised trials comparing results between open resections and thoracoscopic surgery, although retrospectively patients treated by VATS have similar results to patients treated by conventional open thoracotomy (Carballo et al. 2009)

Concerning the number of metastasis, it is clear that technically the fewer there is, the better. Although there is no general consensus, ideally from technical and oncologic point of view, it would be less than five (Hellman and Weichselbaum 1995; Weichselbaum and Hellman 2011) however it is true that in the majority of cases, unique pulmonary metastasectomies are conducted and in these patients there is a greater survival advantage (Fiorentino et al. 2010). Metastases in both lungs are not a contraindication for surgery.

For some patients with metastatic CRC, repeated pulmonary metastasectomy offers an excellent opportunity for long-term survival, and it is associated with a low operative mortality rate. Patients with more than 2 metastatic nodes and a maximum diameter of the metastatic pulmonary node of more than 3 cm present a significantly lower survival rate (Hendriks et al. 2001; Salah et al. 2013).

In the case of patients who do not meet the criteria for a metastasectomy, there are alternative ablative techniques to locally control the lesion, such as **stereotactic radiothera‐ py** and **radiofrequency ablation** or **cryoablation**. The experience with these ablation techniques is limited, but the initial results look promising (Pennathur, Abbas et al. 2009). The role of **chemotherapy** is not yet defined for pulmonary metastases with a colorectal origin, because traditionally, these lesions do not show a good response to adjuvant treatments. Currently, chemotherapy has shown very good responses in primary CRC with regimens such as FOLFOX (fluorouracil, leucovorin and oxaliplatin) and FOLFIRI (fluorour‐ acil, leucovorin and irinotecan), with or without the addition of biological agents such as bevacizumab (anti-vascular endothelial growth factor, VEGF), cetuximab and panitumu‐ mab (anti-epidermal growth factor, EGFR). These therapies have not yet been systematical‐ ly studied, and they may become the most effective treatment for pulmonary metastases. As a last resort, patients whose functional state is poor are candidates for palliative treatment only (Villeneuve & Sundaresan 2009).

External radiotherapy can be an option in very specific cases or in clinical trials, provided that the tumors are not potentially resectable.

#### *2.1.2. Prognostic factors*

metastases are treated with chemotherapy with or without later resection; and if they cannot be resected, then chemotherapy is indicated. Metachronous resectable metastases can be resected with or without neoadjuvant chemotherapy, and chemotherapy is indicated when they cannot be resected. The evaluation of patients in treatment with chemotherapy that can

Although the quality of the currently available evidence on pulmonary **metastasectomy** in cases of colorectal cancer is not enough to draw conclusions on the effectiveness of this kind of surgery (Pfannschmidt et al. 2007; Fiorentino et al. 2010; Pfannschmidt et al. 2010; Salah et al. 2012; Gonzalez et al. 2013), pulmonary metastasectomy in cases of selected patients with metastatic colorectal cancer is a general practice and it is included in the clinical guidelines (Poston et al. 2011). The objective is to limit surgery only for patients who have the highest chances to benefit from it, either with longer survival rates or symptom relief, and to optimize

The **resectability criteria** admitted by the main groups are the following (Ehrenhaft et al. 1958; Martini and McCormack 1998; Greelish and Friedberg 2000; Jaklitsch et al. 2001;

**•** Complete anatomical resection maintaining an adequate pulmonary function (McAfee et al.

**•** The existence of resectable extra-pulmonary metastases does not contraindicate pulmonary resection (Yano et al. 1993; Ambiru et al. 1998; Irshad et al. 2001; Rena et al. 2002); in this

**•** Resectable metastases can be treated with a synchronous resection or a sequential approach. The resection of one or more pulmonary lesions may also be indicated in a patient with a known

**•** There are symptomatic metastases (such as bronchial obstruction with distal suppuration)

**•** Tissue is required for a new therapeutic strategy (such as an autologous vaccine), preferably

The approach depends on the number, size, location and estability during the time in TC. In general, Video-assisted thoracoscopic surgery (VATS) is ideal for peripheral metastases single or few, stable and smaller than 3 cm. The central lesions are likely to require a segmentectomy

Video-assisted thoracoscopic surgery has the advantage that it is less painful, postoperative recovery is faster, hospitalization is shorter and lower long-term morbidity, especially intrathoracic recurrences (Saisho et al. 2009). Recurrence rates appear to be similar to the

case, the metastases must be treatable with surgery or other therapeutic approach.

1992; Regnard et al. 1998; Inoue et al. 2000; Sakamoto et al. 2001)

**•** Removal of the primary tumor without persistence of residual disease (R0)

be transferred to surgery is carried out every 2 months in the selected cases (2013).

the time of the operation.

malignant tumor when:

Pfannschmidt et al. 2003; Kondo et al. 2005):

194 Colorectal Cancer - Surgery, Diagnostics and Treatment

**•** A new primary lung cancer cannot be ruled out

or lobectomy and is best addressed by open thoracotomy.

that cannot be treated in any other way

in the framework of a clinical trial.

There are many factors that have an influence on survival after a metastasectomy. The presence of one or more factors for poor prognosis does not represent an absolute contraindication for a metastasectomy (Quiros and Scott 2008). Unfavourable prognostic factors include number and size of the metastasis, inability to completely resect the entire metastatic disease, a short disease-free interval after treatment for the primary tumor and thoracic node involvement. For its part, the histology of the tumor also influences the results.

**Figure 1.** Comparison of chest scanning during shallow breathing (A) and chest scanning with additional low-dose CT during maximal inspiration (B). (A) Lung metastasis from colorectal cancer is only barely visible during shallow breath‐ ing (arrow). Also note blurred lung vessels and congested lung parenchyma in this image. (B) Metastasis can be clearly detected by low-dose CT during maximal inspiration (arrow). Additionally, lung parenchyma is well inflated, and lung vessels are displayed sharply. http://jnm.snmjournals.org/content/48/1\_suppl/45S/F2.expansion.html

The first metastases usually appear in the paracolic nodes closest to the primary tumor they are draining, and frequently only one or two nodes close to the tumor are involved. However, as the disease evolves, node propagation is larger and affects a variable amount of nodes located further away, on the arteriovenous system that depends on the intestinal segment involved. As the neoplasm moves forward, nodes from the main colic vessels that drain the intestinal neoplastic area are invaded, and the process gradually spreads upwards through the node chain that accompanies the vessels until it finally reaches the nodes that depend on the large mesenteric vessels (and, in the case of the rectum, the nodes that depend on the iliac vessels through the hemorrhoidal venous system). In short, it is known that here is a correlation between each segment of the colon and its venous and lymphatic drainage which, although there may be individual alterations, essentially depends on the superior mesenteric venous system up to the splenic flexure of the colon and, from there, up to the superior rectal vein which depends on the inferior mesenteric vein. Both are affluent to the portal vein and the structure of the lymph drainage system is essentially the same. In the area of the rectum, it has been traditionally accepted that the superior rectal venous system depends on the inferior mesenteric system, that the middle rectal system depends on the inferior mesenteric system

nals/ijso/2011/846512/fig7/

**Figure 3.** Patient with rectal carcinoma and mildly FDG avid metastases to lung. (a) There is a suspicious right upper lobe lung nodule (arrow) on CT in a patient with prior history of rectal carcinoma. (b) The lesion is only mildly FDG avid (arrow) on fused PET-CT. Based on these images the lesion is not definitively malignant. This may be due to the limited resolution of PET and the small lesion size or reduced cellularity. (c) Lung biopsy was subsequently performed confirm‐ ing that the lesion (arrow) represented a metastatic deposit from rectal carcinoma. http://www.hindawi.com/jour‐

(a)

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(b) (c)

**Figure 2.** Multiple metastases Multiple pulmonary metastases from colorectal carcinoma. http://radiopaedia.org/arti‐ cles/pulmonary-metastases, TC/PET metastases from colorectal cancer

## **3. Node metastases**

#### **3.1. Definition and physiopathology**

Node metastases are, like with other cancers, the most important dissemination route for colorectal cancers. This makes lymph node involvement the most important factor in the prognosis and therapeutic approach for colorectal cancer.

Management of Non-Hepatic Metastatic Disease in Colorectal Cancer http://dx.doi.org/10.5772/57487 197

**Figure 3.** Patient with rectal carcinoma and mildly FDG avid metastases to lung. (a) There is a suspicious right upper lobe lung nodule (arrow) on CT in a patient with prior history of rectal carcinoma. (b) The lesion is only mildly FDG avid (arrow) on fused PET-CT. Based on these images the lesion is not definitively malignant. This may be due to the limited resolution of PET and the small lesion size or reduced cellularity. (c) Lung biopsy was subsequently performed confirm‐ ing that the lesion (arrow) represented a metastatic deposit from rectal carcinoma. http://www.hindawi.com/jour‐ nals/ijso/2011/846512/fig7/

**Figure 1.** Comparison of chest scanning during shallow breathing (A) and chest scanning with additional low-dose CT during maximal inspiration (B). (A) Lung metastasis from colorectal cancer is only barely visible during shallow breath‐ ing (arrow). Also note blurred lung vessels and congested lung parenchyma in this image. (B) Metastasis can be clearly detected by low-dose CT during maximal inspiration (arrow). Additionally, lung parenchyma is well inflated, and lung

**Figure 2.** Multiple metastases Multiple pulmonary metastases from colorectal carcinoma. http://radiopaedia.org/arti‐

Node metastases are, like with other cancers, the most important dissemination route for colorectal cancers. This makes lymph node involvement the most important factor in the

cles/pulmonary-metastases, TC/PET metastases from colorectal cancer

prognosis and therapeutic approach for colorectal cancer.

**3. Node metastases**

**3.1. Definition and physiopathology**

196 Colorectal Cancer - Surgery, Diagnostics and Treatment

(a) (b)

vessels are displayed sharply. http://jnm.snmjournals.org/content/48/1\_suppl/45S/F2.expansion.html

The first metastases usually appear in the paracolic nodes closest to the primary tumor they are draining, and frequently only one or two nodes close to the tumor are involved. However, as the disease evolves, node propagation is larger and affects a variable amount of nodes located further away, on the arteriovenous system that depends on the intestinal segment involved. As the neoplasm moves forward, nodes from the main colic vessels that drain the intestinal neoplastic area are invaded, and the process gradually spreads upwards through the node chain that accompanies the vessels until it finally reaches the nodes that depend on the large mesenteric vessels (and, in the case of the rectum, the nodes that depend on the iliac vessels through the hemorrhoidal venous system). In short, it is known that here is a correlation between each segment of the colon and its venous and lymphatic drainage which, although there may be individual alterations, essentially depends on the superior mesenteric venous system up to the splenic flexure of the colon and, from there, up to the superior rectal vein which depends on the inferior mesenteric vein. Both are affluent to the portal vein and the structure of the lymph drainage system is essentially the same. In the area of the rectum, it has been traditionally accepted that the superior rectal venous system depends on the inferior mesenteric system, that the middle rectal system depends on the inferior mesenteric system and the internal iliac system, and that the inferior rectal system depends on the internal and external iliac system.

The studies that want to ensure the diagnosis of node involvement have researched the presence of micrometastases or metastases that have been diagnosed with immunohistochem‐ ical techniques in patients in stages I and II (that is, without node involvement in microscopical terms), and they have found that the presence of micrometastases in these patients does not affect the prognosis and must not be taken into account when treating CRC (Are Lymph Node Micrometastases of any Clinical Significance in Dukes Stages A and B Colorectal Cancer?

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In tumors with a metastasis that takes place through the lymphatic system (breast cancer and melanoma, mainly), there has been a great success in mapping the dissemination of the primary tumor with the so called sentinel lymph node biopsy technique. In view of this situation, several studies have started to analyze it, because lymphadenectomy is an important part in the primary treatment of CRC, both from the staging point of view and in order to prevent recurrence of the tumor if there are infiltrated lymph nodes left. Having a map of lymph dissemination similar to the one obtained with breast cancer would mean knowing the minimum required level of lymphadenectomy, or even of visceral resection. This would allow the medical team to apply an adequate surgical treatment from an oncological perspective but with the minimum morbidity and mortality. Unfortunately, it does not seem that this technique shows reliable results with colorectal cancer ("Técnica del ganglio centinela…". Sardon Ramos

The identification of the sentinel lymph node shows a low sensitivity in the detection of metastasis and micrometastasis. Approximately one half of the adenopathies are lost if a lymphadenectomy is performed based on the results of the sentinel lymph node study. Faerden et al: sentinel node mapping in colonic cancer Disease of the colon & rectum. Volume

Treatment of lymphatic metastasis, given its close relation with the growth of the primary tumor, is the same as for the original lesion: primary resection with exeresis of the nodes of the lymphatic area that drain the tumor. If there is a tumor recurrence in the nodes, the patient is classified as stage IV, which means that there will be the corresponding treatment: chemo‐

Bone metastases from colorectal cancer are uncommon (10-23% in autopsy cases). They usually appear late in the natural history of metastatic disease and are associated with liver or lung metastasis. Acrometastasis is reported to be 0.3-3% of all bone metastases. Cancers of the

therapy and surgery and radiotherapy, which will be provisionally palliative.

Oberg et al. Dis Colon Rectum, October 1998 ol. 41, No. 10 1244-1249).

**3.2. Sentinel lymph node**

et al. CIR ESP. 2013 91(6) 366-371.1).

**3.3. Treatment of lymphatic metastasis**

51: 891–896 (2008).

**4. Bone metastases**

**4.1. Introduction**

On the other hand, there are evidences that show that there are factors of the tumor cells which increase angiogenesis and lymphomagenesis, and which lead to an increased rate of node metastasis and a worse prognosis. Specifically, vascular endothelial growth factor C (VEGF-C) and cyclooxygenase-2 (COX-2) (Coexpression of VEGF-C and Cox-2 in Human Colorectal Cancer and its Association With Lymph Node Metastasis Soumaoro et al. Dis Colon Rectum, March 2006 392-398).

Node involvement plays a fundamental role in the correct definition of the extent of tumor spread, together with the depth of the involvement through the wall of the colon or the rectum, the size of the tumor or the presence of metastases. The number of involved nodes and their distance to the tumor is the basis of some classic classifications, such as Dukes, Astler and Coller and the more modern TNM, whose description is already analyzed elsewhere. All decisions on the treatment must be adopted with reference to the TNM classification, instead of the old Dukes system or the modified Astler-Coller staging system (Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-64).

Given the importance of the whole number of involved nodes in a proper staging and in order to obtain a reliable and comparable prognosis, it is necessary to establish a set of minimum quality criteria for lymphadenectomy. Otherwise, the scenario might be undervalued. Patients in stage I or II (that is, without node involvement) show five-year survival rates of 75%; in contrast to survival rates with N1, which are only 45-60%. Also, the higher the number of nodes studied by the pathologist (and indirectly, resected by the surgeon), the higher the staging accuracy; if that number is low, there is an undervaluing of the tumor dissemination state. (Staging accuracy in colorectal carcinoma. Wong et al. Journal of Clinical Oncology. Vol 17. nº 9 1999pp2896-2900).

A panel sponsored by the American Joint Committee on Cancer (AJCC) and the National Cancer Institute of the USA and presented at the World Conference on Gastroenterology of Sydney in 1990 (J. Gastroenterol Heptol 6:325-244. 1991) has recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer in order to confirm the lack of node involvement due to the tumor. Wong et al. recommend at least the analysis of 14 nodes in pT2 and pT3 tumors.

There is a special situation with stagingpatients withrectal cancer andneoadjuvant chemother‐ apywithypT0-2.Inthesecases, stagingbasedonthe surgical specimenusuallyshowsadecrease in size and in the involvement of the wall of the intestine of the tumor, but if this is taken into account together with the reduction in the number of existing nodes in the specimen re‐ moved from the rectum, it could lead to an undervaluing with negative consequences for the patient's survival (Comparative Analisis of Limph Node Metastasis in Patients UIT ypT0-2 Rectal Cancers. Park et al. Disease of the Colon and Rectum. Volume 56: 2 (2013). Here, it is necessary to insist onthe factthat, just as theprimary treatment of nodemetastases in CRCmust spread as much as possible (total mesorectal excision, or TME); in the case of patients who have undergone neoadjuvant treatment with chemotherapy it is also essential to perform a TME.

The studies that want to ensure the diagnosis of node involvement have researched the presence of micrometastases or metastases that have been diagnosed with immunohistochem‐ ical techniques in patients in stages I and II (that is, without node involvement in microscopical terms), and they have found that the presence of micrometastases in these patients does not affect the prognosis and must not be taken into account when treating CRC (Are Lymph Node Micrometastases of any Clinical Significance in Dukes Stages A and B Colorectal Cancer? Oberg et al. Dis Colon Rectum, October 1998 ol. 41, No. 10 1244-1249).

### **3.2. Sentinel lymph node**

and the internal iliac system, and that the inferior rectal system depends on the internal and

On the other hand, there are evidences that show that there are factors of the tumor cells which increase angiogenesis and lymphomagenesis, and which lead to an increased rate of node metastasis and a worse prognosis. Specifically, vascular endothelial growth factor C (VEGF-C) and cyclooxygenase-2 (COX-2) (Coexpression of VEGF-C and Cox-2 in Human Colorectal Cancer and its Association With Lymph Node Metastasis Soumaoro et al. Dis Colon Rectum,

Node involvement plays a fundamental role in the correct definition of the extent of tumor spread, together with the depth of the involvement through the wall of the colon or the rectum, the size of the tumor or the presence of metastases. The number of involved nodes and their distance to the tumor is the basis of some classic classifications, such as Dukes, Astler and Coller and the more modern TNM, whose description is already analyzed elsewhere. All decisions on the treatment must be adopted with reference to the TNM classification, instead of the old Dukes system or the modified Astler-Coller staging system (Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York,

Given the importance of the whole number of involved nodes in a proper staging and in order to obtain a reliable and comparable prognosis, it is necessary to establish a set of minimum quality criteria for lymphadenectomy. Otherwise, the scenario might be undervalued. Patients in stage I or II (that is, without node involvement) show five-year survival rates of 75%; in contrast to survival rates with N1, which are only 45-60%. Also, the higher the number of nodes studied by the pathologist (and indirectly, resected by the surgeon), the higher the staging accuracy; if that number is low, there is an undervaluing of the tumor dissemination state. (Staging accuracy in colorectal carcinoma. Wong et al. Journal of Clinical Oncology. Vol 17. nº

A panel sponsored by the American Joint Committee on Cancer (AJCC) and the National Cancer Institute of the USA and presented at the World Conference on Gastroenterology of Sydney in 1990 (J. Gastroenterol Heptol 6:325-244. 1991) has recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer in order to confirm the lack of node involvement due to the tumor. Wong et al. recommend at least the analysis of 14 nodes

There is a special situation with stagingpatients withrectal cancer andneoadjuvant chemother‐ apywithypT0-2.Inthesecases, stagingbasedonthe surgical specimenusuallyshowsadecrease in size and in the involvement of the wall of the intestine of the tumor, but if this is taken into account together with the reduction in the number of existing nodes in the specimen re‐ moved from the rectum, it could lead to an undervaluing with negative consequences for the patient's survival (Comparative Analisis of Limph Node Metastasis in Patients UIT ypT0-2 Rectal Cancers. Park et al. Disease of the Colon and Rectum. Volume 56: 2 (2013). Here, it is necessary to insist onthe factthat, just as theprimary treatment of nodemetastases in CRCmust spread as much as possible (total mesorectal excision, or TME); in the case of patients who have undergone neoadjuvant treatment with chemotherapy it is also essential to perform a TME.

external iliac system.

198 Colorectal Cancer - Surgery, Diagnostics and Treatment

March 2006 392-398).

NY: Springer, 2010, pp 143-64).

9 1999pp2896-2900).

in pT2 and pT3 tumors.

In tumors with a metastasis that takes place through the lymphatic system (breast cancer and melanoma, mainly), there has been a great success in mapping the dissemination of the primary tumor with the so called sentinel lymph node biopsy technique. In view of this situation, several studies have started to analyze it, because lymphadenectomy is an important part in the primary treatment of CRC, both from the staging point of view and in order to prevent recurrence of the tumor if there are infiltrated lymph nodes left. Having a map of lymph dissemination similar to the one obtained with breast cancer would mean knowing the minimum required level of lymphadenectomy, or even of visceral resection. This would allow the medical team to apply an adequate surgical treatment from an oncological perspective but with the minimum morbidity and mortality. Unfortunately, it does not seem that this technique shows reliable results with colorectal cancer ("Técnica del ganglio centinela…". Sardon Ramos et al. CIR ESP. 2013 91(6) 366-371.1).

The identification of the sentinel lymph node shows a low sensitivity in the detection of metastasis and micrometastasis. Approximately one half of the adenopathies are lost if a lymphadenectomy is performed based on the results of the sentinel lymph node study. Faerden et al: sentinel node mapping in colonic cancer Disease of the colon & rectum. Volume 51: 891–896 (2008).

#### **3.3. Treatment of lymphatic metastasis**

Treatment of lymphatic metastasis, given its close relation with the growth of the primary tumor, is the same as for the original lesion: primary resection with exeresis of the nodes of the lymphatic area that drain the tumor. If there is a tumor recurrence in the nodes, the patient is classified as stage IV, which means that there will be the corresponding treatment: chemo‐ therapy and surgery and radiotherapy, which will be provisionally palliative.

#### **4. Bone metastases**

#### **4.1. Introduction**

Bone metastases from colorectal cancer are uncommon (10-23% in autopsy cases). They usually appear late in the natural history of metastatic disease and are associated with liver or lung metastasis. Acrometastasis is reported to be 0.3-3% of all bone metastases. Cancers of the rectum and cecum are accompanied by bone metastasis more frequently than cancers of other portions of the colon. Signet ring cell carcinoma shows a high incidence of bone metastasis.

**c.** *Symptoms derived from the metastatic disease*: Regardless of the symptoms that metastases

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**a.** PAIN in the affected area, or referred pain, which may be of insidious, and either progressive or sudden onset, and it may be slight and intermittent or continuous and activity-related. Night pain is a typical symptom, and it does not always disappear with oral analgesics, unlike the pain that derives from degenerative processes, such as osteo‐ arthritis, which increases with loads and articular mobility. When pain affects a long bone, it is easily located by the patient, but when it affects the pelvis or the spinal column, the pain makes it difficult to properly locate the lesion. When it affects the femur or the tibia (load-bearing bones), patients report pain when walking, although the pain usually appears when the bone destruction levels are over 50% and they indicate an imminent

**b.** SWELLING: It may be a sign of lesion aggressiveness when the tumor invades the cortical bone and affects soft tissue. This presentation is characteristic from colorectal carcinoma,

**c.** FUNCTIONAL DEFICIT: it appears as a consequence of pain. It may be a result of a

**d.** IMMINENT FRACTURE: It is a fracture that can appear as a result of a physiological load. Anamnesis and plain X-ray are necessary for the diagnosis, and the cortical involvement, the location and characteristics of the lesion (lytic, sclerotic or mixed) and the existence of fracture lines must be assessed. Permeating and lytic lesions of the proximal third of the femur are prone to fractures. Pain after radiation is also a sign of an imminent fracture. In cases in which an imminent fracture is expected on an active patient, a prophylactic

In the context of colorectal carcinoma, bone metastases normally appear when the disease is already in an advanced stage (with metastases on other areas), and when the diagnosis has already been established. For this reason, a histological diagnosis is not usually necessary, and a treatment can be planned in advance. However, we must also take into account the fact that in 1-2% of the cases, the osteolytic lesion is unrelated to the primary tumor, which means that

**1.** COMPLETE BLOOD COUNT: Anemia, leukopenia or thrombocytopenia may be a sign

medullary or radicular involvement in the case of spinal metastases.

fixation is recommended, especially in load-bearing bones.

Including the thyroid gland, breasts, lungs and digestive system.

**2.** ESR: High levels may indicate a myeloma or an active process.

may produce on other regions, bone metastases can lead to:

fracture.

renal carcinoma and melanoma.

**4.4. Diagnostic assessment**

a biopsy is advisable.

*4.4.2. Laboratory analyses*

*4.4.1. Complete physical examination*

of medullary involvement.

Pain is the most common symptom of bone metastasis. As a result of the loss of bone density affected bones become prone to fracture and injury.

Testing for bone metastasis includes X-ray and bone scanning. Open biopsy is necessary to establish the diagnosis, exclude osteomyelitis and allow treatment. Early diagnosis is impor‐ tant for improving quality of life in these patients.

Therapeutic management of this condition includes chemotherapy, radiotherapy and surgery, but because survival after onset of bone metastasis is very poor, palliative treatment is the main objective.

#### **4.2. Physiopathology**

Bone destruction secondary to metastasis is not caused by the tumor cells, but by the activation of the osteoclasts. The tumor cells secrete an osteoclast activating factor, and the osteoclasts induce the loss of cortical bone and trabecular bone. This process is divided in four stages (Mundy & Yoneda, 1995):


Clohisy et al. have described four mechanisms that stimulate osteoclast-mediated bone destruction (Clohisy et al., 2000):


#### **4.3. Clinical presentation**


#### **4.4. Diagnostic assessment**

rectum and cecum are accompanied by bone metastasis more frequently than cancers of other portions of the colon. Signet ring cell carcinoma shows a high incidence of bone metastasis.

Pain is the most common symptom of bone metastasis. As a result of the loss of bone density

Testing for bone metastasis includes X-ray and bone scanning. Open biopsy is necessary to establish the diagnosis, exclude osteomyelitis and allow treatment. Early diagnosis is impor‐

Therapeutic management of this condition includes chemotherapy, radiotherapy and surgery, but because survival after onset of bone metastasis is very poor, palliative treatment is the main

Bone destruction secondary to metastasis is not caused by the tumor cells, but by the activation of the osteoclasts. The tumor cells secrete an osteoclast activating factor, and the osteoclasts induce the loss of cortical bone and trabecular bone. This process is divided in four stages

**1.** The tumor cells adhere to the basement membrane (laminin, E-cadherin, integrins).

**2.** The tumor cells produce proteolytic enzymes that damage the basement membrane.

**4.** The tumor cells can stimulate the activity of the osteoclasts.

**a.** Stimulation of the union between the osteoclasts and the bone.

**d.** Acceleration of the production of osteoclasts by precursor cells.

**b.** Stimulation of the osteoclast-mediated bone resorption.

**c.** Extension of the survival time of osteoclasts.

**3.** The tumor cells migrate via the basement membrane under the specific control of

Clohisy et al. have described four mechanisms that stimulate osteoclast-mediated bone

**a.** *Constitutional symptoms*: Some patients report anorexia, nausea, vomiting, asthenia,

**b.** *Symptoms derived from the primary location*: Colorectal carcinoma usually presents itself accompanied by an alteration of the intestinal rhythm and by the expulsion of blood originated in the rectum. In advanced stages of the disease, the patient presents consti‐ pation, and a transabdominal mass can be perceived on palpation. A rectal examination needs to be performed, because tumors of the lower part of the rectum can be easily found.

affected bones become prone to fracture and injury.

200 Colorectal Cancer - Surgery, Diagnostics and Treatment

tant for improving quality of life in these patients.

objective.

**4.2. Physiopathology**

(Mundy & Yoneda, 1995):

chemotactic factors.

destruction (Clohisy et al., 2000):

**4.3. Clinical presentation**

malaise, and weight loss.

In the context of colorectal carcinoma, bone metastases normally appear when the disease is already in an advanced stage (with metastases on other areas), and when the diagnosis has already been established. For this reason, a histological diagnosis is not usually necessary, and a treatment can be planned in advance. However, we must also take into account the fact that in 1-2% of the cases, the osteolytic lesion is unrelated to the primary tumor, which means that a biopsy is advisable.

#### *4.4.1. Complete physical examination*

Including the thyroid gland, breasts, lungs and digestive system.

#### *4.4.2. Laboratory analyses*


**3.** ELECTROPHORESIS OF SERUM PROTEINS: They can show a monoclonal gammopathy and they can confirm a possible myeloma diagnosis.

are easy to use. The orthopaedic surgeon must choose the exact location, taking into account the location of the lesion, viable access routes and, whenever possible, the final incision line of the operation, in case of resection surgery, excising the entire area of the biopsy, because it

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When finding certain locations (usually on the pelvis), a CT scan may be necessary in order to identify the best point and route of access that will reach the metastatic area and to avoid

If colorectal carcinoma presents itself with a bone metastasis and the lesion is biopsied, the biopsy may not always provide a diagnosis for the primary tumor, because a tissue compatible with adenocarcinoma does not always tell the difference between primary tumors of the

Around 70% of all patients with a bone metastasis report pain at some point along the course of the disease. The physiopathological pain may be due to medullary compression, distension of the periosteum or peripheral neurovascular involvement, as well as to pathological fractures, whenever they are present and mediated by substances such as histamine, substance

Metastatic osteolysis is caused by the stimulation of osteoclast activity. For this reason, bisphosphonates can play an important role in this process, because they inhibit the osteoclast activity. They bind with the mineral bone matrix and they have a great physicochemical impact

Some authors have suggested that they are not only useful in the treatment of pain and the prevention of osteolytic complications, but that they can also modify the natural course of evolution of cancer in some cases, due to the effect they have on some intermediate products,

Ross et al. carried out a systematic review of all randomized essays on patients with bone metastasis. It is a meta-analysis based on 18 randomized studies in which different bisphosph‐ onates have been compared with a placebo or between themselves. Most of these studies were performed on patients with breast carcinoma (Ross et al, 2004). The review showed a decrease in the incidence and an increase in the time until the appearance of bone complications, with a better evolution of pain and functional capacity, with regard to the control group who received a placebo. Treatment with oral bisphosphonates (clodronate, etidronate) caused a decrease in the number of spinal and non-spinal fractures, but it had no effect on the indications

regions with reactive sclerotic bone, because these parts may not have tumor cells.

might be contaminated.

**4.5. Supportive measures**

*4.5.1. Analgesic therapy*

P or other cytokines.

*4.5.2. Bisphosphonates*

on the hydroxyapatite crystals.

of radiotherapy or in hypercalcaemia.

such as growth factors.

digestive system, prostate, breast and lung.


#### *4.4.3. Imaging tests*


Data from the clinical record, an exhaustive physical examination, blood tests and imaging tests identify more than 85% of all the primary tumors that appear as a bone metastasis. The following tests could also be performed, albeit only when required:


#### *4.4.4. Biopsy*

Puncture biopsy is an excellent way to confirm a diagnosis of bone metastasis. CT-guided fineneedle aspiration and thick- or trephine-needle biopsies are very precise techniques, and they are easy to use. The orthopaedic surgeon must choose the exact location, taking into account the location of the lesion, viable access routes and, whenever possible, the final incision line of the operation, in case of resection surgery, excising the entire area of the biopsy, because it might be contaminated.

When finding certain locations (usually on the pelvis), a CT scan may be necessary in order to identify the best point and route of access that will reach the metastatic area and to avoid regions with reactive sclerotic bone, because these parts may not have tumor cells.

If colorectal carcinoma presents itself with a bone metastasis and the lesion is biopsied, the biopsy may not always provide a diagnosis for the primary tumor, because a tissue compatible with adenocarcinoma does not always tell the difference between primary tumors of the digestive system, prostate, breast and lung.

#### **4.5. Supportive measures**

#### *4.5.1. Analgesic therapy*

**3.** ELECTROPHORESIS OF SERUM PROTEINS: They can show a monoclonal gammopathy

**5.** ALKALINE PHOSPHATASE: It shows high levels in cases of advanced metastatic

**6.** CARCINOEMBRYONIC ANTIGEN: Its levels are high in digestive or hepatocellular

**8.** HEPATIC ENZYMES AND SERUM ELECTROLYTES: They can show bone and liver

**1.** ANTEROPOSTERIOR AND LATERAL X-RAYS OF THE LESION: In order to assess an

**3.** THORACIC AND ABDOMINAL CT SCAN: In order to assess the existence of possible

Data from the clinical record, an exhaustive physical examination, blood tests and imaging tests identify more than 85% of all the primary tumors that appear as a bone metastasis. The

**•** NMR: It is seldom recommended in cases of isolated bone lesions (fig. 1), but it may be useful in cases of a single metastasis in which a resection can be performed, in order to rule out *skip metastases* or metastases inside the bone and on the vertebrae, due to its excellent

**•** POSITRON EMISSION TOMOGRAPHY (PET): This imaging technique is becoming more and more important in the field of orthopaedic oncology. It uses [18F]2-fluoro-2-deoxy-Dglucose (FDG) as a tracer. This is a glucose analog which is taken to the cells by a group of proteins. This marker is absorbed by malignant tissue with an increased metabolic activity. PET scans have a very high sensitivity, and it is an important technique for the identification of primary lesions and other metastases. It can establish the difference between a local recurrence and a scar, and it is also useful in the assessment of response to

Puncture biopsy is an excellent way to confirm a diagnosis of bone metastasis. CT-guided fineneedle aspiration and thick- or trephine-needle biopsies are very precise techniques, and they

**2.** THORACIC X-RAY: In order to see the existence of carcinoma or lung metastases.

and they can confirm a possible myeloma diagnosis.

202 Colorectal Cancer - Surgery, Diagnostics and Treatment

carcinomas.

involvement.

visceral metastases.

*4.4.3. Imaging tests*

treatment.

*4.4.4. Biopsy*

**4.** BIOCHEMICAL ANALYSIS: It can rule out hyperparathyroidism.

disease. Very high levels show an unfavourable prognostic factor.

**7.** PROSTATE-SPECIFIC ANTIGEN: It can detect a prostate carcinoma.

imminent fracture and to analyse the information they provide.

**4.** Tc99m BONE SCINTIGRAPHY: In order to assess bone lesions.

following tests could also be performed, albeit only when required:

properties for the exploration of the bone marrow.

Around 70% of all patients with a bone metastasis report pain at some point along the course of the disease. The physiopathological pain may be due to medullary compression, distension of the periosteum or peripheral neurovascular involvement, as well as to pathological fractures, whenever they are present and mediated by substances such as histamine, substance P or other cytokines.

#### *4.5.2. Bisphosphonates*

Metastatic osteolysis is caused by the stimulation of osteoclast activity. For this reason, bisphosphonates can play an important role in this process, because they inhibit the osteoclast activity. They bind with the mineral bone matrix and they have a great physicochemical impact on the hydroxyapatite crystals.

Some authors have suggested that they are not only useful in the treatment of pain and the prevention of osteolytic complications, but that they can also modify the natural course of evolution of cancer in some cases, due to the effect they have on some intermediate products, such as growth factors.

Ross et al. carried out a systematic review of all randomized essays on patients with bone metastasis. It is a meta-analysis based on 18 randomized studies in which different bisphosph‐ onates have been compared with a placebo or between themselves. Most of these studies were performed on patients with breast carcinoma (Ross et al, 2004). The review showed a decrease in the incidence and an increase in the time until the appearance of bone complications, with a better evolution of pain and functional capacity, with regard to the control group who received a placebo. Treatment with oral bisphosphonates (clodronate, etidronate) caused a decrease in the number of spinal and non-spinal fractures, but it had no effect on the indications of radiotherapy or in hypercalcaemia.

#### *4.5.3. Treatment of hypercalcaemia*

Hypercalcaemia affects 10-40% of cancer patients at some point, and it causes anorexia, nausea, vomiting, polydipsia, polyuria, dehydration, constipation, confusion and coma.

**5. Brain metastases**

(from 6 to 7 to approximately 24 months).

**•** Cerebral hemispheres — approximately 80 percent

poor, despite aggressive treatment.

**•** Cerebellum — 15 percent

**•** Brainstem — 5 percent

**5.1. Clinical presentation**

posterior fossa.

depend upon the location of the metastases.

The increasing incidence of brain metastases in patients with metastatic colorectal cancer has been attributed to the longer survival rates seen with newer systemic therapies. Compared to the era when 5-fluorouracil was the primary agent for metastatic disease, median survival has increased markedly with the introduction of oxaliplatin, irinotecan, and biologic therapies

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However, the incidence of brain metastases in metastatic colorectal cancer is still low, 2.3 percent in one of the series. Brain metastases are usually a late-stage phenomenon, and the vast majority of patients have metastases in other sites, particularly the lung. Outcomes are

The most common mechanism of metastasis to the brain is by hematogenous spread. Meta‐ stases are usually located directly at the junction of the gray matter and white matter where blood vessels decrease in diameter and act as a trap for clumps of tumor cells. Brain metastases also tend to be more common at the terminal "watershed areas" of arterial circulation. The distribution of metastases roughly follows the relative weight and blood flow in each area:

Different primary tumors may have a predilection for metastasis to different areas within the

Brain metastases have highly variable clinical features and should be suspected in any cancer patient who develops neurologic symptoms or behavioural abnormalities. However, multiple other causes can also be responsible. In the majority of patients, a gradually expanding tumor mass and its associated edema cause symptoms. Less commonly, intratumoral hemorrhage,

Headache: Headaches occur in approximately 40 to 50 percent of patients with brain metasta‐ ses. The frequency is higher when multiple lesions are present or a metastasis is located in the

Focal neurologic dysfunction: Focal neurologic dysfunction is the presenting symptom of 20 to 40 percent of patients. Hemiparesis is the most common complaint but the manifestations

Cognitive dysfunction: Cognitive dysfunction, including memory problems and mood or

brain. Gastrointestinal tumors more commonly metastasize to the posterior fossa.

obstructive hydrocephalus, or embolization by tumor cells result in symptoms.

personality changes, is the presenting problem in 30 to 35 percent of patients.

It is the result of PTHrP production, which activates bone metabolism and induces an excess of osteoclast activity. Osteoclasts are then stimulated by local factors produced by tumor cells, such as interleukin 6. Moreover, calcium levels are also increased due to lower levels of renal calcium elimination, because PTHrP acts on the renal receptors of the parathyroid hormone and it increases calcium resorption on the renal tubule. Polyuria and reduction of intravascular volume appear as a consequence, and for this reason, the initial treatment with these patients is rehydration with intravenous saline serum in order to balance the intravascular volume and to improve glomerular filtration and renal secretion of calcium.

Calcitonin inhibits osteoclasts and it has a rapid effect, although for a brief period of time. For this reason, it is mainly used in emergency treatments.

Plicamycin normalizes calcium levels in up to 50% of the cases, but its serious adverse effects make it unadvisable to use it.

#### **4.6. Non-surgical treatment**

#### *4.6.1. Treatment of metastatic bone disease secondary to colorectal carcinoma*

The treatment of bone metastases derived from colorectal tumors is the same as the treatment for other metastases caused by other tumors. Surgical resection of the primary tumor, together with chemotherapy and radiotherapy for the rectal cancer is the treatment of choice, depending on the cases.

#### *4.6.2. Radiotherapy*

Radiotherapy is the most widely used palliative treatment for bone metastasis. It is the treatment of choice for painful lytic bone metastases without short-term risk of fracture, and it is combined with surgery when there is an imminent fracture or when the fracture has already taken place. It leads to the necrosis of tumor cells, which makes it possible for the bone tissue to regenerate afterwards. The result is pain relief and, later on, a re-calcification of the destroyed areas of the bone, which is important for the functional recovery of the patient and the prevention of pathological fractures.

#### *4.6.3. Surgical treatment*

Surgery for bone metastases requires a previous complete general and local assessment. It presents its own indications, objectives, techniques and means, and it is associated to a program for postoperative radiotherapy that follows the lines that have been previously described.

## **5. Brain metastases**

*4.5.3. Treatment of hypercalcaemia*

204 Colorectal Cancer - Surgery, Diagnostics and Treatment

make it unadvisable to use it.

**4.6. Non-surgical treatment**

on the cases.

*4.6.2. Radiotherapy*

*4.6.3. Surgical treatment*

the prevention of pathological fractures.

Hypercalcaemia affects 10-40% of cancer patients at some point, and it causes anorexia, nausea,

It is the result of PTHrP production, which activates bone metabolism and induces an excess of osteoclast activity. Osteoclasts are then stimulated by local factors produced by tumor cells, such as interleukin 6. Moreover, calcium levels are also increased due to lower levels of renal calcium elimination, because PTHrP acts on the renal receptors of the parathyroid hormone and it increases calcium resorption on the renal tubule. Polyuria and reduction of intravascular volume appear as a consequence, and for this reason, the initial treatment with these patients is rehydration with intravenous saline serum in order to balance the intravascular volume and

Calcitonin inhibits osteoclasts and it has a rapid effect, although for a brief period of time. For

Plicamycin normalizes calcium levels in up to 50% of the cases, but its serious adverse effects

The treatment of bone metastases derived from colorectal tumors is the same as the treatment for other metastases caused by other tumors. Surgical resection of the primary tumor, together with chemotherapy and radiotherapy for the rectal cancer is the treatment of choice, depending

Radiotherapy is the most widely used palliative treatment for bone metastasis. It is the treatment of choice for painful lytic bone metastases without short-term risk of fracture, and it is combined with surgery when there is an imminent fracture or when the fracture has already taken place. It leads to the necrosis of tumor cells, which makes it possible for the bone tissue to regenerate afterwards. The result is pain relief and, later on, a re-calcification of the destroyed areas of the bone, which is important for the functional recovery of the patient and

Surgery for bone metastases requires a previous complete general and local assessment. It presents its own indications, objectives, techniques and means, and it is associated to a program for postoperative radiotherapy that follows the lines that have been previously described.

vomiting, polydipsia, polyuria, dehydration, constipation, confusion and coma.

to improve glomerular filtration and renal secretion of calcium.

*4.6.1. Treatment of metastatic bone disease secondary to colorectal carcinoma*

this reason, it is mainly used in emergency treatments.

The increasing incidence of brain metastases in patients with metastatic colorectal cancer has been attributed to the longer survival rates seen with newer systemic therapies. Compared to the era when 5-fluorouracil was the primary agent for metastatic disease, median survival has increased markedly with the introduction of oxaliplatin, irinotecan, and biologic therapies (from 6 to 7 to approximately 24 months).

However, the incidence of brain metastases in metastatic colorectal cancer is still low, 2.3 percent in one of the series. Brain metastases are usually a late-stage phenomenon, and the vast majority of patients have metastases in other sites, particularly the lung. Outcomes are poor, despite aggressive treatment.

The most common mechanism of metastasis to the brain is by hematogenous spread. Meta‐ stases are usually located directly at the junction of the gray matter and white matter where blood vessels decrease in diameter and act as a trap for clumps of tumor cells. Brain metastases also tend to be more common at the terminal "watershed areas" of arterial circulation. The distribution of metastases roughly follows the relative weight and blood flow in each area:


Different primary tumors may have a predilection for metastasis to different areas within the brain. Gastrointestinal tumors more commonly metastasize to the posterior fossa.

#### **5.1. Clinical presentation**

Brain metastases have highly variable clinical features and should be suspected in any cancer patient who develops neurologic symptoms or behavioural abnormalities. However, multiple other causes can also be responsible. In the majority of patients, a gradually expanding tumor mass and its associated edema cause symptoms. Less commonly, intratumoral hemorrhage, obstructive hydrocephalus, or embolization by tumor cells result in symptoms.

Headache: Headaches occur in approximately 40 to 50 percent of patients with brain metasta‐ ses. The frequency is higher when multiple lesions are present or a metastasis is located in the posterior fossa.

Focal neurologic dysfunction: Focal neurologic dysfunction is the presenting symptom of 20 to 40 percent of patients. Hemiparesis is the most common complaint but the manifestations depend upon the location of the metastases.

Cognitive dysfunction: Cognitive dysfunction, including memory problems and mood or personality changes, is the presenting problem in 30 to 35 percent of patients.

Seizures: New onset of seizures is the presenting symptom in 10 to 20 percent of patients. Seizures in patients with brain metastases are almost exclusively associated with supratento‐ rial disease.

bilateral lesions, solid and bulbous, and they have a gastrointestinal origin in more than 90% of the cases. Although the form of presentation and the treatment are not different from the rest of metastatic ovarian lesions secondary to a primary tumor with a digestive origin, the prognosis is worse. It has been proven that a combined therapy of radical surgery and

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Colorectal cancer is a pathological process that spreads through the lymphatic channels through hematogenous ways and through the invasion of the intestine wall. These mechanisms result in metastases to the lymph nodes, liver and also peritoneal dissemination. Although the spread to the lymph and venous systems implies the existence of a local invasive process, peritoneal dissemination can appear in tumors with high as well as low malignancy. The dissemination of the cancer that leads to liver and lymph node metastases takes place before the surgical resection of the primary colorectal neoplasm. Peritoneal dissemination, as well as dissemination in the resection area (local recurrence) can also take place as a result of the surgical trauma associated to the resection of the primary neoplasm. The filtration of malignant cells through the severed lymph channels can also be a mechanism in this intraoperative phenomenon of cancer dissemination. Dissemination inside the peritoneal cavity is one of the most severe forms of carcinomatous dissemination from the colon, because it rapidly takes away —provisionally— all hope for a surgical resection of the lesion. Together with lymphatic and hematogenous dissemination, transcoelomic spread is one of the routes of tumor dissem‐ ination. In the early stages of peritoneal invasion, transcoelomic spread may be limited to the neighbouring structures just around the primary tumor, with a potential development of isolated carcinoid plaques in the adjacent peritoneum. It is of course a possibility that some of these nodes are not originated in a transperitoneal spread but in a dissemination of the subperitoneal lymph nodes, as Miles proposes (1926). In a later stage, peritoneal metastases spread until there is a diffuse peritoneal carcinomatosis in which there are tumor nodes that spread through the entire parietal peritoneum, greater omentum and adjacent viscera, and abundant ascites appears (Cirugía del ano, recto y colon. John Golligher 2ª edición). For Hara (Hara *et al*. Comparative analysis of intraperitoneal minimal free cancer cells between color‐ ectal and gastric cancer patients using quantitative RT-PCR: possible reason for rare peritoneal recurrence in colorectal cancer. Clin Exp Metastasis 2007;24:179–89), peritoneal metastases take place in two stages: first of all, the tumor cells detach themselves from the serosal surface of the primary tumor and are transported in the peritoneal cavity, and in the second stage, malignant cells in the peritoneum adhere to places like the omentum and the mesenterium,

radiochemotherapy can achieve a slight improvement in long-term survival rates.

and they grow and spread through the peritoneal cavity afterwards.

Four characteristics have been identified as risk factors for tumor cell exfoliation in the peritoneal cavity: 1. Depth of the invasion, 2. Involvement of lymph nodes, 3. Lymph node

**7. Peritoneum metastases**

**7.1. Definition and physiopathology**

Stroke: Another 5 to 10 percent present acutely due to stroke caused by hemorrhage into a metastasis, hypercoagulability, invasion or compression of an artery by tumor, or embolization of tumor cells.

#### **5.2. Diagnosis**

Imaging studies provide useful information but brain biopsy is necessary in some cases for a definitive diagnosis.

Contrast-enhanced MRI is the preferred imaging study for the diagnosis of brain metastases.

Biopsy should be performed when the diagnosis of brain metastases is in doubt. This is particularly important in patients with a single lesion.

Positron emission tomography (PET) may also be useful in these patients by finding other sites of metastatic disease.

#### **5.3. Treatment**

Patients with BM from CRC have a poor prognosis, because they often have substantial extracranial metastatic disease.

Traditionally, the therapeutic goal in many of these patients has been to palliate debilitating neurologic symptoms, because most of these patients die of systemic disease. However, new advances in metastatic CRC management—including the incorporation of monoclonal antibody therapies bevacizumab, cetuximab, and panitumumab— are enhancing the out‐ comes of patients with systemic disease.

## **6. Ovarian metastases**

Isolated ovarian metastases from primary CRC occur with a low frequency. The incidence of ovarian metastases (synchronous or metachronous) in patients with CRC is 1 to 14 percent. Bulky ovarian metastases are often symptomatic and less responsive to systemic chemother‐ apy than are other sites of disease. Resection is associated with fairly low morbidity and, in some cases, may improve quality of life and prolong survival, even in the setting of widespread extraovarian metastatic disease. There is a debate regarding prophylactic oophorectomy at the time of curative resection for primary CRC.

There is a rare variety of ovarian metastasis known as Krukenberg tumor (KT), which has been the focus of extensive research due to its poor prognosis. Although the age range of patients is highly variable, KT usually appears in premenopausal women, and for some authors, the diagnosis of primary tumor after KT is a factor for poor prognosis. They are usually large bilateral lesions, solid and bulbous, and they have a gastrointestinal origin in more than 90% of the cases. Although the form of presentation and the treatment are not different from the rest of metastatic ovarian lesions secondary to a primary tumor with a digestive origin, the prognosis is worse. It has been proven that a combined therapy of radical surgery and radiochemotherapy can achieve a slight improvement in long-term survival rates.

### **7. Peritoneum metastases**

Seizures: New onset of seizures is the presenting symptom in 10 to 20 percent of patients. Seizures in patients with brain metastases are almost exclusively associated with supratento‐

Stroke: Another 5 to 10 percent present acutely due to stroke caused by hemorrhage into a metastasis, hypercoagulability, invasion or compression of an artery by tumor, or embolization

Imaging studies provide useful information but brain biopsy is necessary in some cases for a

Contrast-enhanced MRI is the preferred imaging study for the diagnosis of brain metastases.

Biopsy should be performed when the diagnosis of brain metastases is in doubt. This is

Positron emission tomography (PET) may also be useful in these patients by finding other sites

Patients with BM from CRC have a poor prognosis, because they often have substantial

Traditionally, the therapeutic goal in many of these patients has been to palliate debilitating neurologic symptoms, because most of these patients die of systemic disease. However, new advances in metastatic CRC management—including the incorporation of monoclonal antibody therapies bevacizumab, cetuximab, and panitumumab— are enhancing the out‐

Isolated ovarian metastases from primary CRC occur with a low frequency. The incidence of ovarian metastases (synchronous or metachronous) in patients with CRC is 1 to 14 percent. Bulky ovarian metastases are often symptomatic and less responsive to systemic chemother‐ apy than are other sites of disease. Resection is associated with fairly low morbidity and, in some cases, may improve quality of life and prolong survival, even in the setting of widespread extraovarian metastatic disease. There is a debate regarding prophylactic oophorectomy at the

There is a rare variety of ovarian metastasis known as Krukenberg tumor (KT), which has been the focus of extensive research due to its poor prognosis. Although the age range of patients is highly variable, KT usually appears in premenopausal women, and for some authors, the diagnosis of primary tumor after KT is a factor for poor prognosis. They are usually large

rial disease.

206 Colorectal Cancer - Surgery, Diagnostics and Treatment

of tumor cells.

**5.2. Diagnosis**

definitive diagnosis.

of metastatic disease.

extracranial metastatic disease.

**6. Ovarian metastases**

comes of patients with systemic disease.

time of curative resection for primary CRC.

**5.3. Treatment**

particularly important in patients with a single lesion.

#### **7.1. Definition and physiopathology**

Colorectal cancer is a pathological process that spreads through the lymphatic channels through hematogenous ways and through the invasion of the intestine wall. These mechanisms result in metastases to the lymph nodes, liver and also peritoneal dissemination. Although the spread to the lymph and venous systems implies the existence of a local invasive process, peritoneal dissemination can appear in tumors with high as well as low malignancy. The dissemination of the cancer that leads to liver and lymph node metastases takes place before the surgical resection of the primary colorectal neoplasm. Peritoneal dissemination, as well as dissemination in the resection area (local recurrence) can also take place as a result of the surgical trauma associated to the resection of the primary neoplasm. The filtration of malignant cells through the severed lymph channels can also be a mechanism in this intraoperative phenomenon of cancer dissemination. Dissemination inside the peritoneal cavity is one of the most severe forms of carcinomatous dissemination from the colon, because it rapidly takes away —provisionally— all hope for a surgical resection of the lesion. Together with lymphatic and hematogenous dissemination, transcoelomic spread is one of the routes of tumor dissem‐ ination. In the early stages of peritoneal invasion, transcoelomic spread may be limited to the neighbouring structures just around the primary tumor, with a potential development of isolated carcinoid plaques in the adjacent peritoneum. It is of course a possibility that some of these nodes are not originated in a transperitoneal spread but in a dissemination of the subperitoneal lymph nodes, as Miles proposes (1926). In a later stage, peritoneal metastases spread until there is a diffuse peritoneal carcinomatosis in which there are tumor nodes that spread through the entire parietal peritoneum, greater omentum and adjacent viscera, and abundant ascites appears (Cirugía del ano, recto y colon. John Golligher 2ª edición). For Hara (Hara *et al*. Comparative analysis of intraperitoneal minimal free cancer cells between color‐ ectal and gastric cancer patients using quantitative RT-PCR: possible reason for rare peritoneal recurrence in colorectal cancer. Clin Exp Metastasis 2007;24:179–89), peritoneal metastases take place in two stages: first of all, the tumor cells detach themselves from the serosal surface of the primary tumor and are transported in the peritoneal cavity, and in the second stage, malignant cells in the peritoneum adhere to places like the omentum and the mesenterium, and they grow and spread through the peritoneal cavity afterwards.

Four characteristics have been identified as risk factors for tumor cell exfoliation in the peritoneal cavity: 1. Depth of the invasion, 2. Involvement of lymph nodes, 3. Lymph node invasion, and 4. Venous invasion (Peritoneal cytology in colorectal cancer. Noura *et al*: Diseases of the Colon & Rectum. volume 52: 7 2009).

**7.2. Peritoneal cytology**

**7.3. Treatment**

systemic or intraperitoneal chemotherapy.

In this situation, peritoneal cytology before the resection of the primary tumor and, when needed, cytoreduction, is a useful tool to assess the prognosis of the patients (both with and without peritoneal carcinomatosis). And it can also be useful when deciding whether to choose

Management of Non-Hepatic Metastatic Disease in Colorectal Cancer

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209

In a multivariate analysis, peritoneal cytology appears as an independent predictor for survival in patients with tumors pT3 or pT4 (Peritoneal cytology in colorectal cancer. Noura *et al*: Diseases of the Colon & Rectum. volume 52: 7 2009). Patients with negative cytology results show better five-year survival rates in cases in which at least the serosal layer is affected by the tumor than patients with positive results (68% vs. 20.6%). These results are also reflected in the fact that patients with positive cytology results present a higher rate of peritoneal dissemination than patients with negative cytology results. Some patients with macroscopic peritoneal dissemination and negative cytology have been proven to have survived for a long time (more than 10 years, in some cases); whereas patients with peritoneal dissemination and positive cytology results show five-year survival rates close to zero. When the peritoneal cytology results are positive, monitoring has to be particularly careful in order to obtain an early detection of recurrence (Peritoneal Cytology in Colorectal Cancer. Nishikawa et al. Disease of the Colon and Rectum. Volume 52:12 (2009). All these promising results with regard to peritoneal cytology must be included in the evaluation, prognosis and therapeutic approach, and this requires subsequent prospective studies that homogenize the way in which the cytology is performed (technique, staining, etc.) and its inclusion in the different studies, such

as its inclusion in the selection protocols to perform Sugarbaker technique.

Peritoneal carcinomatosis and ascites are usually signs of advanced colorectal cancer, and survival rates, as we have said, are low. However, a more aggressive approach for surgical cytoreduction of the peritoneal disease has been used as in the treatment for ovarian cancer, primary peritoneal cancer and appendicular mucinous tumors such as pseudomyxoma and cystadenocarcinoma, and it shows better results than palliative surgery and conventional chemotherapy by themselves. The extrapolation of these therapies to the treatment of CRC seems inappropriate, because these tumors are biologically different, and they are mainly of a low grade. The arrival of intraperitoneal chemotherapy combined with peritoneal debulking seems to offer an increased survival rate in selected patients with colorectal carcinomatosis. Sugarbaker described in 1995 the surgical techniques that lead, when this is not possible, to a complete resection of the peritoneal neoplastic disease. As in other scenarios of resectable metastatic disease, it is advisable to consolidate the results obtained thanks to surgery with a complementary treatment that eradicates the residual microscopic disease. The intraperitoneal administration of certain cytostatic drugs leads to a higher exposure of the peritoneal surface to the drugs than with the usual systemic administration. The perioperative administration (hypertermia-modulated intraoperative administration and/or early postoperative adminis‐ tration) avoids the difficulties that have been traditionally associated with the intraperitoneal

The identification of these tumor cells with preoperative peritoneal washing cytology can identify those patients at risk of presenting a peritoneal recurrence of the tumor process.

Peritoneal carcinomatosis is a common form of recurrence, and it is frequently the only one, after surgical curative treatment in digestive and gynecological tumors. It is logical to think that the dissemination of tumor cells by the tumor is a common previous mechanism for peritoneal carcinomatosis of abdominal tumors.

There are studies about the mechanisms and incidence of intraperitoneal dissemination of CRC that have contributed to a better comprehension and a different perception of the pathological basis of peritoneal carcinomatosis. Although the incidence rates for the presence of tumor cells during the resection of primary tumors widely vary, the presence of free tumor cells in the peritoneal cavity (similar to the micrometastases in the blood or the bone marrow) is not an independent prognostic factor, and it seems possible that these tumor cells can effectively contribute to the failure of the treatment at an intraperitoneal level. In fact, two studies found a correlation between the presence of free tumor cells in the peritoneal cavity and the recur‐ rence of the tumor in the peritoneal cavity (Peritoneal Carcinomatosis of Colorectal Origin. M.J. Koppe. Ann Surg 2006 Febrero. 243("): 212-222).

Approximately 50% of the patients with CRC stage IV present peritoneal carcinomatosis, and approximately 25% of the patients present a recurrence of their tumor in the peritoneal cavity (peritoneal carcinomatosis), without a clear involvement of the liver or the lungs (Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis in nongynecologic malignancy: a prospective study of prognostic factors. *Cancer*. 1989;63:364–367. Sugarbaker PH, Cunliffe WJ, Belliveau J, et al. Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer. *Semin Oncol*. 1989;16:83–97).

Local or peritoneal metastases are factors that represent a poor prognosis for colorectal cancer (Graf et al, 1991; Mahteme et al, 1996; Shepherd et al, 1997; Assersohn et al, 1999) and their treatment is still an important challenge.

The EVOCAPE study shows an average survival of 5.2 months in patients with peritoneal carcinomatosis of colorectal origin. (Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carci‐ nomatosis from non-gynecologic malignancies: results of the EVOCAPE Multicentric pro‐ spective study. *Cancer*. 2000;88:358–363.).

Patients with peritoneal metastases or locally advanced tumors without distance metastases can benefit from cytoreductive surgery with intraperitoneal chemotherapy (Mahteme et al. British Journal of Cancer (2004) 90 403-407).

The average survival rate for patients with carcinomatosis treated with chemotherapy is around 6-12 months (Gramont er al.2000), although this does not factor the modern therapeutic approaches that include immunomodulating agents, which have not yet been evaluated enough and appeared after the year 2000.

#### **7.2. Peritoneal cytology**

invasion, and 4. Venous invasion (Peritoneal cytology in colorectal cancer. Noura *et al*: Diseases

The identification of these tumor cells with preoperative peritoneal washing cytology can identify those patients at risk of presenting a peritoneal recurrence of the tumor process.

Peritoneal carcinomatosis is a common form of recurrence, and it is frequently the only one, after surgical curative treatment in digestive and gynecological tumors. It is logical to think that the dissemination of tumor cells by the tumor is a common previous mechanism for

There are studies about the mechanisms and incidence of intraperitoneal dissemination of CRC that have contributed to a better comprehension and a different perception of the pathological basis of peritoneal carcinomatosis. Although the incidence rates for the presence of tumor cells during the resection of primary tumors widely vary, the presence of free tumor cells in the peritoneal cavity (similar to the micrometastases in the blood or the bone marrow) is not an independent prognostic factor, and it seems possible that these tumor cells can effectively contribute to the failure of the treatment at an intraperitoneal level. In fact, two studies found a correlation between the presence of free tumor cells in the peritoneal cavity and the recur‐ rence of the tumor in the peritoneal cavity (Peritoneal Carcinomatosis of Colorectal Origin.

Approximately 50% of the patients with CRC stage IV present peritoneal carcinomatosis, and approximately 25% of the patients present a recurrence of their tumor in the peritoneal cavity (peritoneal carcinomatosis), without a clear involvement of the liver or the lungs (Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis in nongynecologic malignancy: a prospective study of prognostic factors. *Cancer*. 1989;63:364–367. Sugarbaker PH, Cunliffe WJ, Belliveau J, et al. Rationale for integrating early postoperative intraperitoneal chemotherapy

Local or peritoneal metastases are factors that represent a poor prognosis for colorectal cancer (Graf et al, 1991; Mahteme et al, 1996; Shepherd et al, 1997; Assersohn et al, 1999) and their

The EVOCAPE study shows an average survival of 5.2 months in patients with peritoneal carcinomatosis of colorectal origin. (Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carci‐ nomatosis from non-gynecologic malignancies: results of the EVOCAPE Multicentric pro‐

Patients with peritoneal metastases or locally advanced tumors without distance metastases can benefit from cytoreductive surgery with intraperitoneal chemotherapy (Mahteme et al.

The average survival rate for patients with carcinomatosis treated with chemotherapy is around 6-12 months (Gramont er al.2000), although this does not factor the modern therapeutic approaches that include immunomodulating agents, which have not yet been evaluated

into the surgical treatment of gastrointestinal cancer. *Semin Oncol*. 1989;16:83–97).

of the Colon & Rectum. volume 52: 7 2009).

208 Colorectal Cancer - Surgery, Diagnostics and Treatment

peritoneal carcinomatosis of abdominal tumors.

M.J. Koppe. Ann Surg 2006 Febrero. 243("): 212-222).

treatment is still an important challenge.

spective study. *Cancer*. 2000;88:358–363.).

British Journal of Cancer (2004) 90 403-407).

enough and appeared after the year 2000.

In this situation, peritoneal cytology before the resection of the primary tumor and, when needed, cytoreduction, is a useful tool to assess the prognosis of the patients (both with and without peritoneal carcinomatosis). And it can also be useful when deciding whether to choose systemic or intraperitoneal chemotherapy.

In a multivariate analysis, peritoneal cytology appears as an independent predictor for survival in patients with tumors pT3 or pT4 (Peritoneal cytology in colorectal cancer. Noura *et al*: Diseases of the Colon & Rectum. volume 52: 7 2009). Patients with negative cytology results show better five-year survival rates in cases in which at least the serosal layer is affected by the tumor than patients with positive results (68% vs. 20.6%). These results are also reflected in the fact that patients with positive cytology results present a higher rate of peritoneal dissemination than patients with negative cytology results. Some patients with macroscopic peritoneal dissemination and negative cytology have been proven to have survived for a long time (more than 10 years, in some cases); whereas patients with peritoneal dissemination and positive cytology results show five-year survival rates close to zero. When the peritoneal cytology results are positive, monitoring has to be particularly careful in order to obtain an early detection of recurrence (Peritoneal Cytology in Colorectal Cancer. Nishikawa et al. Disease of the Colon and Rectum. Volume 52:12 (2009). All these promising results with regard to peritoneal cytology must be included in the evaluation, prognosis and therapeutic approach, and this requires subsequent prospective studies that homogenize the way in which the cytology is performed (technique, staining, etc.) and its inclusion in the different studies, such as its inclusion in the selection protocols to perform Sugarbaker technique.

#### **7.3. Treatment**

Peritoneal carcinomatosis and ascites are usually signs of advanced colorectal cancer, and survival rates, as we have said, are low. However, a more aggressive approach for surgical cytoreduction of the peritoneal disease has been used as in the treatment for ovarian cancer, primary peritoneal cancer and appendicular mucinous tumors such as pseudomyxoma and cystadenocarcinoma, and it shows better results than palliative surgery and conventional chemotherapy by themselves. The extrapolation of these therapies to the treatment of CRC seems inappropriate, because these tumors are biologically different, and they are mainly of a low grade. The arrival of intraperitoneal chemotherapy combined with peritoneal debulking seems to offer an increased survival rate in selected patients with colorectal carcinomatosis. Sugarbaker described in 1995 the surgical techniques that lead, when this is not possible, to a complete resection of the peritoneal neoplastic disease. As in other scenarios of resectable metastatic disease, it is advisable to consolidate the results obtained thanks to surgery with a complementary treatment that eradicates the residual microscopic disease. The intraperitoneal administration of certain cytostatic drugs leads to a higher exposure of the peritoneal surface to the drugs than with the usual systemic administration. The perioperative administration (hypertermia-modulated intraoperative administration and/or early postoperative adminis‐ tration) avoids the difficulties that have been traditionally associated with the intraperitoneal administration of cytostatic drugs (difficulty of access, erratic distribution, pain…), which have been one of the main causes of its poor reception by specialists in medical oncology.

Morbidity rates in the procedure of cytoreduction and HIPEC are around 30% and 60%, and mortality is less than 2%. Logically, covering the logistic needs for intensive care, chemother‐ apy and trained surgeons with an established protocol allow for an adequate morbidity and mortality. This therapy must be applied to patients in whom a complete or almost complete cytoreduction can be achieved. With these conditions, the existing studies (although retro‐ spective) show an important improvement of survival, with some results showing a five-year survival rate of 49% when cytoreduction is complete. (Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. *J Clin*

Management of Non-Hepatic Metastatic Disease in Colorectal Cancer

http://dx.doi.org/10.5772/57487

211

It is possible to apply delayed and repeated intraperitoneal systemic chemotherapy after the cytoreduction with acceptable morbidity rates. It is also possible to administer delayed intraperitoneal chemotherapy in up to 83% of the patients who had previously undergone cytoreduction (Delayed Repeated Intraperotoneal Chemotherapy. Fajardo et al. Diseases of

On the other hand, there are reasons to be optimistic about the use of immunomodulat‐ ing treatments (targeted monoclonal antibodies) which, when combined with other 'traditional' chemotherapeutic approaches, are showing some really promising results. We still need more studies that let us know what conditions lead to a successful outcome (such as the KRAS status of the primary tumor) and also whether they have a beneficial effect in

Chemotherapy and targeted therapies: There are currently eight active and approved drugs for patients with metastatic colorectal cancer which are used separately or combined with other

5-FU, Capecitabine, Irinotecan., Oxaliplatin, Bevacizumab, Cetuximab, Aflibercept and

These chemotherapeutic agents, some of which are monoclonal antibodies, can be combined in different ways and represent an encouraging future for patients with peritoneal metastases

Initial management of the primary site in patients who present with stage IV disease is controversial, and there are no data from prospective randomized studies to guide treatment. In general, the choice and sequence of treatment is guided by the presence or absence of symptoms from the primary tumor and whether or not the metastases are

Surgery provides a potentially curative option for selected patients who present with limited

**Management in patients with unresectable metastatic disease**: systemic and hepatic arterial infusion chemotherapy may be useful treatment options in patients with unresectable disease.

*Oncol*. 2006;24: 4011–409).

peritoneal carcinomatosis.

drugs:

Panitumumab.

potentially resectable.

metastatic colorectal cancer.

Colon and Rectum. Volumen 55.: 10 (2012)).

who were previously called 'terminally ill'.

Other established treatment is radiofrequency ablation.

**7.4. Treatment of metastatic disease**

This way, and after decades of preclinical and clinical efforts, cytoreductive surgery combined with preoperative hyperthermic intraperitoneal chemotherapy (HIPEC) appear in this new century as an indissoluble and feasible multimodal strategy with proven effectiveness in the treatment of selected cases of peritoneal carcinomatosis in colorectal cancer, although, as we have said before, it can also be useful for other tumors (González-Moreno S. Cirugía citore‐ ductora y quimioterapia intraperitoneal perioperatoria para las neoplasias con diseminación peritoneal: ha llegado el momento. Cir Esp. 2005;78(6):341-3)(Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D. Update on chemotherapeutic agents utilized for periopera‐ tive intraperitonealchemotherapy. Oncologist. 2005;10:112-22.)(Treatments and Outcomes of Peritoneal Surface Tumors Through a Centralized National Service (United Kingdom) S. Rout, Diseases Of The Colon & Rectum Volume 52: 10 (2009).

There are protocols for the selection of patients which, among other things, try to establish the mass of the tumor and its location by mapping the abdominal cavity in order to assess the size of the tumor and the possibility of achieving an adequate cytoreduction. Laparoscopy is a technique that is currently included in the treatment protocols when there is suspicion or preoperative evidence of peritoneal carcinomatosis. After obtaining a laparoscopic diagnosis of the affected areas (including images obtained during the process, if possible), the patient is sent to a health centre with experience in cytoreductive surgery and HIPEC in order to assess the procedure (commonly referred to as Sugarbaker technique).

The prognosis and results depend on the level of cytoreduction. It is necessary to take into account the fact that this cytoreduction goes through a peritonectomy and the resection of visceral metastases that sometimes involve several days of surgery, with the corresponding increase of morbidity and mortality. For this reason, it is essential to have specialized or experienced centres when assessing the results.

As we have said, the level of cytoreduction is directly related to the prognosis. The success rate of cytoreduction has been established according to different systems, although it is generally classified as CCR 0 (Completeness of Cancer Resection) when there is no microscopic tumor, CCR 1 when there are no nodes larger than 0.5 cm and CCR 2 when there are clearly visible tumors (more than 0.5 cm). Average survival is 33 months for CCR 0, 12.5 months for CCR 1 and 8.5 months for CCR 2 (Glehen O, Cotte E, Schreiber V, Sayag-Beaujard AC, Vignal J, Gilly FN. Intraperitoneal chemohyperthermia and attempted cytoreductive surgery in patients with peritoneal carcinomatosis of colorectal origin. *Br J Surg*. 2004;91:747–754).

The most commonly used chemotherapeutic agents are mitomycin C and cisplatin combined with 5-FU. These agents are heated to 47-59 ºC and inserted in the peritoneal cavity, which lets the surgeon spread it to all necessary spaces. They are left in the cavity for one hour and a half to two hours, and then they are drained. The catheters are left in place for postoperative drainage (Royal RE, Pingpank JF Jr. Diagnosis and management of peritoneal carcinomatosis arising from adenocarcinoma of the colon and rectum. *Semin Oncol*. 2008;35:183–191).

Morbidity rates in the procedure of cytoreduction and HIPEC are around 30% and 60%, and mortality is less than 2%. Logically, covering the logistic needs for intensive care, chemother‐ apy and trained surgeons with an established protocol allow for an adequate morbidity and mortality. This therapy must be applied to patients in whom a complete or almost complete cytoreduction can be achieved. With these conditions, the existing studies (although retro‐ spective) show an important improvement of survival, with some results showing a five-year survival rate of 49% when cytoreduction is complete. (Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. *J Clin Oncol*. 2006;24: 4011–409).

It is possible to apply delayed and repeated intraperitoneal systemic chemotherapy after the cytoreduction with acceptable morbidity rates. It is also possible to administer delayed intraperitoneal chemotherapy in up to 83% of the patients who had previously undergone cytoreduction (Delayed Repeated Intraperotoneal Chemotherapy. Fajardo et al. Diseases of Colon and Rectum. Volumen 55.: 10 (2012)).

On the other hand, there are reasons to be optimistic about the use of immunomodulat‐ ing treatments (targeted monoclonal antibodies) which, when combined with other 'traditional' chemotherapeutic approaches, are showing some really promising results. We still need more studies that let us know what conditions lead to a successful outcome (such as the KRAS status of the primary tumor) and also whether they have a beneficial effect in peritoneal carcinomatosis.

Chemotherapy and targeted therapies: There are currently eight active and approved drugs for patients with metastatic colorectal cancer which are used separately or combined with other drugs:

5-FU, Capecitabine, Irinotecan., Oxaliplatin, Bevacizumab, Cetuximab, Aflibercept and Panitumumab.

These chemotherapeutic agents, some of which are monoclonal antibodies, can be combined in different ways and represent an encouraging future for patients with peritoneal metastases who were previously called 'terminally ill'.

#### **7.4. Treatment of metastatic disease**

administration of cytostatic drugs (difficulty of access, erratic distribution, pain…), which have

This way, and after decades of preclinical and clinical efforts, cytoreductive surgery combined with preoperative hyperthermic intraperitoneal chemotherapy (HIPEC) appear in this new century as an indissoluble and feasible multimodal strategy with proven effectiveness in the treatment of selected cases of peritoneal carcinomatosis in colorectal cancer, although, as we have said before, it can also be useful for other tumors (González-Moreno S. Cirugía citore‐ ductora y quimioterapia intraperitoneal perioperatoria para las neoplasias con diseminación peritoneal: ha llegado el momento. Cir Esp. 2005;78(6):341-3)(Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D. Update on chemotherapeutic agents utilized for periopera‐ tive intraperitonealchemotherapy. Oncologist. 2005;10:112-22.)(Treatments and Outcomes of Peritoneal Surface Tumors Through a Centralized National Service (United Kingdom) S. Rout,

There are protocols for the selection of patients which, among other things, try to establish the mass of the tumor and its location by mapping the abdominal cavity in order to assess the size of the tumor and the possibility of achieving an adequate cytoreduction. Laparoscopy is a technique that is currently included in the treatment protocols when there is suspicion or preoperative evidence of peritoneal carcinomatosis. After obtaining a laparoscopic diagnosis of the affected areas (including images obtained during the process, if possible), the patient is sent to a health centre with experience in cytoreductive surgery and HIPEC in order to assess

The prognosis and results depend on the level of cytoreduction. It is necessary to take into account the fact that this cytoreduction goes through a peritonectomy and the resection of visceral metastases that sometimes involve several days of surgery, with the corresponding increase of morbidity and mortality. For this reason, it is essential to have specialized or

As we have said, the level of cytoreduction is directly related to the prognosis. The success rate of cytoreduction has been established according to different systems, although it is generally classified as CCR 0 (Completeness of Cancer Resection) when there is no microscopic tumor, CCR 1 when there are no nodes larger than 0.5 cm and CCR 2 when there are clearly visible tumors (more than 0.5 cm). Average survival is 33 months for CCR 0, 12.5 months for CCR 1 and 8.5 months for CCR 2 (Glehen O, Cotte E, Schreiber V, Sayag-Beaujard AC, Vignal J, Gilly FN. Intraperitoneal chemohyperthermia and attempted cytoreductive surgery in patients with

The most commonly used chemotherapeutic agents are mitomycin C and cisplatin combined with 5-FU. These agents are heated to 47-59 ºC and inserted in the peritoneal cavity, which lets the surgeon spread it to all necessary spaces. They are left in the cavity for one hour and a half to two hours, and then they are drained. The catheters are left in place for postoperative drainage (Royal RE, Pingpank JF Jr. Diagnosis and management of peritoneal carcinomatosis

arising from adenocarcinoma of the colon and rectum. *Semin Oncol*. 2008;35:183–191).

been one of the main causes of its poor reception by specialists in medical oncology.

Diseases Of The Colon & Rectum Volume 52: 10 (2009).

210 Colorectal Cancer - Surgery, Diagnostics and Treatment

the procedure (commonly referred to as Sugarbaker technique).

peritoneal carcinomatosis of colorectal origin. *Br J Surg*. 2004;91:747–754).

experienced centres when assessing the results.

Initial management of the primary site in patients who present with stage IV disease is controversial, and there are no data from prospective randomized studies to guide treatment. In general, the choice and sequence of treatment is guided by the presence or absence of symptoms from the primary tumor and whether or not the metastases are potentially resectable.

Surgery provides a potentially curative option for selected patients who present with limited metastatic colorectal cancer.

**Management in patients with unresectable metastatic disease**: systemic and hepatic arterial infusion chemotherapy may be useful treatment options in patients with unresectable disease.

Other established treatment is radiofrequency ablation.

## **Author details**

C. Alberto Blanco1\*, R. Sánchez2 , F. Piniella3 , D. Pescador3 , G. Borobio3 , A. García3 and C. Cano3

[10] González-Moreno S. Cirugía citoreductora y quimioterapia intraperitoneal perioper‐ atoria para las neoplasias con diseminación peritoneal: ha llegado el momento. Cir

Management of Non-Hepatic Metastatic Disease in Colorectal Cancer

http://dx.doi.org/10.5772/57487

213

[11] Sugarbaker et al.. Update on chemotherapeutic agents utilized for perioperative in‐

[12] Rout et al. Treatments and Outcomes of Peritoneal Surface Tumors Through a Cen‐ tralized National Service (United Kingdom) Dis Colon Rectum Volume 52: 10

[13] Glehen et a*l*. Intraperitoneal chemohyperthermia and attempted cytoreductive sur‐ gery in patients with peritoneal carcinomatosis of colorectal origin. *Br J Surg*.

[14] Royal et al.. Diagnosis and management of peritoneal carcinomatosis arising from

[15] Yan et al. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from color‐

[16] Fajardo et al. Delayed repeated intraperotoneal chemotherapy.. Dis Colon Rectum.

[17] Soumaoro et al. Coexpression of VEGF-C and Cox-2 in Human Colorectal Cancer and its Association With Lymph Node Metastasis Dis Colon Rectum, March 2006 vol

[18] Óberg, A. e*t al*. Are lymph node micrometastases of any clinical significance in Dukes stages A and B colorectal cancer? Dis Colon Rectum, October 1998 Vol 41, No.

[19] Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.

[20] Wong et al. Staging accuracy in colorectal carcinoma. Journal of Clinical Oncology.

[21] Wang et al. Curative resection of T1 colorectal carcinoma: risk of lymph node meta‐ stasis and long-term prognosis. Dis Colon Rectum June 2005. Vol 48, No. 6,

[22] Kelder et al. Impact of the number of histologically examined lymph nodes on prog‐ nosis in colon cancer: a population-based study in the Netherlands. Dis Colon Rec‐

adenocarcinoma of the colon and rectum. *Semin Oncol*. 2008;35:183–191

traperitonealchemotherapy. Oncologist. 2005;10:112-22

ectal carcinoma. *J Clin Oncol*. 2006;24: 4011–409.

New York, NY: Springer, 2010, pp 143-64.

Vol 17. nº 9 (1999) 2896-2900.

tum. Vol. 52 (2009); 260-267.

[23] J. Gastroenterol Heptol 6:325-244. 1991

Esp. 2005 ;78(6):341-343

(2009)1705-1715.

2004;91:747–754.

49, nº 3; 392-398.

10 1244-1249.

1182-1192.

Vol 55.: 10 (2012);1044-1052


### **References**


[10] González-Moreno S. Cirugía citoreductora y quimioterapia intraperitoneal perioper‐ atoria para las neoplasias con diseminación peritoneal: ha llegado el momento. Cir Esp. 2005 ;78(6):341-343

**Author details**

C. Cano3

**References**

(2009)

212-222.

1989;16:83–97.

52:12 (2009)

C. Alberto Blanco1\*, R. Sánchez2

212 Colorectal Cancer - Surgery, Diagnostics and Treatment

, F. Piniella3

\*Address all correspondence to: titoberto2002@hotmail.com

1 Hospital Santos Reyes, Aranda de Duero (Burgos), Spain

2 Health Care Centers of Aranda de Duero (Burgos), Ávila, Spain

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, D. Pescador3

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**Chapter 10**

**New Strategies to Enhance the Efficacy of Surgical**

Colorectal cancer (CRC) is the second most common cause of cancer death worldwide [1]. The liver is the most frequent site of metastasis in CRC, both at the time of diagnosis (15-20% of cases) and after apparently radical surgery on the primary tumour (nearly 40% of cases). If patients with colorectal liver metastasis (CRC-LM) are not treated, prognosis is very poor, with a near zero five-year survival rate. At present, liver resection is the only treatment modality that has the potential to achieve long-term survival and to offer the possibility of a cure. Patients who undergo complete (R0) resection of liver metastases have a five-year survival rate of approximately 40-50% [2]. Unfortunately, however, 50% to 70% of patients develop secondary

In order to obtain the best results in a systemic disease such as metastatic CRC (mCRC), the optimal integration of medical treatment and surgery is essential. The introduction of several effective cytotoxic and targeting agents, in combination with surgical treatment, has extended survival [4]. In addition, promising emerging therapies –cancer stem cell (CSC)-targeted therapies, pathway inhibitors for CRC, induction of tumour cell differentiation, improving liver regeneration, and nanoparticle (NP)-guided tumour ablation, among others– may be found to be effective in achieving better control and even complete eradication of CRC-LM. If confirmed, these strategies will bring significant benefits to patients, particularly in terms of long-term survival. Further, in this era of multimodality treatment of CRC, it is critically important to identify effective biomarkers for prognosis and prediction of individual treatment responses, and these are expected to become useful tools for improving therapeutic ap‐

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Treatment for Colorectal Liver Metastasis**

Teodoro Palomares, Ana Alonso-Varona, Ignacio García-Alonso and Vicente Portugal

Additional information is available at the end of the chapter

metastatic disease after R0-resection of CRC-LM [3].

http://dx.doi.org/10.5772/57326

**1. Introduction**

proaches.


## **New Strategies to Enhance the Efficacy of Surgical Treatment for Colorectal Liver Metastasis**

Teodoro Palomares, Ana Alonso-Varona, Ignacio García-Alonso and Vicente Portugal

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57326

## **1. Introduction**

[76] Nozue, M; Oshiro, Y; Kurata, M; Seino, K; Koike, N; Kawamoto, T et al (2002). Treat‐ ment and prognosis in colorectal cancer patients with bone metastasis. *Oncol Rep*

[77] Ross, J.R; Saunders ,Y; Edmonds, P.M; Patel, S; Wonderling, D; Normand, C. (2004). A systematic review of the role of bisphosphonates in metastatic disease. *Health Tech‐*

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[79] Schlüter, K; Gassmann, P; Enns, A.(2006) Organ-Specific Metastatic Tumor Cell Ad‐ hesion and Extravasation of Colon Carcinoma Cells with Different Metastatic Poten‐

[80] Schlüter, K; Gassmann, P; Enns, A; Korb, T; Hemping-Bovenkerk, A; Hölzen, J; Hai‐ er,J. (2006). Organ-Specific Metastatic Tumor Cell Adhesion and Extravasation of Co‐ lon Carcinoma Cells with Different Metastatic Potential. *American Journal of Pathology.*

[81] Spiteri, V; Bibra, A; Ashwood, N; Cobb, J. Managing acrometastases treatment strat‐ egy with a case illustration (2008). *Ann R Coll Surg Engl 2008 October; 90(7): 8-11.* [82] Sundermeyer, M. L; Meropol, N.J; Rogatko, A; Wang, H; Cohen, S.J. (2004). Changing patterns of colorectal cancer metastases: A 10-year retrospective review. *Journal of*

[83] Sundermeyer, M. L; Meropol, N.J; Rogatko, A; Wang, H; Cohen, S.J. (2005).Changing Patterns of Bone and Brain Metastases in Patients with Colorectal Cancer. Clinical

*Clinical Oncology*, vol 22, nº 14S ,(July 15 Supplement 2004), 3548.

Colorrectal Cancer. vol 5, nº 2 (July 2005). 108-113. www.intechopen.

tial. *The American Journal of Pathology. vol.169,* (September 2006),1064–1073.

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*2002 Jan-Feb; 9(1): 109-112.*

218 Colorectal Cancer - Surgery, Diagnostics and Treatment

*nol Assess*. vol 8. (August 2004). 1-176.

Vol 169, (September 2006), 1064-1073.

Colorectal cancer (CRC) is the second most common cause of cancer death worldwide [1]. The liver is the most frequent site of metastasis in CRC, both at the time of diagnosis (15-20% of cases) and after apparently radical surgery on the primary tumour (nearly 40% of cases). If patients with colorectal liver metastasis (CRC-LM) are not treated, prognosis is very poor, with a near zero five-year survival rate. At present, liver resection is the only treatment modality that has the potential to achieve long-term survival and to offer the possibility of a cure. Patients who undergo complete (R0) resection of liver metastases have a five-year survival rate of approximately 40-50% [2]. Unfortunately, however, 50% to 70% of patients develop secondary metastatic disease after R0-resection of CRC-LM [3].

In order to obtain the best results in a systemic disease such as metastatic CRC (mCRC), the optimal integration of medical treatment and surgery is essential. The introduction of several effective cytotoxic and targeting agents, in combination with surgical treatment, has extended survival [4]. In addition, promising emerging therapies –cancer stem cell (CSC)-targeted therapies, pathway inhibitors for CRC, induction of tumour cell differentiation, improving liver regeneration, and nanoparticle (NP)-guided tumour ablation, among others– may be found to be effective in achieving better control and even complete eradication of CRC-LM. If confirmed, these strategies will bring significant benefits to patients, particularly in terms of long-term survival. Further, in this era of multimodality treatment of CRC, it is critically important to identify effective biomarkers for prognosis and prediction of individual treatment responses, and these are expected to become useful tools for improving therapeutic ap‐ proaches.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The present chapter aims i, to present the state of the art related to criteria for appropriate decision making for CRC-LM treatment; ii, to review the current data on the role of biomarkers used for the prediction of response to CRC-LM therapies; and iii, to outline emerging targeting agents and new therapeutic techniques to improve life expectancy and quality of life in CRC-LM patients.

ng/ml, synchronous metastases or metachronous metastases with a disease-free interval of less than twelve months, more than one metastasis, extrahepatic disease, a tumour > 5 cm in

New Strategies to Enhance the Efficacy of Surgical Treatment for Colorectal Liver Metastasis

http://dx.doi.org/10.5772/57326

221

Over recent years, several studies, well summarised in the systematic review of Quan *et al*. [10], have investigated the validity of these various criteria. Notably, the value of the following indicators have been questioned: the number of lesions, maximum lesion dimensions, timing of metastases, absence of metastatic spread outside the liver, and margin of healthy liver tissue,

In summary, the criteria listed in this section can be regarded as an invaluable tool for patient stratification before liver resection, but failure to meet them should not constitute an absolute

In the case of resectable CRC-LM, current guidelines recommend the administration of a course of an active systemic chemotherapy regimen for a total perioperative treatment time of approximately six months [12]. The preferred regimens are combination chemotherapy based on fluoropyrimidines XELOX (capecitabine plus oxaliplatin), FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) and FOLFIRI (5-fluorouracil, leucovorin and irinotecan), option‐ ally together with antiangiogenic biological agents (bevacizumab, cetuximab or panitumu‐ mab). In order to improve the selection of the regimen to be used, KRAS mutation status should be determined in all patients at the time of diagnosis of metastatic disease. If no KRAS mutations are identified, BRAF testing should be considered [13]. New targeting biological agents are emerging and they can be expected to lead to improvements in clinical effectiveness. Their effects, pathways and theoretical and practical applications will be discussed in more detail below in the section entitled *Emerging targeting agents for colorectal liver metastases*.

In patients with few metastases that are easy to surgically resect and no poor prognostic indicators, postoperative chemotherapy is usually preferred [14]. On the other hand, in other clinical situations, perioperative (neoadjuvant plus postoperative) chemotherapy can be used [15]. The optimal sequencing of chemotherapy is not clear, however, and recent studies have assessed the pros and cons of different possible timings of administration [16-17]. Potential advantages of administering chemotherapy preoperatively include earlier treatment of micrometastatic disease, evaluation of responsiveness to chemotherapy (which can be prognostic and help decision making) and avoidance of surgery in patients who progress early. On the other hand, several disadvantages have also been highlighted: the risk of missing the window of opportunity for resection, which may be due to disease progression or due to a complete response making it difficult to identify areas for resection; radiological complete response does not always mean pathological response, as viable cancer cells can remain at the original sites of metastases [18]; hepatotoxicity develops with some regimens with serious clinical implications both before and after surgery [19]; and finally, frequent radiological examinations must be undertaken to determine the appropriate timing for surgery [20]. There is now a general trend towards the use of perioperative chemotherapy for patients with

diameter and lymph node involvement associated with the primary tumour.

as has the definition of an adequate liver remnant after resection [11].

contraindication to surgery.

**2.2. Optimal chemotherapy timing and regimes**

## **2. Therapeutic approaches to colorectal liver metastases: The state of the art**

More than half of patients with CRC will develop liver metastases, and nearly 80% of them are initially unresectable. Hence, optimal management of hepatic metastases often requires a multidisciplinary approach. The availability of new medical therapies, including neoadjuvant chemotherapy and targeted therapies, render a considerable percentage (up to 40%) of initially unresectable patients potentially resectable, improving the overall outcomes of patients with mCRC.

Nowadays, to optimise the integration between surgery and medical approaches in the treatment of mCRC it is necessary to consider different groups, based on current guidelines for stratification of patients according to clinical goals and treatment. In this section, we summarise the recommended therapeutic approaches for CRC-LM according to the afore‐ mentioned patient stratification.

#### **2.1. Selection criteria for resection of colorectal liver metastases: Definition of resectability**

Patients diagnosed with mCRC should undergo an upfront evaluation by a multidisciplinary team, including medical oncologists, surgeons, radiotherapists and radiologists, in order to assess resectability status and to achieve the best therapeutic results [5]. The target end point for assessing resectability is the potential of surgery to cure the disease when achieving RO resection of all evident disease. Incomplete resection (macroscopic or microscopic), so-called debulking surgery, has not been found to help achieve this end point [6].

Classically, surgical criteria have determined resectability [7], but over recent years several authors have questioned the relevance of many of them. Nowadays, the only surgical criteria that continue to be widely used are complete tumour resection with the preservation of two contiguous liver segments (with adequate vascular inflow and outflow) and an adequate liver remnant (at least 25% of the total liver volume considering the healthy organ) [8]. If, however, we seek a more comprehensive definition of resectability, we should also take into account prognostic evaluation and predicted response to different treatments, by including multiple clinical and molecular factors, which influence patient outcome. Some validated clinical scores are already available, while molecular factors are still under investigation (discussed in more detail below in the section entitled *Predictive biomarkers for response to treatment in colorectal cancer*. In relation to this, the study conducted by Fong *et al*. [9]at the Memorial-Sloan Kettering Cancer Center has been one of the most useful attempts to define prognosis after surgical management of CRC-LM. The score proposed integrates a range of risk factors which influence the risk of death after surgery: preoperative carcinoembryonic antigen (CEA) level > 200 ng/ml, synchronous metastases or metachronous metastases with a disease-free interval of less than twelve months, more than one metastasis, extrahepatic disease, a tumour > 5 cm in diameter and lymph node involvement associated with the primary tumour.

Over recent years, several studies, well summarised in the systematic review of Quan *et al*. [10], have investigated the validity of these various criteria. Notably, the value of the following indicators have been questioned: the number of lesions, maximum lesion dimensions, timing of metastases, absence of metastatic spread outside the liver, and margin of healthy liver tissue, as has the definition of an adequate liver remnant after resection [11].

In summary, the criteria listed in this section can be regarded as an invaluable tool for patient stratification before liver resection, but failure to meet them should not constitute an absolute contraindication to surgery.

#### **2.2. Optimal chemotherapy timing and regimes**

The present chapter aims i, to present the state of the art related to criteria for appropriate decision making for CRC-LM treatment; ii, to review the current data on the role of biomarkers used for the prediction of response to CRC-LM therapies; and iii, to outline emerging targeting agents and new therapeutic techniques to improve life expectancy and quality of life in CRC-

**2. Therapeutic approaches to colorectal liver metastases: The state of the art**

More than half of patients with CRC will develop liver metastases, and nearly 80% of them are initially unresectable. Hence, optimal management of hepatic metastases often requires a multidisciplinary approach. The availability of new medical therapies, including neoadjuvant chemotherapy and targeted therapies, render a considerable percentage (up to 40%) of initially unresectable patients potentially resectable, improving the overall outcomes of patients with

Nowadays, to optimise the integration between surgery and medical approaches in the treatment of mCRC it is necessary to consider different groups, based on current guidelines for stratification of patients according to clinical goals and treatment. In this section, we summarise the recommended therapeutic approaches for CRC-LM according to the afore‐

**2.1. Selection criteria for resection of colorectal liver metastases: Definition of resectability** Patients diagnosed with mCRC should undergo an upfront evaluation by a multidisciplinary team, including medical oncologists, surgeons, radiotherapists and radiologists, in order to assess resectability status and to achieve the best therapeutic results [5]. The target end point for assessing resectability is the potential of surgery to cure the disease when achieving RO resection of all evident disease. Incomplete resection (macroscopic or microscopic), so-called

Classically, surgical criteria have determined resectability [7], but over recent years several authors have questioned the relevance of many of them. Nowadays, the only surgical criteria that continue to be widely used are complete tumour resection with the preservation of two contiguous liver segments (with adequate vascular inflow and outflow) and an adequate liver remnant (at least 25% of the total liver volume considering the healthy organ) [8]. If, however, we seek a more comprehensive definition of resectability, we should also take into account prognostic evaluation and predicted response to different treatments, by including multiple clinical and molecular factors, which influence patient outcome. Some validated clinical scores are already available, while molecular factors are still under investigation (discussed in more detail below in the section entitled *Predictive biomarkers for response to treatment in colorectal cancer*. In relation to this, the study conducted by Fong *et al*. [9]at the Memorial-Sloan Kettering Cancer Center has been one of the most useful attempts to define prognosis after surgical management of CRC-LM. The score proposed integrates a range of risk factors which influence the risk of death after surgery: preoperative carcinoembryonic antigen (CEA) level > 200

debulking surgery, has not been found to help achieve this end point [6].

LM patients.

mCRC.

mentioned patient stratification.

220 Colorectal Cancer - Surgery, Diagnostics and Treatment

In the case of resectable CRC-LM, current guidelines recommend the administration of a course of an active systemic chemotherapy regimen for a total perioperative treatment time of approximately six months [12]. The preferred regimens are combination chemotherapy based on fluoropyrimidines XELOX (capecitabine plus oxaliplatin), FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) and FOLFIRI (5-fluorouracil, leucovorin and irinotecan), option‐ ally together with antiangiogenic biological agents (bevacizumab, cetuximab or panitumu‐ mab). In order to improve the selection of the regimen to be used, KRAS mutation status should be determined in all patients at the time of diagnosis of metastatic disease. If no KRAS mutations are identified, BRAF testing should be considered [13]. New targeting biological agents are emerging and they can be expected to lead to improvements in clinical effectiveness. Their effects, pathways and theoretical and practical applications will be discussed in more detail below in the section entitled *Emerging targeting agents for colorectal liver metastases*.

In patients with few metastases that are easy to surgically resect and no poor prognostic indicators, postoperative chemotherapy is usually preferred [14]. On the other hand, in other clinical situations, perioperative (neoadjuvant plus postoperative) chemotherapy can be used [15]. The optimal sequencing of chemotherapy is not clear, however, and recent studies have assessed the pros and cons of different possible timings of administration [16-17]. Potential advantages of administering chemotherapy preoperatively include earlier treatment of micrometastatic disease, evaluation of responsiveness to chemotherapy (which can be prognostic and help decision making) and avoidance of surgery in patients who progress early. On the other hand, several disadvantages have also been highlighted: the risk of missing the window of opportunity for resection, which may be due to disease progression or due to a complete response making it difficult to identify areas for resection; radiological complete response does not always mean pathological response, as viable cancer cells can remain at the original sites of metastases [18]; hepatotoxicity develops with some regimens with serious clinical implications both before and after surgery [19]; and finally, frequent radiological examinations must be undertaken to determine the appropriate timing for surgery [20]. There is now a general trend towards the use of perioperative chemotherapy for patients with resectable CRC-LM, but more studies are necessary to provide stronger evidence regarding the benefit of this approach.

Furthermore, it must be taken into account that sometimes a radiological complete response can be achieved in patients with one or more metastases. However, a systematic review of the literature suggests that between 17 and 51% of such patients will have residual microscopic disease [28-29]. Accordingly, all liver metastases, including those with radiological complete response after chemotherapy, should be resected when technically feasible. In addition, almost

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Overall, recent studies have reported that resectability is achieved in 10 to 40% of selected patients after chemotherapy. It remains difficult, however, to draw firm conclusions as the definition of unresectable disease, patient selection criteria, drug regimens, and outcome

Liver resection remains the only treatment modality that can achieve long-term survival and offers a possibility of a cure [2]. Selection criteria for resection of CRC-LM are continually being refined (see the aforementioned *Definition of resectability*). In this field, advances in surgical strategy (timing, techniques, etc.) have improved results, but patient management is complex and tends to require a combination of different approaches (colorectal resection, liver resection,

At present, when oncology committees evaluate CRC-LM for surgical treatment, several clinical scenarios are considered: resectable synchronous metastases, resectable metachronous

Close to a third (15-34%) of patients have liver metastases at the time of diagnosis (synchronous metastases). Evidence-based protocols for the management of synchronous metastases are, however, poor, and few prospective studies have been published recently, such results as are available being difficult to generalise [30]. In any case, some suggestions can be made.

One of the open questions is the timing of colorectal and liver surgery (simultaneous versus staged). The traditional approach has been to perform surgery on the primary lesions (color‐ ectal resection), followed by chemotherapy and subsequent liver surgery. Nowadays, simul‐ taneous colorectal and liver resections are preferred when feasible [31]. This combined surgery can be safely performed whenever minor hepatectomies are planned, but there is no consensus on the best approach in cases requiring major hepatectomies. Considering the largest series, some show similar rates in simultaneous and staged resections [32], but a multicentre database analysis in the USA found increased morbidity and mortality after simultaneous major hepatectomy and colorectal resection [33]. Thus, in the absence of clear evidence, the decision to undertake more complex procedures must be made on a case-by-case basis. Even though surgery is the key treatment in patients with CRC-LM, chemotherapy (and sometimes radiotherapy) must also be administered. The sequencing of chemotherapy has been discussed

metastases and unresectable disease amenable to conversion chemotherapy.

measures vary, and there is insufficient data from randomised controlled trials [10].

all authors recommend postoperative chemotherapy in these cases.

chemotherapy, and radiotherapy, among others).

*2.4.1. Resectable synchronous metastases*

above, and often influences surgical timing.

**2.4. Surgical strategy**

It is important to note that patients diagnosed with rectal cancer and resectable synchronous liver metastases usually need a specific approach due to the risk of locoregional failure. Preoperative chemoradiotherapy in locally advanced rectal tumours (cT3/4, cN+) decreases the risk of pelvic recurrence after surgery, and postoperative chemotherapy is also mandatory [21]. Some studies suggest that pelvic radiotherapy diminishes tolerance to biological agents, but there is not enough data to guide decisions on when this approach may be suitable. After surgical resection of metastases and rectal lesions, pathological rectal disease determines adjuvant therapy. Specifically, postoperative chemoradiotherapy is advised for patients who have not received prior chemoradiation and have a higher risk of pelvic recurrence (pT3/4 or pN1/2) [22]. Patients with pT1-2pN0 tumours should receive six months of adjuvant chemo‐ therapy without pelvic radiation.

In brief, the choices of type of chemotherapy/chemoradiotherapy regimen and its timing depend on a number of factors, namely a patient's disease history and pathological status, tumour gene expression, and previous treatment (including chemotherapy and associated drug toxicity/safety), as well as institutional preferences.

#### **2.3. Conversion or downsizing chemotherapy**

When patients present initially unresectable disease, owing to technical difficulties and/or the presence of poor prognostic factors, treatment decisions are difficult. In this clinical situation, preoperative chemotherapy is being considered in highly selected cases in an attempt to downsize CRC-LM and convert them to a resectable status. In these cases, any active metastatic chemotherapy regimen can be used, the goal being to reduce the size of the visible metastases as much as possible. Several trials have been conducted using different combinations of chemotherapy and biological agents, but they have not provided compelling evidence to favour one regimen over another [23-24].

Further, there are other factors we must keep in mind when considering this kind of treatment. Some chemotherapy regimens may cause hepatotoxicity (steatohepatitis and sinusoidal liver injury, among others) [25]with clinical implications for liver surgery, and we must measure responsiveness, so radiological and clinical reassessment should be scheduled approximately every two months after the initiation of chemotherapy. If the disease becomes resectable, surgery should be performed as soon as possible, in order to limit toxicity.

In addition, we must optimise imaging of CRC-LM choosing the most accurate methods. Radiological imaging techniques, namely computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-PET/CT in selected cases, are the essential tools to measure patient tumour response and resectability, while intraoperative ultrasonog‐ raphy (IOUS) remains mandatory in all patients undergoing surgical resection of CRC-LM. Indeed, several authors have demonstrated that IOUS can change the surgical management in up to 35% of patients [26-27].

Furthermore, it must be taken into account that sometimes a radiological complete response can be achieved in patients with one or more metastases. However, a systematic review of the literature suggests that between 17 and 51% of such patients will have residual microscopic disease [28-29]. Accordingly, all liver metastases, including those with radiological complete response after chemotherapy, should be resected when technically feasible. In addition, almost all authors recommend postoperative chemotherapy in these cases.

Overall, recent studies have reported that resectability is achieved in 10 to 40% of selected patients after chemotherapy. It remains difficult, however, to draw firm conclusions as the definition of unresectable disease, patient selection criteria, drug regimens, and outcome measures vary, and there is insufficient data from randomised controlled trials [10].

#### **2.4. Surgical strategy**

resectable CRC-LM, but more studies are necessary to provide stronger evidence regarding

It is important to note that patients diagnosed with rectal cancer and resectable synchronous liver metastases usually need a specific approach due to the risk of locoregional failure. Preoperative chemoradiotherapy in locally advanced rectal tumours (cT3/4, cN+) decreases the risk of pelvic recurrence after surgery, and postoperative chemotherapy is also mandatory [21]. Some studies suggest that pelvic radiotherapy diminishes tolerance to biological agents, but there is not enough data to guide decisions on when this approach may be suitable. After surgical resection of metastases and rectal lesions, pathological rectal disease determines adjuvant therapy. Specifically, postoperative chemoradiotherapy is advised for patients who have not received prior chemoradiation and have a higher risk of pelvic recurrence (pT3/4 or pN1/2) [22]. Patients with pT1-2pN0 tumours should receive six months of adjuvant chemo‐

In brief, the choices of type of chemotherapy/chemoradiotherapy regimen and its timing depend on a number of factors, namely a patient's disease history and pathological status, tumour gene expression, and previous treatment (including chemotherapy and associated

When patients present initially unresectable disease, owing to technical difficulties and/or the presence of poor prognostic factors, treatment decisions are difficult. In this clinical situation, preoperative chemotherapy is being considered in highly selected cases in an attempt to downsize CRC-LM and convert them to a resectable status. In these cases, any active metastatic chemotherapy regimen can be used, the goal being to reduce the size of the visible metastases as much as possible. Several trials have been conducted using different combinations of chemotherapy and biological agents, but they have not provided compelling evidence to

Further, there are other factors we must keep in mind when considering this kind of treatment. Some chemotherapy regimens may cause hepatotoxicity (steatohepatitis and sinusoidal liver injury, among others) [25]with clinical implications for liver surgery, and we must measure responsiveness, so radiological and clinical reassessment should be scheduled approximately every two months after the initiation of chemotherapy. If the disease becomes resectable,

In addition, we must optimise imaging of CRC-LM choosing the most accurate methods. Radiological imaging techniques, namely computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-PET/CT in selected cases, are the essential tools to measure patient tumour response and resectability, while intraoperative ultrasonog‐ raphy (IOUS) remains mandatory in all patients undergoing surgical resection of CRC-LM. Indeed, several authors have demonstrated that IOUS can change the surgical management

surgery should be performed as soon as possible, in order to limit toxicity.

the benefit of this approach.

222 Colorectal Cancer - Surgery, Diagnostics and Treatment

therapy without pelvic radiation.

drug toxicity/safety), as well as institutional preferences.

**2.3. Conversion or downsizing chemotherapy**

favour one regimen over another [23-24].

in up to 35% of patients [26-27].

Liver resection remains the only treatment modality that can achieve long-term survival and offers a possibility of a cure [2]. Selection criteria for resection of CRC-LM are continually being refined (see the aforementioned *Definition of resectability*). In this field, advances in surgical strategy (timing, techniques, etc.) have improved results, but patient management is complex and tends to require a combination of different approaches (colorectal resection, liver resection, chemotherapy, and radiotherapy, among others).

At present, when oncology committees evaluate CRC-LM for surgical treatment, several clinical scenarios are considered: resectable synchronous metastases, resectable metachronous metastases and unresectable disease amenable to conversion chemotherapy.

#### *2.4.1. Resectable synchronous metastases*

Close to a third (15-34%) of patients have liver metastases at the time of diagnosis (synchronous metastases). Evidence-based protocols for the management of synchronous metastases are, however, poor, and few prospective studies have been published recently, such results as are available being difficult to generalise [30]. In any case, some suggestions can be made.

One of the open questions is the timing of colorectal and liver surgery (simultaneous versus staged). The traditional approach has been to perform surgery on the primary lesions (color‐ ectal resection), followed by chemotherapy and subsequent liver surgery. Nowadays, simul‐ taneous colorectal and liver resections are preferred when feasible [31]. This combined surgery can be safely performed whenever minor hepatectomies are planned, but there is no consensus on the best approach in cases requiring major hepatectomies. Considering the largest series, some show similar rates in simultaneous and staged resections [32], but a multicentre database analysis in the USA found increased morbidity and mortality after simultaneous major hepatectomy and colorectal resection [33]. Thus, in the absence of clear evidence, the decision to undertake more complex procedures must be made on a case-by-case basis. Even though surgery is the key treatment in patients with CRC-LM, chemotherapy (and sometimes radiotherapy) must also be administered. The sequencing of chemotherapy has been discussed above, and often influences surgical timing.

On the other hand, we should not forget that patients with synchronous metastases have a poorer prognosis [34]. Various strategies have been proposed in an attempt to improve results. One possibility, suggested by Mentha *et al.* [35], is a change in the treatment sequence, the socalled reverse approach, which consists of treatment with systemic chemotherapy followed by liver resection and subsequent primary tumour treatment (with the option of radiotherapy of the rectal tumour prior to resection). More recently, Bruquet *et al.* [36], have reported their experience at the MD Anderson Cancer Center comparing the traditional approach, combined or simultaneous resection, and a "reverse" strategy. These authors found similar oncological outcomes, morbidity and mortality with the three options. This lack of strong evidence makes us cautious, but we believe that the reverse strategy can be considered a reasonable option in patients with asymptomatic primary CRC but advanced CRC-LM.

tomy: this is a two-stage hepatectomy for bilobular liver metastases in combination with selected use of portal venous embolization. It offers the best chance of achieving an adequate degree of liver remnant hypertrophy, being more effective than portal venous embolization

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Although the standard of care for resectable liver metastases is surgical resection, in selected patients other liver-directed therapies can be used in addition to or instead of surgical resection. These include intrahepatic arterial chemotherapy [41], radiofrequency tumour ablation [42], radioembolization [43]and stereotactic external beam radiation [44]. Some of these innovative techniques will be discussed in more depth below in the section entitled *New*

**3. Predictive biomarkers for response to treatment in colorectal cancer**

Over the past decade, developments in CRC-LM therapy have improved the prognosis of patients. Combination chemotherapy, such as FOLFOX or FOLFIRI, has become the standard regimen for unresectable advanced or recurrent CRC, and high response rates have been reported. On the other hand, not all patients respond well to these therapies, and it has been suggested that differential responses are due to the specific molecular profile of each patient and/or tumour. To facilitate the design of personalised therapeutic strategies for CRC patients, it is therefore important to identify biomarkers which are able to accurately predict the sensitivity of patients to the potential therapies and to estimate the likely course of the illness. Recent advances in the fields of genomics and proteomics have contributed to our under‐ standing of CRC at the molecular level by evaluating the expression profiles of genes and proteins in tissues and body fluids. To date, some of the candidate biomarkers have yielded somewhat contradictory results. On the other hand, several studies have identified candidate molecular biomarkers that may help to predict the response to cytotoxic chemotherapy and

*5-Flurouracil (5-FU)* is the main stay of all current standard CRC chemotherapy regimens, despite the fact that it causes serious side effects (grade 3 or 4) in up to 30% of patients. Sev‐ eral enzymes involved in 5-FU metabolism have been proposed as predictors of response to fluopyrimidine treatment: 5-FU exerts its activity by inhibiting thymidylate synthase (TS), a key enzyme of nucleotide pyrimidine metabolism that is essential for DNA synthesis and cellular proliferation. Thymidine phosphorylase (TP) is another enzyme involved in thymi‐ dine metabolism, which regulates the conversion of thymine to thymidine; this is why it is thought to limit the toxicity of high levels of thymidine and prevent replication errors dur‐ ing DNA synthesis. In this role, TP degrades 5-FU, limiting the activity of this chemothera‐ peutic agent. Dihydropyridimine dehydrogenase (DPD) is a rate-limiting hepatic enzyme involved in the catabolism of 5-FU [45]. It was found that low levels of expression of TP, DPD and TS were independently associated with improved overall survival [46]. Specifical‐

before a single hepatectomy [40].

guide treatment selection.

**3.1. Molecular predictors of response to chemotherapy**

*therapeutic techniques for colorectal liver metastases*.

#### *2.4.2. Resectable metachronous metastases*

Most patients with CRC-LM (2/3 of cases) develop liver metastases after initial treatment, during the course of the disease (metachronous metastases). The management of resectable metachronous disease is distinct from that of synchronous disease, though it should also include diagnostic imaging of CRC-LM, as well as evaluation of the chemotherapy and surgical history.

Inthis groupofpatients,PET/CTshouldbe consideredpreoperatively to characterise the extent of metastatic disease and to identify possible sites of extrahepatic disease that could preclude surgery [37]. In addition, it is important to evaluate previous chemotherapy to guide the choice of regimen. In general, six months of perioperative (pre- and/or postoperative) chemotherapy is recommended, but in selected cases observation is also considered appropriate. In addi‐ tion, previous hepatotoxicity and other side effects should be taken into account [12].

In relation to the type of surgery to be performed, previous surgery can preclude surgical treatment of metachronous metastases, especially if upfront liver resection was performed, it being necessary to assess the remnant liver and technical difficulties. Finally, recent data suggest that it is safe to adopt a surgical approach to the treatment of recurrent hepatic disease isolated to the liver, but that survival decreases with each subsequent curative surgical approach [38].

#### *2.4.3. Unresectable disease amenable to conversion chemotherapy*

Inthis clinical situation,preoperative chemotherapy is consideredinhighly selectedcases, with the aim of downsizing CRC-LM [39]. After disease becomes resectable, surgery should be performed as soon as possible and all liver metastases, including those with radiographic complete response after chemotherapy, should be resected when technically feasible [10]. The treatmentoftheprimarytumourcanbepostponeduntilthecompletionofadjuvanttherapy[36].

#### *2.4.4. New surgical techniques*

A feasible approach has emerged for patients who would be left with an inadequate future liver remnant (FLR) if complete disease clearance were to be attempted with a single hepatec‐ tomy: this is a two-stage hepatectomy for bilobular liver metastases in combination with selected use of portal venous embolization. It offers the best chance of achieving an adequate degree of liver remnant hypertrophy, being more effective than portal venous embolization before a single hepatectomy [40].

Although the standard of care for resectable liver metastases is surgical resection, in selected patients other liver-directed therapies can be used in addition to or instead of surgical resection. These include intrahepatic arterial chemotherapy [41], radiofrequency tumour ablation [42], radioembolization [43]and stereotactic external beam radiation [44]. Some of these innovative techniques will be discussed in more depth below in the section entitled *New therapeutic techniques for colorectal liver metastases*.

## **3. Predictive biomarkers for response to treatment in colorectal cancer**

Over the past decade, developments in CRC-LM therapy have improved the prognosis of patients. Combination chemotherapy, such as FOLFOX or FOLFIRI, has become the standard regimen for unresectable advanced or recurrent CRC, and high response rates have been reported. On the other hand, not all patients respond well to these therapies, and it has been suggested that differential responses are due to the specific molecular profile of each patient and/or tumour. To facilitate the design of personalised therapeutic strategies for CRC patients, it is therefore important to identify biomarkers which are able to accurately predict the sensitivity of patients to the potential therapies and to estimate the likely course of the illness.

Recent advances in the fields of genomics and proteomics have contributed to our under‐ standing of CRC at the molecular level by evaluating the expression profiles of genes and proteins in tissues and body fluids. To date, some of the candidate biomarkers have yielded somewhat contradictory results. On the other hand, several studies have identified candidate molecular biomarkers that may help to predict the response to cytotoxic chemotherapy and guide treatment selection.

#### **3.1. Molecular predictors of response to chemotherapy**

On the other hand, we should not forget that patients with synchronous metastases have a poorer prognosis [34]. Various strategies have been proposed in an attempt to improve results. One possibility, suggested by Mentha *et al.* [35], is a change in the treatment sequence, the socalled reverse approach, which consists of treatment with systemic chemotherapy followed by liver resection and subsequent primary tumour treatment (with the option of radiotherapy of the rectal tumour prior to resection). More recently, Bruquet *et al.* [36], have reported their experience at the MD Anderson Cancer Center comparing the traditional approach, combined or simultaneous resection, and a "reverse" strategy. These authors found similar oncological outcomes, morbidity and mortality with the three options. This lack of strong evidence makes us cautious, but we believe that the reverse strategy can be considered a reasonable option in

Most patients with CRC-LM (2/3 of cases) develop liver metastases after initial treatment, during the course of the disease (metachronous metastases). The management of resectable metachronous disease is distinct from that of synchronous disease, though it should also include diagnostic imaging of CRC-LM, as well as evaluation of the chemotherapy and surgical

Inthis groupofpatients,PET/CTshouldbe consideredpreoperatively to characterise the extent of metastatic disease and to identify possible sites of extrahepatic disease that could preclude surgery [37]. In addition, it is important to evaluate previous chemotherapy to guide the choice of regimen. In general, six months of perioperative (pre- and/or postoperative) chemotherapy is recommended, but in selected cases observation is also considered appropriate. In addi‐

In relation to the type of surgery to be performed, previous surgery can preclude surgical treatment of metachronous metastases, especially if upfront liver resection was performed, it being necessary to assess the remnant liver and technical difficulties. Finally, recent data suggest that it is safe to adopt a surgical approach to the treatment of recurrent hepatic disease isolated to the liver, but that survival decreases with each subsequent curative surgical

Inthis clinical situation,preoperative chemotherapy is consideredinhighly selectedcases, with the aim of downsizing CRC-LM [39]. After disease becomes resectable, surgery should be performed as soon as possible and all liver metastases, including those with radiographic complete response after chemotherapy, should be resected when technically feasible [10]. The treatmentoftheprimarytumourcanbepostponeduntilthecompletionofadjuvanttherapy[36].

A feasible approach has emerged for patients who would be left with an inadequate future liver remnant (FLR) if complete disease clearance were to be attempted with a single hepatec‐

tion, previous hepatotoxicity and other side effects should be taken into account [12].

patients with asymptomatic primary CRC but advanced CRC-LM.

*2.4.3. Unresectable disease amenable to conversion chemotherapy*

*2.4.2. Resectable metachronous metastases*

224 Colorectal Cancer - Surgery, Diagnostics and Treatment

history.

approach [38].

*2.4.4. New surgical techniques*

*5-Flurouracil (5-FU)* is the main stay of all current standard CRC chemotherapy regimens, despite the fact that it causes serious side effects (grade 3 or 4) in up to 30% of patients. Sev‐ eral enzymes involved in 5-FU metabolism have been proposed as predictors of response to fluopyrimidine treatment: 5-FU exerts its activity by inhibiting thymidylate synthase (TS), a key enzyme of nucleotide pyrimidine metabolism that is essential for DNA synthesis and cellular proliferation. Thymidine phosphorylase (TP) is another enzyme involved in thymi‐ dine metabolism, which regulates the conversion of thymine to thymidine; this is why it is thought to limit the toxicity of high levels of thymidine and prevent replication errors dur‐ ing DNA synthesis. In this role, TP degrades 5-FU, limiting the activity of this chemothera‐ peutic agent. Dihydropyridimine dehydrogenase (DPD) is a rate-limiting hepatic enzyme involved in the catabolism of 5-FU [45]. It was found that low levels of expression of TP, DPD and TS were independently associated with improved overall survival [46]. Specifical‐ ly, deficiency in DPD activity caused by mutations in the gene encoding DPD (the *DYPD* gene) can lead to severe 5-FU-related toxicities, which can be fatal. However, as mutations in the *DPYD* gene are responsible for only some of the adverse reactions to 5-FU and the asso‐ ciation between genotype and phenotype is not clear [47], further assay development and prospective trials are needed to evaluate the clinical usefulness of these enzymes in predict‐ ing which patients are likely to develop serious, life-threatening toxicity to 5-FU [48].*Irinote‐ can (CPT-11),* a topoisomerase inhibitor, shows efficacy in the treatment of mCRC when used either as a single agent or in combination with radiotherapy and/or other chemothera‐ peutic drugs. Irinotecan acts as an inhibitor of DNA topoisomerase I (Topo I) and exerts a cytotoxic effect in replicating cells by inducing DNA strand breaks [49]. The active metabo‐ lite of irinotecan is SN-38, which is metabolised *in vivo* through conjugation by the liver en‐ zyme uridine diphosphate glucuronosyltransferase (UGT1A1). A variant of the gene encoding this enzyme (UGTA1\*28) has come to be considered the main pharmacogenetic marker for severe haematological toxicity (neutropaenia) of the drug. Nevertheless, UGT1A1\*28 testing as a predictive marker of adverse effects needs to be further investigated before translation to clinical practice and the available data are not conclusive in defining a precise genotype-based dosage [50-51]. In addition, tumour expression of Topo-I has been explored as a biomarker of the efficacy of irinotecan-based therapies [52]. Although further studies are needed, it has been shown that high levels of Topo-I in tumour tissue are associ‐ ated with a good response to irinotecan [53-54]; these data are consistent with the hypothe‐ sis that a larger amount of Topo I would facilitate the activity of a Topo I inhibitor [55].*Oxaliplatin* is a platinum analogue that improves response rate and survival in patients with advanced CRC. DNA kinking is the major feature of platinum-DNA adducts that block DNA replication and lead to cancer cell death. These DNA strand breaks are recognised and repaired by the nucleotide excision repair (NER) pathway, whose major components are ex‐ cision repair cross-complementation group (ERCC1 and ERCC2) proteins, acting as the ratelimiting enzymes of oxaliplatin efficacy. Several studies have demonstrated that low levels of ERCC1 and/or ERCC2 gene expression correlate well with better response rates following oxaliplatin-based therapy in advanced CRC patients, leading to improved survival [56-58]. Despite these promising findings, most of the studies have been retrospective and differed significantly in design, and results have not been consistent. Further prospective trials are needed to assess the correlation between decreased expression of *ERCC1* and *ERCC2* and platinum toxicities.

tion and, on the other, KRAS activates BRAF, which in turn triggers the mitogen-activated protein kinases [61]. Abnormal expression of EGFR has been demonstrated in many advanced tumours, including in breast cancers, gliomas and lung cancer. In the case of mCRC, EGFR overexpression has been detected in 60-80% of cases [59]and a correlation has been reported with early tumour recurrence and extra-hepatic metastasis [62]. For these reasons, researchers

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Cetuximab,achimericIgG1monoclonalantibody(mAb),andpanitumumab,ahumanisedIgG2 mAb, target the EGFR and have small, but nonetheless clinically important response rates of around 10% in unselected patients with chemotherapy-refractory metastatic CRCs. However, its exact role in the CRC metastatic cascade has not yet been characterised due to controver‐ sial results obtained with anti-EGFR antibody therapy. In fact, it has been shown that the response to this therapy is independent of EGFR expression in tumour tissue [63]. In relation to this, some studies suggest that EGFR expression in the primary tumour does not necessari‐ lycorrespondwiththe levelof expressioninmetastatic tissue,whileother studieshave reported 78-100% concordance in EGFR expression in the two tissue compartments [64]. These find‐ ings prompted an effort to identify alternative predictive molecular biomarkers that could help to select patients more likely to benefit from anti-EGFR agents. Candidates that have been investigated so far include not only molecular alterations affecting the EGFR, but also molecu‐ lareventsdownstreaminthepathway,suchasaberrationsintheinterlinkedRAS-RAF-mitogen-

activated protein kinase and PI3K-AKT-mTOR intracellular signalling transducers.

including NRAS, BRAF, PIK3CA and PTEN.

wild-type and mutant *NRAS.*

*KRAS* encodes for a cytoplasmic GTP-binding protein with low inherent GTPase activity. When the KRAS protein is bound to GTP, it relays signals of cellular proliferation and inhib‐ ition of apoptosis, acting as a typical oncogene. Activating mutations in KRAS lead to a gain in function of this gene, and hence over-expression of RAS/RAF-dependent proteins. Specifi‐ cally, mutations in codons 12 and 13 of exon 2 have been demonstrated to predict low re‐ sponse rate to EGFR monoclonal antibodies-targeted therapy [65]. A lack of efficacy and also a possible detrimental effect on anti-EGFR–based chemotherapy in KRAS-mutated patients have been suggested by some trials using cetuximab in first-line therapy for mCRC, such as OPUS (oxaliplatin plus cetuximab) [66] and CRYSTAL (irinotecan plus cetuximab) [67]. These data indicate that KRAS mutations can be considered a highly specific biomarker to predict poor response to treatment with anti-EGFR mAbs. In addition, due to the fact that anti-EGFR agents fail to achieve either objective responses or disease stabilization in a sub‐ stantial proportion of patients with wild-type KRAS tumours also, it seems necessary to in‐ vestigate mutations in other genes involved in signalling pathways downstream of EGFR,

Activating mutations in other members of the RAS family are less common than those found in KRAS. For instance, the reported frequency of *NRAS* mutations is 2.2 to 2.6%. Patients with tumours with these mutations had a significantly poorer response rate to anti-EGFR therapy [68], although no significant differences were seen in overall survival between patients with

Mutations in *BRAF,* the major effector of *KRAS,* have also been associated with reduced sensitivity to EGFR-directed therapy. In a retrospective study, Di Nicolantino *et al*.

started to explore therapeutic strategies to disrupt EGFR function.

#### **3.2. Molecular predictors of response to anti-EGFR therapy**

We should also consider other markers which it has been suggested may be useful for predicting patient responses to biological agents, in particular anti-epidermal growth factor receptor (EGFR) monoclonal therapy. EGFR is a member of the transmembrane tyrosine kinase receptor family ErbB, involved in tumour cell proliferation, inhibition of apoptosis, invasion, migration and angiogenesis [59-60]. When a ligand binds the EGFR homo or hetero-dimers are formed with other ErbB family members, initiating two main intracellular cascades, which are important for cell survival, proliferation and migration. On the one hand, membrane localization of the lipid kinase PIK3CA counteracts PTEN and promotes AKT1 phosphoryla‐ tion and, on the other, KRAS activates BRAF, which in turn triggers the mitogen-activated protein kinases [61]. Abnormal expression of EGFR has been demonstrated in many advanced tumours, including in breast cancers, gliomas and lung cancer. In the case of mCRC, EGFR overexpression has been detected in 60-80% of cases [59]and a correlation has been reported with early tumour recurrence and extra-hepatic metastasis [62]. For these reasons, researchers started to explore therapeutic strategies to disrupt EGFR function.

ly, deficiency in DPD activity caused by mutations in the gene encoding DPD (the *DYPD* gene) can lead to severe 5-FU-related toxicities, which can be fatal. However, as mutations in the *DPYD* gene are responsible for only some of the adverse reactions to 5-FU and the asso‐ ciation between genotype and phenotype is not clear [47], further assay development and prospective trials are needed to evaluate the clinical usefulness of these enzymes in predict‐ ing which patients are likely to develop serious, life-threatening toxicity to 5-FU [48].*Irinote‐ can (CPT-11),* a topoisomerase inhibitor, shows efficacy in the treatment of mCRC when used either as a single agent or in combination with radiotherapy and/or other chemothera‐ peutic drugs. Irinotecan acts as an inhibitor of DNA topoisomerase I (Topo I) and exerts a cytotoxic effect in replicating cells by inducing DNA strand breaks [49]. The active metabo‐ lite of irinotecan is SN-38, which is metabolised *in vivo* through conjugation by the liver en‐ zyme uridine diphosphate glucuronosyltransferase (UGT1A1). A variant of the gene encoding this enzyme (UGTA1\*28) has come to be considered the main pharmacogenetic marker for severe haematological toxicity (neutropaenia) of the drug. Nevertheless, UGT1A1\*28 testing as a predictive marker of adverse effects needs to be further investigated before translation to clinical practice and the available data are not conclusive in defining a precise genotype-based dosage [50-51]. In addition, tumour expression of Topo-I has been explored as a biomarker of the efficacy of irinotecan-based therapies [52]. Although further studies are needed, it has been shown that high levels of Topo-I in tumour tissue are associ‐ ated with a good response to irinotecan [53-54]; these data are consistent with the hypothe‐ sis that a larger amount of Topo I would facilitate the activity of a Topo I inhibitor [55].*Oxaliplatin* is a platinum analogue that improves response rate and survival in patients with advanced CRC. DNA kinking is the major feature of platinum-DNA adducts that block DNA replication and lead to cancer cell death. These DNA strand breaks are recognised and repaired by the nucleotide excision repair (NER) pathway, whose major components are ex‐ cision repair cross-complementation group (ERCC1 and ERCC2) proteins, acting as the ratelimiting enzymes of oxaliplatin efficacy. Several studies have demonstrated that low levels of ERCC1 and/or ERCC2 gene expression correlate well with better response rates following oxaliplatin-based therapy in advanced CRC patients, leading to improved survival [56-58]. Despite these promising findings, most of the studies have been retrospective and differed significantly in design, and results have not been consistent. Further prospective trials are needed to assess the correlation between decreased expression of *ERCC1* and *ERCC2* and

226 Colorectal Cancer - Surgery, Diagnostics and Treatment

platinum toxicities.

**3.2. Molecular predictors of response to anti-EGFR therapy**

We should also consider other markers which it has been suggested may be useful for predicting patient responses to biological agents, in particular anti-epidermal growth factor receptor (EGFR) monoclonal therapy. EGFR is a member of the transmembrane tyrosine kinase receptor family ErbB, involved in tumour cell proliferation, inhibition of apoptosis, invasion, migration and angiogenesis [59-60]. When a ligand binds the EGFR homo or hetero-dimers are formed with other ErbB family members, initiating two main intracellular cascades, which are important for cell survival, proliferation and migration. On the one hand, membrane localization of the lipid kinase PIK3CA counteracts PTEN and promotes AKT1 phosphoryla‐

Cetuximab,achimericIgG1monoclonalantibody(mAb),andpanitumumab,ahumanisedIgG2 mAb, target the EGFR and have small, but nonetheless clinically important response rates of around 10% in unselected patients with chemotherapy-refractory metastatic CRCs. However, its exact role in the CRC metastatic cascade has not yet been characterised due to controver‐ sial results obtained with anti-EGFR antibody therapy. In fact, it has been shown that the response to this therapy is independent of EGFR expression in tumour tissue [63]. In relation to this, some studies suggest that EGFR expression in the primary tumour does not necessari‐ lycorrespondwiththe levelof expressioninmetastatic tissue,whileother studieshave reported 78-100% concordance in EGFR expression in the two tissue compartments [64]. These find‐ ings prompted an effort to identify alternative predictive molecular biomarkers that could help to select patients more likely to benefit from anti-EGFR agents. Candidates that have been investigated so far include not only molecular alterations affecting the EGFR, but also molecu‐ lareventsdownstreaminthepathway,suchasaberrationsintheinterlinkedRAS-RAF-mitogenactivated protein kinase and PI3K-AKT-mTOR intracellular signalling transducers.

*KRAS* encodes for a cytoplasmic GTP-binding protein with low inherent GTPase activity. When the KRAS protein is bound to GTP, it relays signals of cellular proliferation and inhib‐ ition of apoptosis, acting as a typical oncogene. Activating mutations in KRAS lead to a gain in function of this gene, and hence over-expression of RAS/RAF-dependent proteins. Specifi‐ cally, mutations in codons 12 and 13 of exon 2 have been demonstrated to predict low re‐ sponse rate to EGFR monoclonal antibodies-targeted therapy [65]. A lack of efficacy and also a possible detrimental effect on anti-EGFR–based chemotherapy in KRAS-mutated patients have been suggested by some trials using cetuximab in first-line therapy for mCRC, such as OPUS (oxaliplatin plus cetuximab) [66] and CRYSTAL (irinotecan plus cetuximab) [67]. These data indicate that KRAS mutations can be considered a highly specific biomarker to predict poor response to treatment with anti-EGFR mAbs. In addition, due to the fact that anti-EGFR agents fail to achieve either objective responses or disease stabilization in a sub‐ stantial proportion of patients with wild-type KRAS tumours also, it seems necessary to in‐ vestigate mutations in other genes involved in signalling pathways downstream of EGFR, including NRAS, BRAF, PIK3CA and PTEN.

Activating mutations in other members of the RAS family are less common than those found in KRAS. For instance, the reported frequency of *NRAS* mutations is 2.2 to 2.6%. Patients with tumours with these mutations had a significantly poorer response rate to anti-EGFR therapy [68], although no significant differences were seen in overall survival between patients with wild-type and mutant *NRAS.*

Mutations in *BRAF,* the major effector of *KRAS,* have also been associated with reduced sensitivity to EGFR-directed therapy. In a retrospective study, Di Nicolantino *et al*. [69]examined tumours from patients who had received anti-EGFR therapy. They found that none of the patients carrying the BRAF V600E mutation responded and that none of the responders had a BRAF mutation. Moreover, De Roock *et al*. [68]recently conducted a large trial in which they analysed tumour specimens from CRC patients treated with the anti-EGFR agent cetuximab. They found that KRAS and BRAF mutations were mutually exclusive; the *BRAF* mutation was identified in 4.7% of cases and those carrying the mutation had a signifi‐ cantly lower response to anti-EGFR therapy, than those with BRAF wild-type tumours.

levels was significantly associated with response rate after receiving bevacizumab-containing

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Recently, the development of quantitative predictive biomarkers has led to the increased use of imaging in the evaluation of tumour angiogenesis. Dynamic contrast enhanced-MRI (DCE-MRI) is a technique that can assess tumour perfusion and microvascular vessel wall permea‐ bility. Although it is difficult to evaluate the subtle changes occurring during bevacizumab treatment, correlations between tumour grade, microvessel density and VEGF expression in clinical trials of angiogenesis inhibitors have led to DCE-MRI parameters being proposed as biomarkers of drug efficacy [73]. Lastly, some authors have investigated changes in plasma cytokines and angiogenic factors during treatment as potential markers of therapeutic

Due to the genetic heterogeneity of CRC, many authors agree that it is likely to be necessary to assemble a panel of biomarkers to obtain high enough sensitivity to use these types of biomarkers as a screening test in clinical practice [48, 52]. To date, however, a limited number of markers have been identified in CRC, and their individual use has led to conflicting results. In this context, advances in genomic techniques, such as DNA microarrays (allowing highthroughput analysis of genes), are very important as they provide large volumes of data which increases the probability of uncovering potential biomarkers. Recently, a total of 66 genes associated with benefit from adjuvant 5-FU/leucovorin treatment were identified. Six of the socalled "chemotherapy benefit genes" were selected to create treatment score algorithms. If validated, these signatures will quantify the likelihood of differential treatment benefit from 5- FU-based therapy [79]. Further, DNA microarray-based gene expression profiling provides a strategy to search systematically for molecular markers of colon cancer. Gene expression analysis studies have already resulted in many new insights into cancer biology and mRNA expressionanalysis is turning outto be a veryusefultoolfordisease outcomeprediction[80-81].

**4. Emerging targeting agents for colorectal liver metastasis**

The current treatment recommendations for mCRC indicate that therapeutic approach should be multidisciplinary [82], as surgery plus perioperative treatment offers better survival than surgery alone in patients with resectable or potentially resectable disease. Thus, whereas primary surgery is the gold standard for individuals with a single mestatasis, it seems that for multinodular disease, neoadyuvant chemotherapy followed by surgery may be more appro‐ priate [83]. Though in cases of unresectable aggressive disease, treatment should be decided on a case-by-case basis (adapting the strategy to the characteristics of the patient), a multidis‐ ciplinary approach should be taken to planning treatment from the outset. In fact, in select unresectable patients chemotherapy allows subsequent rescue surgery and achieves a significant increase in five-year survival rates [39]. An essential aspect of the treatment strategy for advanced CRC is the consideration of treatment as a continuum. Thus, sequential admin‐

treatment, though results should be further validated [77].

**3.4. DNA microarray-based gene expression profiling**

response and resistance [78].

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, *PI3K/AKT/mTOR,* pathway is another major intracellular signalling effector pathway activated by EGFR stimulation. Mutations in this pathway are present in as many as 30-40% of CRC patients. In particular, mutations in PI3KCA have been described in 15% of colon carcinomas, 20% of these being found in exon 20. Patients carrying these mutations and treated with anti-EGFR therapy have poorer clinical outcomes than wild-type PIK3CA carriers. However, because the number of patients with these mutations is very low in most studies, there is a need for controlled trials to assess whether the use of BRAF and PIK3CA mutation analysis as predictors of anti-EGFR therapy efficacy improves clinical outcomes [70].

*PTEN* is the only tumour suppressor gene involved in the PI3K/AKT-mTOR pathway. Loss of PTEN function, due to mutations, deletions or epigenetic silencing, leads to activation of this pathway. On the other hand, intact PTEN expression in metastatic tissue was found to be predictive of response to cetuximab, while this was not observed in patients with intact PTEN expression in primary tumour tissue [71]. These data are, however, limited and the findings need to be explored in larger confirmatory studies.

#### **3.3. Molecular predictors of response to anti-VEGFR therapy**

VEGF is overexpressed in CRC and the level of expression is directly correlated with the development of metastasis [72]. The VEGF family is made up of six growth factors (GFs) which exert their effects via binding to one of the three VEGFRs which belong to the tyrosine kinase receptor (TKR) family, mostly found in endothelial cells and angioblasts [64]. Bevacizumab is a humanised mAb which binds to VEGFA blocking the binding of this GF to VEGFR, thereby avoiding the corresponding intracellular signal transduction. Although several groups have focused their research efforts on finding a biomarker to accurately predict the clinical benefit of adding bevacizumab to therapy, no predictive molecules have yet been identified.

Several candidate predictive biomarkers similar to the KRAS mutation for cetuximab, have been proposed for bevacizumab, but they have remained elusive [73]. Specifically, it has been shown that the efficacy of bevacizumab therapy is independent of KRAS, BRAF and p53 status [74-75].

Another candidate is Ang-2, a regulator of angiogenesis that exerts context-dependent effects on endothelial cells. Although this ligand binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of angiogenesis, recent data from analysis of tumours indicate that, under certain conditions, Ang-2 can stimulate endothelial cells, acting as an anti-apoptotic agent in these cells [76]. In this context, serum Ang-2 has been proposed as a candidate biomarker due to the fact that patients having low pre-therapeutic Ang-2 serum levels was significantly associated with response rate after receiving bevacizumab-containing treatment, though results should be further validated [77].

Recently, the development of quantitative predictive biomarkers has led to the increased use of imaging in the evaluation of tumour angiogenesis. Dynamic contrast enhanced-MRI (DCE-MRI) is a technique that can assess tumour perfusion and microvascular vessel wall permea‐ bility. Although it is difficult to evaluate the subtle changes occurring during bevacizumab treatment, correlations between tumour grade, microvessel density and VEGF expression in clinical trials of angiogenesis inhibitors have led to DCE-MRI parameters being proposed as biomarkers of drug efficacy [73]. Lastly, some authors have investigated changes in plasma cytokines and angiogenic factors during treatment as potential markers of therapeutic response and resistance [78].

#### **3.4. DNA microarray-based gene expression profiling**

[69]examined tumours from patients who had received anti-EGFR therapy. They found that none of the patients carrying the BRAF V600E mutation responded and that none of the responders had a BRAF mutation. Moreover, De Roock *et al*. [68]recently conducted a large trial in which they analysed tumour specimens from CRC patients treated with the anti-EGFR agent cetuximab. They found that KRAS and BRAF mutations were mutually exclusive; the *BRAF* mutation was identified in 4.7% of cases and those carrying the mutation had a signifi‐ cantly lower response to anti-EGFR therapy, than those with BRAF wild-type tumours.

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, *PI3K/AKT/mTOR,* pathway is another major intracellular signalling effector pathway activated by EGFR stimulation. Mutations in this pathway are present in as many as 30-40% of CRC patients. In particular, mutations in PI3KCA have been described in 15% of colon carcinomas, 20% of these being found in exon 20. Patients carrying these mutations and treated with anti-EGFR therapy have poorer clinical outcomes than wild-type PIK3CA carriers. However, because the number of patients with these mutations is very low in most studies, there is a need for controlled trials to assess whether the use of BRAF and PIK3CA mutation analysis as predictors of anti-EGFR

*PTEN* is the only tumour suppressor gene involved in the PI3K/AKT-mTOR pathway. Loss of PTEN function, due to mutations, deletions or epigenetic silencing, leads to activation of this pathway. On the other hand, intact PTEN expression in metastatic tissue was found to be predictive of response to cetuximab, while this was not observed in patients with intact PTEN expression in primary tumour tissue [71]. These data are, however, limited and the

VEGF is overexpressed in CRC and the level of expression is directly correlated with the development of metastasis [72]. The VEGF family is made up of six growth factors (GFs) which exert their effects via binding to one of the three VEGFRs which belong to the tyrosine kinase receptor (TKR) family, mostly found in endothelial cells and angioblasts [64]. Bevacizumab is a humanised mAb which binds to VEGFA blocking the binding of this GF to VEGFR, thereby avoiding the corresponding intracellular signal transduction. Although several groups have focused their research efforts on finding a biomarker to accurately predict the clinical benefit

of adding bevacizumab to therapy, no predictive molecules have yet been identified.

Several candidate predictive biomarkers similar to the KRAS mutation for cetuximab, have been proposed for bevacizumab, but they have remained elusive [73]. Specifically, it has been shown that the efficacy of bevacizumab therapy is independent of KRAS, BRAF and

Another candidate is Ang-2, a regulator of angiogenesis that exerts context-dependent effects on endothelial cells. Although this ligand binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of angiogenesis, recent data from analysis of tumours indicate that, under certain conditions, Ang-2 can stimulate endothelial cells, acting as an anti-apoptotic agent in these cells [76]. In this context, serum Ang-2 has been proposed as a candidate biomarker due to the fact that patients having low pre-therapeutic Ang-2 serum

therapy efficacy improves clinical outcomes [70].

228 Colorectal Cancer - Surgery, Diagnostics and Treatment

p53 status [74-75].

findings need to be explored in larger confirmatory studies.

**3.3. Molecular predictors of response to anti-VEGFR therapy**

Due to the genetic heterogeneity of CRC, many authors agree that it is likely to be necessary to assemble a panel of biomarkers to obtain high enough sensitivity to use these types of biomarkers as a screening test in clinical practice [48, 52]. To date, however, a limited number of markers have been identified in CRC, and their individual use has led to conflicting results.

In this context, advances in genomic techniques, such as DNA microarrays (allowing highthroughput analysis of genes), are very important as they provide large volumes of data which increases the probability of uncovering potential biomarkers. Recently, a total of 66 genes associated with benefit from adjuvant 5-FU/leucovorin treatment were identified. Six of the socalled "chemotherapy benefit genes" were selected to create treatment score algorithms. If validated, these signatures will quantify the likelihood of differential treatment benefit from 5- FU-based therapy [79]. Further, DNA microarray-based gene expression profiling provides a strategy to search systematically for molecular markers of colon cancer. Gene expression analysis studies have already resulted in many new insights into cancer biology and mRNA expressionanalysis is turning outto be a veryusefultoolfordisease outcomeprediction[80-81].

## **4. Emerging targeting agents for colorectal liver metastasis**

The current treatment recommendations for mCRC indicate that therapeutic approach should be multidisciplinary [82], as surgery plus perioperative treatment offers better survival than surgery alone in patients with resectable or potentially resectable disease. Thus, whereas primary surgery is the gold standard for individuals with a single mestatasis, it seems that for multinodular disease, neoadyuvant chemotherapy followed by surgery may be more appro‐ priate [83]. Though in cases of unresectable aggressive disease, treatment should be decided on a case-by-case basis (adapting the strategy to the characteristics of the patient), a multidis‐ ciplinary approach should be taken to planning treatment from the outset. In fact, in select unresectable patients chemotherapy allows subsequent rescue surgery and achieves a significant increase in five-year survival rates [39]. An essential aspect of the treatment strategy for advanced CRC is the consideration of treatment as a continuum. Thus, sequential admin‐ istration of conventional drug combinations based on fluoropyrimidines plus oxaliplatin or irinotecan, results in longer survival. While XELOX, FOLFOX and FOLFIRI are the schemes most commonly used, the trend has been for the standard of care chemotherapy for first-line mCRC to change from FOLFIRI to FOLFOX [84]. In order to improve the poor prognosis of patients with mCRC, treatment intensification has been also tested using the combination of the three active agents 5-FU/leucovorin, oxaliplatin and irinotecan (FOLFOXIRI), and this has achieved increase in R0 secondary resection rate and in overall survival [85]. Other schemes are currently being evaluated in randomised phase II trials as first-line chemotherapy for advanced CRC; these include TOMOX (oxaliplatin plus raltitrexed) which has been found to have a similar efficacy to FOLFOX [86].

The other two antiangiogenenic biological agents, cetuximab and panitumumab target the ligand-binding domain of EGFR. Signalling of this receptor appears to modulate angiogenesis via the upregulation of VEGF and other angiogenic factors [60]. The use of these EGFR inhibitors was approved for mCRC in patients with wild-type KRAS, whose tumours express EGFR. In fact, as described previously, BRAF and codon 12 KRAS mutations are predictive of adverse outcome in CRC patients receiving cetuximab, being associated with a shorter time to progression and poor survival [91]. In contrast, it has been demonstrated that the combination of chemotherapy, such as irinotecan or FOLFIRI, and cetuximab as a first line in patients with wild-type KRAS significantly improves survival [67, 92]. Cetuximab is also indicated as a monotherapy in such patients following failure of both irinotecan- and oxaliplatin-based chemotherapy [93], while panitumumab is also a valid second-line option for wild-type KRAS patients, as a monotherapy or combined with FOLFIRI [94], though the addition of this EGFR inhibitor to oxaliplatin-based chemotherapy in first-line treatment of mCRC did not improve survival or response rate [95]. In an attempt to increase anti-tumour activity by simultaneously blocking both VEGF and EGFR pathways, some randomised studies have explored the combination of cetuximab or panitumumab with bevacizumab plus chemotherapy, but no benefits were observed, and in some cases the outcome was actually poorer with a greater

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toxicity, so this type of combination is not recommended for mCRC [64].

(regorafenib, brivanib alaninate, cediranib and linifanib) [93, 97].

boembolic events, bleeding and proteinuria, with bevacizumab treatment [93].

In relation to toxicity, treatment with these biological agents is associated with a wide range of adverse events that sometimes require discontinuation of treatment; these include severe hypersensitivity and skin toxicities, in the case of EGFR mAbs, and hypertension, throm‐

Despite the aforementioned advances, the targeted biological agents currently available are only effective in a small subset of patients (for example, less than half of the KRAS-wild type patient population benefits from anti-EGFR strategies) [96]and their overall impact on the treatment of mCRC has been relatively modest (beneficial effects only lasting on the order of weeks to a few months). These limited results, coupled with the undesirable effects, has led to intensification of the search for novel antiangiogenic therapies to increase the anti-tumour activity in advanced CRC. There are currently several molecules in phase II and III trials for treatment of mCRC that target various members of the VEGF family (aflibercept), signalling by VEGFRs (ramucirumab and IMC-18F1) or the tyrosine kinase components of these receptors

Aflibercept is a multiple angiogenic factor trap designed to block the angiogenesis network by binding VEGF-A, VEGF-B and placental growth factor (PLGF) [98]. The recent results of a multinational phase III study (VELOUR trial: aflibercept/FOLFIRI *vs.* placebo/FOLFIRI) demonstrated significant improvements in median overall survival, supporting the use of this VEGF Trap as a second-line option for patients with prior oxaliplatin treatment [99]. Ramu‐ cirumab is a fully humanised mAb directed against the extracellular domain of VEGFR-2, which binds VEGF-A and is believed to be the key VEGFR involved in tumour angiogenesis. Like aflibercept, ramucirumab is currently being evaluated in combination with FOLFIRI in a phase III trial for the second-line treatment of mCRC patients for whom prior oxaliplatin- and bevacizumab-containing initial therapy has failed [100]. In addition, a phase II study of

The development of new drugs that selectively target specific molecular pathways involved in tumour progression (targeted therapy) has resulted in one of the most important advances in mCRC in the last decade, with biological agents today being a commonly used weapon in the armamentarium against mCRC, particularly in chemorefractory patients and those who are not initially suitable liver resection candidates [87]. In recent years, intense efforts have been focused on developing new molecules to inhibit targets that are critical for CRC, including new anti-angiogenesis agents, novel tyrosine kinase inhibitors (TKIs), agents to act on the PI3K/ Akt signalling pathway, modulators of autophagy, and proteasome inhibitors, as well as targeted therapies against cancer stem cells, among others.

#### **4.1. Targeting angiogenesis**

GFs have been identified as important targets [88]and the development of targeting biological agents, directed to block effects of GFs on tumour cells, and their integration with cytotoxic chemotherapy regimens has resulted in significant improvements in efficacy outcomes.

One of the most important effects of some GFs is the promotion of angiogenesis, an essential mechanism for both primary tumour growth and metastasis. Due to this, novel therapeutic approaches have focused on the role of angiogenesis-targeting inhibitors. So far, three antiangiogenic biological agents have been approved for the treatment of patients with mCRC: bevacizumab, cetuximab and panitumab. The first successful targeting agent was bevacizu‐ mab; today, there is clear evidence to recommend addition of this anti-VEGF antibody to cytotoxic therapy (irrespective of the selected chemotherapy regimen) in both the first- and second-line treatment, this significantly increasing overall survival [75]. Moreover, it has been shown that bevacizumab, combined with FOLFOX or FOLFIRI, may also be active in chemo‐ refractory and selected mCRC patients [89]. Currently, new trials (CHARTA and PERIMAX) are being conducted with bevacizumab plus FOLFIRI, designed to assess the benefits and limitations of a highly active four-drug regimen in mCRC [4]. In addition, it is also important to note that in patients with mCRC on a bevacizumab-containing regimen who show disease progression and hence need a change in the chemotherapy regimen, maintenance therapy with bevacizumab appears to be associated with significantly longer overall survival than the same regimen without bevacizumab [90]; this fact highlights the importance of bevacizumab therapy beyond disease progression in patients with mCRC, although this use is not currently recom‐ mended outside clinical trials.

The other two antiangiogenenic biological agents, cetuximab and panitumumab target the ligand-binding domain of EGFR. Signalling of this receptor appears to modulate angiogenesis via the upregulation of VEGF and other angiogenic factors [60]. The use of these EGFR inhibitors was approved for mCRC in patients with wild-type KRAS, whose tumours express EGFR. In fact, as described previously, BRAF and codon 12 KRAS mutations are predictive of adverse outcome in CRC patients receiving cetuximab, being associated with a shorter time to progression and poor survival [91]. In contrast, it has been demonstrated that the combination of chemotherapy, such as irinotecan or FOLFIRI, and cetuximab as a first line in patients with wild-type KRAS significantly improves survival [67, 92]. Cetuximab is also indicated as a monotherapy in such patients following failure of both irinotecan- and oxaliplatin-based chemotherapy [93], while panitumumab is also a valid second-line option for wild-type KRAS patients, as a monotherapy or combined with FOLFIRI [94], though the addition of this EGFR inhibitor to oxaliplatin-based chemotherapy in first-line treatment of mCRC did not improve survival or response rate [95]. In an attempt to increase anti-tumour activity by simultaneously blocking both VEGF and EGFR pathways, some randomised studies have explored the combination of cetuximab or panitumumab with bevacizumab plus chemotherapy, but no benefits were observed, and in some cases the outcome was actually poorer with a greater toxicity, so this type of combination is not recommended for mCRC [64].

istration of conventional drug combinations based on fluoropyrimidines plus oxaliplatin or irinotecan, results in longer survival. While XELOX, FOLFOX and FOLFIRI are the schemes most commonly used, the trend has been for the standard of care chemotherapy for first-line mCRC to change from FOLFIRI to FOLFOX [84]. In order to improve the poor prognosis of patients with mCRC, treatment intensification has been also tested using the combination of the three active agents 5-FU/leucovorin, oxaliplatin and irinotecan (FOLFOXIRI), and this has achieved increase in R0 secondary resection rate and in overall survival [85]. Other schemes are currently being evaluated in randomised phase II trials as first-line chemotherapy for advanced CRC; these include TOMOX (oxaliplatin plus raltitrexed) which has been found to

The development of new drugs that selectively target specific molecular pathways involved in tumour progression (targeted therapy) has resulted in one of the most important advances in mCRC in the last decade, with biological agents today being a commonly used weapon in the armamentarium against mCRC, particularly in chemorefractory patients and those who are not initially suitable liver resection candidates [87]. In recent years, intense efforts have been focused on developing new molecules to inhibit targets that are critical for CRC, including new anti-angiogenesis agents, novel tyrosine kinase inhibitors (TKIs), agents to act on the PI3K/ Akt signalling pathway, modulators of autophagy, and proteasome inhibitors, as well as

GFs have been identified as important targets [88]and the development of targeting biological agents, directed to block effects of GFs on tumour cells, and their integration with cytotoxic chemotherapy regimens has resulted in significant improvements in efficacy outcomes.

One of the most important effects of some GFs is the promotion of angiogenesis, an essential mechanism for both primary tumour growth and metastasis. Due to this, novel therapeutic approaches have focused on the role of angiogenesis-targeting inhibitors. So far, three antiangiogenic biological agents have been approved for the treatment of patients with mCRC: bevacizumab, cetuximab and panitumab. The first successful targeting agent was bevacizu‐ mab; today, there is clear evidence to recommend addition of this anti-VEGF antibody to cytotoxic therapy (irrespective of the selected chemotherapy regimen) in both the first- and second-line treatment, this significantly increasing overall survival [75]. Moreover, it has been shown that bevacizumab, combined with FOLFOX or FOLFIRI, may also be active in chemo‐ refractory and selected mCRC patients [89]. Currently, new trials (CHARTA and PERIMAX) are being conducted with bevacizumab plus FOLFIRI, designed to assess the benefits and limitations of a highly active four-drug regimen in mCRC [4]. In addition, it is also important to note that in patients with mCRC on a bevacizumab-containing regimen who show disease progression and hence need a change in the chemotherapy regimen, maintenance therapy with bevacizumab appears to be associated with significantly longer overall survival than the same regimen without bevacizumab [90]; this fact highlights the importance of bevacizumab therapy beyond disease progression in patients with mCRC, although this use is not currently recom‐

have a similar efficacy to FOLFOX [86].

230 Colorectal Cancer - Surgery, Diagnostics and Treatment

**4.1. Targeting angiogenesis**

mended outside clinical trials.

targeted therapies against cancer stem cells, among others.

In relation to toxicity, treatment with these biological agents is associated with a wide range of adverse events that sometimes require discontinuation of treatment; these include severe hypersensitivity and skin toxicities, in the case of EGFR mAbs, and hypertension, throm‐ boembolic events, bleeding and proteinuria, with bevacizumab treatment [93].

Despite the aforementioned advances, the targeted biological agents currently available are only effective in a small subset of patients (for example, less than half of the KRAS-wild type patient population benefits from anti-EGFR strategies) [96]and their overall impact on the treatment of mCRC has been relatively modest (beneficial effects only lasting on the order of weeks to a few months). These limited results, coupled with the undesirable effects, has led to intensification of the search for novel antiangiogenic therapies to increase the anti-tumour activity in advanced CRC. There are currently several molecules in phase II and III trials for treatment of mCRC that target various members of the VEGF family (aflibercept), signalling by VEGFRs (ramucirumab and IMC-18F1) or the tyrosine kinase components of these receptors (regorafenib, brivanib alaninate, cediranib and linifanib) [93, 97].

Aflibercept is a multiple angiogenic factor trap designed to block the angiogenesis network by binding VEGF-A, VEGF-B and placental growth factor (PLGF) [98]. The recent results of a multinational phase III study (VELOUR trial: aflibercept/FOLFIRI *vs.* placebo/FOLFIRI) demonstrated significant improvements in median overall survival, supporting the use of this VEGF Trap as a second-line option for patients with prior oxaliplatin treatment [99]. Ramu‐ cirumab is a fully humanised mAb directed against the extracellular domain of VEGFR-2, which binds VEGF-A and is believed to be the key VEGFR involved in tumour angiogenesis. Like aflibercept, ramucirumab is currently being evaluated in combination with FOLFIRI in a phase III trial for the second-line treatment of mCRC patients for whom prior oxaliplatin- and bevacizumab-containing initial therapy has failed [100]. In addition, a phase II study of ramucirumab in the first-line setting in combination with FOLFOX6 therapy is also in progress [101]. Another anti-VEGFR mAb, IMC-18F1, which targets VEGFR-1 has been developed recently [102], and is also being studied in a phase II trial in mCRC.

pathways that may overcome resistance [107]. In relation to this, it has been demonstrated that addition of the multikinase inhibitor, sorafenib, enhances the therapeutic effect of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs [108]. In addition, it has been suggested that mTOR inhibition by metformin (an antidiabeticdrug), via activation oftheAMP-activatedprotein kinase (AMPK)pathway, which functions as a sensorfor cellularnutrient andenergylevels, couldbe anewoptionforCRC[109].

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Autophagy is a multistep process of sequestration and subsequent elimination of cytosolic proteins, damaged organelles and protein aggregates in autophagosomes [110]. This selfdegradation, via the lysosome, is responsible for the maintenance of intracellular homeostasis and enables cell survival under stress conditions. In the cancer cell, autophagy can be used as a strategy of self-adaption to generate nutrients and energy during tumour progression and in periods of hypoxia and stress, such as induced by chemotherapy, leading to development of drug resistance. The role of autophagy after chemotherapy remains controversial, it having been suggested that autophagy induction may increase efficacy of other anti-tumour agents, while most evidence suggests that the inhibition of autophagy is what can increase the effectiveness of these agents. As autophagy inhibitor, an analogue of chloroquine, hydroxy‐ chloroquine (HCQ), is currently involved in two different phase II studies for advanced CRC in combination with FOLFOX/bevacizumab or capecitabine/oxaliplatin/bevacizumab [111]. Given that HCQ induces ocular toxicities, such as retinopathy, novel autophagy inducers, such

In relation to autophagy inducers, since the PI3K/Akt/mTOR pathway is a key regulator of autophagy [113], mTOR inhibitors have been also used to modulate this mechanism, proving to be effective in many models for CRCs, but their clinical use has been less successful [114]. Proteasome inhibitors have also been described as autophagy inducers. It has been shown that proteasome inhibition generates a stress response through alteration of the protein milieu, which, in turn, induces endoplasmic reticulum stress; this causes an accumulation of misfolded proteins in the endoplasmic reticulum lumen and, consequently, induction of cellular stress responses, such as the unfolded protein response and autophagy to maintain endoplasmic reticulum homeostasis [110]. Bortezomib, the main proteasome inhibitor, was shown to induce autophagy in CRC cells [115]. However, in a randomised phase II study in relapsed or refractory CRC, bortezomib alone or in combination with irinotecan was not effective [116]. There are current trials examining combinations of bortezomib with other chemotherapies, such as oxaliplatin, 5-FU and leucovorin, in patients with advanced CRC [117]. In view of the limited results with autophagy inducers, some authors have suggested that optimal antitumour efficacy might be achieved by the combination of proteasome inhibitors and autoph‐

**4.4. Targeting cancer stem cells, Wnt pathway inhibitors, and tumour cell differentiation**

Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the capacity to selfrenew and to give rise to the heterogeneous lineages of cancer cells that comprise the tumour,

**4.3. Autophagy modulators and proteasome inhibitors**

as Lys05, are currently being investigated in CRC [112].

agy inhibitors [118].

**inducers**

Other candidate molecules represent new approaches to intracellular signal blockade of the VEGF and fibroblast growth factor (FGF) signalling pathways, via TKIs. In a recent phase III study (CORRECT trial), regorafenib has been found to improve survival in mCRC patients who progressed after all standard therapies, making it the first small-molecule multikinase inhibitor to have demonstrated survival benefits in such patients [103]. Brivanib alaninate is an oral TKI that specifically inhibits the VEGFR-1 and FGFR. This FGF signalling blockade may represent an important advantage, since it has been suggested that resistance to bevaci‐ zumab is associated with increased expression of FGF [78], and hence brivanib could have antiangiogenic activity in bevacizumab-resistant patients. In addition, a phase III trial com‐ bining brivanib and cetuximab in second/third line therapy in patients with advanced wildtype *KRAS* mCRC found improved progression free survival with no impact in overall survival [97]. Cediranib is an inhibitor of VEGFRs, platelet-derived growth factor-(PDGF) receptor beta and FGF receptor, whose activity has been compared with that of bevacizumab as a first-line treatment in combination with FOLFOX (HORIZON phase III trial) for mCRC patients; although cediranib activity was comparable to that of bevacizumab, the patient-reported outcomes were significantly less favourable [104]. Similarly, linifanib (a TKI that targets both VEGFRs and PDGFRs), in combination with FOLFOX, did not offer any advantages (over bevacizumab) in a randomised phase II trial as a second-line treatment for mCRC [105].

#### **4.2. Targeting PI3K/Akt/mTOR pathway**

The PI3K/Akt/mTOR pathway, an essential regulator of protein translation and cell prolifer‐ ation, is another important target being investigated for mCRC in phase II and III trials. The PI3K/AKT/mTOR signalling cascade is constitutively active in many types of cancer and, in particular, it plays a critical role in the growth and progression of CRC. In addition, it has been demonstrated that this pathway may be upregulated after blockade of both VEGF- and EGFRmediated signalling [101].

These aforementioned data provide the rationale for targeting this pathway therapeutically in CRC patients. Perifosine is an oral alkylphospholipid that targets both AKT and nuclear transcription factor-kappa B (NF-ĸB) pathways. This novel molecule appears to enhance the cytotoxic effects of 5-FU: it has produced promising results in a phase II randomised trial of capecitabine ± perifosine in previously treated patients with mCRC and, hence, is currently in phase III clinical development in combination with this 5-FU prodrug [106].

Activation of the PI3K/AKT cascade promotes mTOR, a serine-threonine kinase whose activation results in cell cycle progression and protein synthesis, and is involved in the CRC metastatic process. The mTOR inhibitors are analogues of rapamycin, including everolimus and temsirolimus, which are being investigated in clinical trials in combination with irinote‐ can, cetuximab, FOLFOX, bevacizumab or panatimumab in patients with mCRC progressing on prior chemotherapy [101]. Current expert opinion suggests that mTOR inhibitors may represent an attractive anti-tumour target in combination with strategies to target other pathways that may overcome resistance [107]. In relation to this, it has been demonstrated that addition of the multikinase inhibitor, sorafenib, enhances the therapeutic effect of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs [108]. In addition, it has been suggested that mTOR inhibition by metformin (an antidiabeticdrug), via activation oftheAMP-activatedprotein kinase (AMPK)pathway, which functions as a sensorfor cellularnutrient andenergylevels, couldbe anewoptionforCRC[109].

#### **4.3. Autophagy modulators and proteasome inhibitors**

ramucirumab in the first-line setting in combination with FOLFOX6 therapy is also in progress [101]. Another anti-VEGFR mAb, IMC-18F1, which targets VEGFR-1 has been developed

Other candidate molecules represent new approaches to intracellular signal blockade of the VEGF and fibroblast growth factor (FGF) signalling pathways, via TKIs. In a recent phase III study (CORRECT trial), regorafenib has been found to improve survival in mCRC patients who progressed after all standard therapies, making it the first small-molecule multikinase inhibitor to have demonstrated survival benefits in such patients [103]. Brivanib alaninate is an oral TKI that specifically inhibits the VEGFR-1 and FGFR. This FGF signalling blockade may represent an important advantage, since it has been suggested that resistance to bevaci‐ zumab is associated with increased expression of FGF [78], and hence brivanib could have antiangiogenic activity in bevacizumab-resistant patients. In addition, a phase III trial com‐ bining brivanib and cetuximab in second/third line therapy in patients with advanced wildtype *KRAS* mCRC found improved progression free survival with no impact in overall survival [97]. Cediranib is an inhibitor of VEGFRs, platelet-derived growth factor-(PDGF) receptor beta and FGF receptor, whose activity has been compared with that of bevacizumab as a first-line treatment in combination with FOLFOX (HORIZON phase III trial) for mCRC patients; although cediranib activity was comparable to that of bevacizumab, the patient-reported outcomes were significantly less favourable [104]. Similarly, linifanib (a TKI that targets both VEGFRs and PDGFRs), in combination with FOLFOX, did not offer any advantages (over bevacizumab) in a randomised phase II trial as a second-line treatment for mCRC [105].

The PI3K/Akt/mTOR pathway, an essential regulator of protein translation and cell prolifer‐ ation, is another important target being investigated for mCRC in phase II and III trials. The PI3K/AKT/mTOR signalling cascade is constitutively active in many types of cancer and, in particular, it plays a critical role in the growth and progression of CRC. In addition, it has been demonstrated that this pathway may be upregulated after blockade of both VEGF- and EGFR-

These aforementioned data provide the rationale for targeting this pathway therapeutically in CRC patients. Perifosine is an oral alkylphospholipid that targets both AKT and nuclear transcription factor-kappa B (NF-ĸB) pathways. This novel molecule appears to enhance the cytotoxic effects of 5-FU: it has produced promising results in a phase II randomised trial of capecitabine ± perifosine in previously treated patients with mCRC and, hence, is currently in

Activation of the PI3K/AKT cascade promotes mTOR, a serine-threonine kinase whose activation results in cell cycle progression and protein synthesis, and is involved in the CRC metastatic process. The mTOR inhibitors are analogues of rapamycin, including everolimus and temsirolimus, which are being investigated in clinical trials in combination with irinote‐ can, cetuximab, FOLFOX, bevacizumab or panatimumab in patients with mCRC progressing on prior chemotherapy [101]. Current expert opinion suggests that mTOR inhibitors may represent an attractive anti-tumour target in combination with strategies to target other

phase III clinical development in combination with this 5-FU prodrug [106].

recently [102], and is also being studied in a phase II trial in mCRC.

**4.2. Targeting PI3K/Akt/mTOR pathway**

232 Colorectal Cancer - Surgery, Diagnostics and Treatment

mediated signalling [101].

Autophagy is a multistep process of sequestration and subsequent elimination of cytosolic proteins, damaged organelles and protein aggregates in autophagosomes [110]. This selfdegradation, via the lysosome, is responsible for the maintenance of intracellular homeostasis and enables cell survival under stress conditions. In the cancer cell, autophagy can be used as a strategy of self-adaption to generate nutrients and energy during tumour progression and in periods of hypoxia and stress, such as induced by chemotherapy, leading to development of drug resistance. The role of autophagy after chemotherapy remains controversial, it having been suggested that autophagy induction may increase efficacy of other anti-tumour agents, while most evidence suggests that the inhibition of autophagy is what can increase the effectiveness of these agents. As autophagy inhibitor, an analogue of chloroquine, hydroxy‐ chloroquine (HCQ), is currently involved in two different phase II studies for advanced CRC in combination with FOLFOX/bevacizumab or capecitabine/oxaliplatin/bevacizumab [111]. Given that HCQ induces ocular toxicities, such as retinopathy, novel autophagy inducers, such as Lys05, are currently being investigated in CRC [112].

In relation to autophagy inducers, since the PI3K/Akt/mTOR pathway is a key regulator of autophagy [113], mTOR inhibitors have been also used to modulate this mechanism, proving to be effective in many models for CRCs, but their clinical use has been less successful [114]. Proteasome inhibitors have also been described as autophagy inducers. It has been shown that proteasome inhibition generates a stress response through alteration of the protein milieu, which, in turn, induces endoplasmic reticulum stress; this causes an accumulation of misfolded proteins in the endoplasmic reticulum lumen and, consequently, induction of cellular stress responses, such as the unfolded protein response and autophagy to maintain endoplasmic reticulum homeostasis [110]. Bortezomib, the main proteasome inhibitor, was shown to induce autophagy in CRC cells [115]. However, in a randomised phase II study in relapsed or refractory CRC, bortezomib alone or in combination with irinotecan was not effective [116]. There are current trials examining combinations of bortezomib with other chemotherapies, such as oxaliplatin, 5-FU and leucovorin, in patients with advanced CRC [117]. In view of the limited results with autophagy inducers, some authors have suggested that optimal antitumour efficacy might be achieved by the combination of proteasome inhibitors and autoph‐ agy inhibitors [118].

#### **4.4. Targeting cancer stem cells, Wnt pathway inhibitors, and tumour cell differentiation inducers**

Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the capacity to selfrenew and to give rise to the heterogeneous lineages of cancer cells that comprise the tumour, and it is believed that they could be crucial in controlling and curing cancer [119]. Specifically, there is increasing evidence that CSCs play an important role in the occurrence, growth, and progression of tumours, as well as possibly in the initiation of distant metastases. In addition, CSCs are also involved in resistance to conventional chemotherapeutic drugs, novel tumourtargeted drugs, and radiation therapy [120].

tions of these agents and conventional therapy could significantly reduce tumour growth,

New Strategies to Enhance the Efficacy of Surgical Treatment for Colorectal Liver Metastasis

http://dx.doi.org/10.5772/57326

235

CSCs are characterised by two main properties of normal stem cells, self-renewal and differ‐ entiation. Given this, the induction of differentiation using retinoids would be a plausible therapeutic strategy. ATRA, a potent differentiating agent, has been demonstrated to induce CSC growth inhibition, and this has been associated with down-regulation of Wnt/β-catenin signalling [128]. In a CRC tumour model of liver metastasis, we have demonstrated the antitumour effects of ATRA. This pro-differentiating agent hindered or completely abolished the pro-tumour stimulus produced by serum obtained from hepatectomised rats, and by a wide variety of GFs (HGF, VEGF, PDGF, EGF, and bFGF). In addition, in combination with 5-FU, an additive effect was observed in *in vitro* studies [129]. In *in vivo* experiments, ATRA also reduced tumour progression, though it failed to increase survival, both alone and in combi‐

Although surgical excision of tumour tissue remains the only potentially curative treatment for CRC-LM, several other techniques are now being developed to be used when surgery is

The list of possible new therapeutic techniques for CRC-LM seems likely to increase over the

**•** Surgical approaches focused on increasing the size of the liver lobes (staged surgery or portal branch ligatures), as the percentage of remnant liver after hepatectomy is a limiting factor

**•** Techniques for percutaneous tumour ablation, which can reduce CRC-LM volume and

**•** Nanoparticles (NPs) to selectively deliver drugs to tumour cells or induce local hyper‐

First, let us consider patients who could benefit from surgical excision of their liver metastases, but in whom the FLR would be less than 25%, which is currently considered the threshold of what can be tolerated. Initially, strategies for such cases were focused on selectively increasing the liver mass of liver lobes free of tumour. Some clinical trials have found that portal vein embolization (PVE) of the lobes bearing metastases induces regeneration of the other lobes, and this has been found to result in a 20-45% increase in their relative volume in two to eight weeks [130]. However, the clinical benefit of this procedure is not clear and, as there were also

In patients who have inadequate FLR to undergo disease clearance with a single hepatectomy, two-stage hepatectomy for bilobar liver metastases in combination with selected use of portal venous embolization is feasible. It offers the best chance of achieving adequate FLR hypertro‐

reports of tumour progression due to hepatectomy, it has not been widely adopted.

**5. New therapeutic techniques for colorectal liver metastasis**

allow surgery or at least delay the progression of the illness

metastasis and recurrence [127].

nation with 5-FU (unpublished data).

not feasible or to improve surgical results.

next five years, including:

in many patients

thermia.

CSCs have been identified not only in leukaemias, but also in solid tumours, including CRC. In fact, it has been suggested that CRC stem cells are responsible for tumour relapse, because conventional drugs fail to eliminate the CSC reservoir [121]. Due to this important clinical feature, CRC stem cells have recently been identified as a rational therapeutic target. Several CSC-targeted therapies have been proposed, including microbial- and plant-derived biomo‐ lecules; therapies directed at CSC-specific surface markers; some classical drugs, such as tranilast, curcumin and thioridazine; and reversal of their resistance to anti-tumour agents; so far, however, the toxicity of some of these approaches in normal stem cells and treatment resistance remain important limitations [122].

Various signalling pathways, such as Wingless/Int (Wnt), Hedgehog and Notch, are involved in maintaining the stemness of CSCs. Among these, Wnt, stands out for being particularly active in the majority of CRCs, and hence is the first being investigated for therapeutic targeting in CRC. A primary consequence of Wnt signalling activation is the stabilization of β-catenin in the cytoplasm, resulting in an increased translocation of β-catenin to the nucleus and, in turn, activation of Wnt target gene expression. Misregulation of the canonical Wnt/β-catenin pathway and aberrant activation of Wnt signalling target genes are common in CRC and contribute to cancer progression [123]. Despite the importance of this pathway, few com‐ pounds have progressed beyond preclinical development. Efforts have been made to investi‐ gate the inhibition of a number Wnt genes, including the matrix metalloproteinases (MMPs), which play an important role in the degradation of extracellular matrix component, crucial for invasion and metastasis. Some studies have shown that increased expression of various MMPs (MMP-1, MMP-2 and MMP-9) favours CRC progression and could predict liver metastasis. Further, several therapeutic MMP inhibitors have been developed, but so far they have failed to produce a survival benefit and, in addition, they have been associated with adverse effects, such as musculoskeletal syndrome. The development of more selective MMP inhibitors is seen as a possible way forward [124].

Another novel compound is salinomycin, a polyether ionophore antibiotic that has been shown to kill CSCs in various types of human cancer, including CRC cells, mostly by interfering with ABC drug transporters and the Wnt/β-catenin signalling pathway. Salinomycin inhibits the migratory and invasive capacity, and reduces the proportion of CD133 CSCs in HT29 and SW480 CRC cells [125]. The results from preclinical trials and its ability to kill therapy-resistant cancer cells make salinomycin a promising anticancer drug [126].

In recent years, other agents have been shown to suppress the self-renewal of CSCs *in vitro* and *in vivo*; these include metformin, DECA-14, rapamycin, oncostatin M, some natural compounds, oncolytic viruses, microRNAs, TNF-related apoptosis inducing ligand, telomer‐ ase inhibitors, mAbs and all-*trans* retinoic acid (ATRA). It has been suggested that combina‐ tions of these agents and conventional therapy could significantly reduce tumour growth, metastasis and recurrence [127].

and it is believed that they could be crucial in controlling and curing cancer [119]. Specifically, there is increasing evidence that CSCs play an important role in the occurrence, growth, and progression of tumours, as well as possibly in the initiation of distant metastases. In addition, CSCs are also involved in resistance to conventional chemotherapeutic drugs, novel tumour-

CSCs have been identified not only in leukaemias, but also in solid tumours, including CRC. In fact, it has been suggested that CRC stem cells are responsible for tumour relapse, because conventional drugs fail to eliminate the CSC reservoir [121]. Due to this important clinical feature, CRC stem cells have recently been identified as a rational therapeutic target. Several CSC-targeted therapies have been proposed, including microbial- and plant-derived biomo‐ lecules; therapies directed at CSC-specific surface markers; some classical drugs, such as tranilast, curcumin and thioridazine; and reversal of their resistance to anti-tumour agents; so far, however, the toxicity of some of these approaches in normal stem cells and treatment

Various signalling pathways, such as Wingless/Int (Wnt), Hedgehog and Notch, are involved in maintaining the stemness of CSCs. Among these, Wnt, stands out for being particularly active in the majority of CRCs, and hence is the first being investigated for therapeutic targeting in CRC. A primary consequence of Wnt signalling activation is the stabilization of β-catenin in the cytoplasm, resulting in an increased translocation of β-catenin to the nucleus and, in turn, activation of Wnt target gene expression. Misregulation of the canonical Wnt/β-catenin pathway and aberrant activation of Wnt signalling target genes are common in CRC and contribute to cancer progression [123]. Despite the importance of this pathway, few com‐ pounds have progressed beyond preclinical development. Efforts have been made to investi‐ gate the inhibition of a number Wnt genes, including the matrix metalloproteinases (MMPs), which play an important role in the degradation of extracellular matrix component, crucial for invasion and metastasis. Some studies have shown that increased expression of various MMPs (MMP-1, MMP-2 and MMP-9) favours CRC progression and could predict liver metastasis. Further, several therapeutic MMP inhibitors have been developed, but so far they have failed to produce a survival benefit and, in addition, they have been associated with adverse effects, such as musculoskeletal syndrome. The development of more selective MMP inhibitors is seen

Another novel compound is salinomycin, a polyether ionophore antibiotic that has been shown to kill CSCs in various types of human cancer, including CRC cells, mostly by interfering with ABC drug transporters and the Wnt/β-catenin signalling pathway. Salinomycin inhibits the migratory and invasive capacity, and reduces the proportion of CD133 CSCs in HT29 and SW480 CRC cells [125]. The results from preclinical trials and its ability to kill therapy-resistant

In recent years, other agents have been shown to suppress the self-renewal of CSCs *in vitro* and *in vivo*; these include metformin, DECA-14, rapamycin, oncostatin M, some natural compounds, oncolytic viruses, microRNAs, TNF-related apoptosis inducing ligand, telomer‐ ase inhibitors, mAbs and all-*trans* retinoic acid (ATRA). It has been suggested that combina‐

cancer cells make salinomycin a promising anticancer drug [126].

targeted drugs, and radiation therapy [120].

234 Colorectal Cancer - Surgery, Diagnostics and Treatment

resistance remain important limitations [122].

as a possible way forward [124].

CSCs are characterised by two main properties of normal stem cells, self-renewal and differ‐ entiation. Given this, the induction of differentiation using retinoids would be a plausible therapeutic strategy. ATRA, a potent differentiating agent, has been demonstrated to induce CSC growth inhibition, and this has been associated with down-regulation of Wnt/β-catenin signalling [128]. In a CRC tumour model of liver metastasis, we have demonstrated the antitumour effects of ATRA. This pro-differentiating agent hindered or completely abolished the pro-tumour stimulus produced by serum obtained from hepatectomised rats, and by a wide variety of GFs (HGF, VEGF, PDGF, EGF, and bFGF). In addition, in combination with 5-FU, an additive effect was observed in *in vitro* studies [129]. In *in vivo* experiments, ATRA also reduced tumour progression, though it failed to increase survival, both alone and in combi‐ nation with 5-FU (unpublished data).

## **5. New therapeutic techniques for colorectal liver metastasis**

Although surgical excision of tumour tissue remains the only potentially curative treatment for CRC-LM, several other techniques are now being developed to be used when surgery is not feasible or to improve surgical results.

The list of possible new therapeutic techniques for CRC-LM seems likely to increase over the next five years, including:


First, let us consider patients who could benefit from surgical excision of their liver metastases, but in whom the FLR would be less than 25%, which is currently considered the threshold of what can be tolerated. Initially, strategies for such cases were focused on selectively increasing the liver mass of liver lobes free of tumour. Some clinical trials have found that portal vein embolization (PVE) of the lobes bearing metastases induces regeneration of the other lobes, and this has been found to result in a 20-45% increase in their relative volume in two to eight weeks [130]. However, the clinical benefit of this procedure is not clear and, as there were also reports of tumour progression due to hepatectomy, it has not been widely adopted.

In patients who have inadequate FLR to undergo disease clearance with a single hepatectomy, two-stage hepatectomy for bilobar liver metastases in combination with selected use of portal venous embolization is feasible. It offers the best chance of achieving adequate FLR hypertro‐ phy, better than a strategy involving PVE before a single hepatectomy. In addition, rates of macroscopic surgical clearance greater than 65% have been reported [131].

A different, perhaps more subtle, approach is embolization of the arterial vessels supplying the tumour. Transarterial embolisation with 300- to 500-μm microspheres has been widely used either as a downstaging procedure or as a palliative treatment. This classic technique was improved by adding selective transarterial chemotherapy prior to embolisation, which

New Strategies to Enhance the Efficacy of Surgical Treatment for Colorectal Liver Metastasis

http://dx.doi.org/10.5772/57326

237

One of the problems in treating CRC-LM is the low tolerance of the liver parenchyma to radiation [140]. An elegant solution to overcome this limitation is known as *selective internal radiation therapy* and consists in the administration of 90Y-resin microspheres through the arterial branches supplying the tumour. First applied to non-resectable hepatocarcinoma patients, achieving a reduction in tumour burden, relief of symptoms and increase in survival, it is now being tested in CLR-LM with promising results. However, the type of radiolabelled

A novel approach has been the use of precharged particles to chemoembolise liver tumours. Smaller (50- to 100-μm) electrically-activated microspheres are exposed to a chemotherapeutic agent which binds to them by electrostatic forces. These spheres are delivered to the vascular tumour bed where they are widely and uniformly seeded; then the drug is released and exerts its effect specifically on the tumour tissue, while the spheres block further blood supply. Preliminary reports have been quite promising, and may lead to the procedure being applied

All these techniques can, however, only be applied to selected macroscopic liver metastases, leaving untreated residual microfoci responsible for tumour recurrence. We need therapeutic tools to attack individual cancer cells seeded throughout the whole liver parenchyma from the primary colorectal tumour. Currently, one of the most promising avenues is radioimmuno‐ therapy, with ongoing preclinical and clinical studies in CRC. This type of therapy involves the administration of radiolabeled mAbs that are directed specifically against tumourassociated antigens or against the tumour microenvironment. Some phase II trials have suggested that radioiodinated antibodies against CEA, as an adjuvant treatment after R0 resection of CRC-LM, improve overall survival [143]. More recently, new studies are being undertaken to assess the safety and efficacy of combining anti-CEA-RIT and kinase inhibitors,

On the other hand, the new field of nanosystems for cancer diagnostics and treatment is highly promising [145]. NPs, which easily escape detection and destruction by our immune system, are being used to deliver drugs directly to the tumour bed and selectively destroy cancer cells. It has been suggested that this strategy may be able to overcome tumour resistance and reduce toxicity in healthy organs. Tumour tissue tends to retain NPs, probably due to its particular characteristics (abnormally leaky endothelium and underdeveloped lymphatic drainage) [146], and this could explain the tendency of NPs to accumulate in liver metastases more than in normal liver parenchyma when administered through the hepatic artery, as we have recently shown [147]. Further, in order to decrease the severe dose-limiting toxicity of 5-FU and to enhance the concentration of this agent in the tumour mass, some researchers are investigating the use of 5-FU-loaded biodegradable NPs, and have already shown a significant improvement in the anticancer activity of the drug in an *in vitro* CRC model [148]. Finally, magnetic NPs are

allowed higher doses of chemotherapy with fewer side effects [139].

in CRC-LM [142].

microspheres, indications and dosing schedules have to be better defined [141].

such as imatinib, to increase antibody distribution in CRC tumours [144].

Surgical strategies must be individualised after careful assessment of disease distribution and its relationship to key underlying vascular and biliary structures. Thus, the majority of authors perform the first surgical stage focused on the minor hepatectomy and concurrent procedures as required. When necessary, ligature or embolization of the portal vein is carried out, to enhance the hepatic regeneration response induced by hepatectomy [132]. Nowadays, embolization is preferred to avoid surgical manipulation of the porta hepatis prior to major hepatectomies, and to achieve segment IV total portal inflow occlusion if a right hepatectomy is planned. Hypertrophy after PVE is maximal in the first three weeks, and tends to plateau after this period [133]. The time interval between hepatectomies must be long enough for adequate recovery from the first hepatectomy and liver hypertrophy, but not so long as to enable disease progression, since tumour volume may still increase within the occluded liver [134]. This interval is not well defined but is believed to be around eight to sixteen weeks. In the second-stage operation, the liver surgery usually is complex, often involving other procedures such as radiofrequency ablation. Consequently, postoperative morbidity is significant (50-60%) after this second surgery, particularly due to transient or permanent liver insufficiency. Nevertheless, when performed in referral centres for hepatic surgery the mortality rate is low (2.6-5%). Further, reported three-year survival rates after two-staged hepatectomy range from 30 to 58% [135], and in all series were significantly higher than in those patients treated with best palliative chemotherapy. Given this survival benefit and the feasibility of the surgery, this two-stage approach can be justified in suitably selected patients.

More recently, *in situ* liver transection with portal vein ligation has been proposed as a useful alternative for patients who have some segments of the left liver free of tumour, but an FLR that is too small [136]. In a first surgical intervention, arterial vessels and veins draining the lobes containing metastases are dissected and marked with vessel loops; then, the portal branches to those lobes are severed (most commonly, all right portal branches and segment I and IV branches). Some clinical trials have found that a 40-80% increase in FLR is achieved after three to eight days, and the patient can be re-operated on to remove the previously prepared lobes [137]. The results so far reported (daily increases of FRL up to 22%) are promising, but further clinical trials need to be carried out before this procedure can be generally recommended.

A quite different approach is percutaneous tumour ablation, an old design that is continuously being refined and improved with new technical developments. Initially, ablation of liver metastases was achieved by alcoholisation (ethanol injection), this being used as a downstag‐ ing procedure prior to surgery, then came radiofrequency thermoablation [42], and this was soon followed by microwave thermoablation. These procedures proved to be useful tools to reduce tumour volume, but only provided a transient effect when applied to CRC-LM. More recently, laser tumour ablation and cryoablation have gone through experimental trials in animals and are now being tested in patients, but still limited to primary liver tumours. As with previous treatments, if and when they prove to be useful in hepatocarcinomas, they will be tried in CRC-LM [138]

A different, perhaps more subtle, approach is embolization of the arterial vessels supplying the tumour. Transarterial embolisation with 300- to 500-μm microspheres has been widely used either as a downstaging procedure or as a palliative treatment. This classic technique was improved by adding selective transarterial chemotherapy prior to embolisation, which allowed higher doses of chemotherapy with fewer side effects [139].

phy, better than a strategy involving PVE before a single hepatectomy. In addition, rates of

Surgical strategies must be individualised after careful assessment of disease distribution and its relationship to key underlying vascular and biliary structures. Thus, the majority of authors perform the first surgical stage focused on the minor hepatectomy and concurrent procedures as required. When necessary, ligature or embolization of the portal vein is carried out, to enhance the hepatic regeneration response induced by hepatectomy [132]. Nowadays, embolization is preferred to avoid surgical manipulation of the porta hepatis prior to major hepatectomies, and to achieve segment IV total portal inflow occlusion if a right hepatectomy is planned. Hypertrophy after PVE is maximal in the first three weeks, and tends to plateau after this period [133]. The time interval between hepatectomies must be long enough for adequate recovery from the first hepatectomy and liver hypertrophy, but not so long as to enable disease progression, since tumour volume may still increase within the occluded liver [134]. This interval is not well defined but is believed to be around eight to sixteen weeks. In the second-stage operation, the liver surgery usually is complex, often involving other procedures such as radiofrequency ablation. Consequently, postoperative morbidity is significant (50-60%) after this second surgery, particularly due to transient or permanent liver insufficiency. Nevertheless, when performed in referral centres for hepatic surgery the mortality rate is low (2.6-5%). Further, reported three-year survival rates after two-staged hepatectomy range from 30 to 58% [135], and in all series were significantly higher than in those patients treated with best palliative chemotherapy. Given this survival benefit and the feasibility of the surgery, this two-stage approach can be justified in suitably selected patients.

More recently, *in situ* liver transection with portal vein ligation has been proposed as a useful alternative for patients who have some segments of the left liver free of tumour, but an FLR that is too small [136]. In a first surgical intervention, arterial vessels and veins draining the lobes containing metastases are dissected and marked with vessel loops; then, the portal branches to those lobes are severed (most commonly, all right portal branches and segment I and IV branches). Some clinical trials have found that a 40-80% increase in FLR is achieved after three to eight days, and the patient can be re-operated on to remove the previously prepared lobes [137]. The results so far reported (daily increases of FRL up to 22%) are promising, but further clinical trials need to be carried out before this procedure can be

A quite different approach is percutaneous tumour ablation, an old design that is continuously being refined and improved with new technical developments. Initially, ablation of liver metastases was achieved by alcoholisation (ethanol injection), this being used as a downstag‐ ing procedure prior to surgery, then came radiofrequency thermoablation [42], and this was soon followed by microwave thermoablation. These procedures proved to be useful tools to reduce tumour volume, but only provided a transient effect when applied to CRC-LM. More recently, laser tumour ablation and cryoablation have gone through experimental trials in animals and are now being tested in patients, but still limited to primary liver tumours. As with previous treatments, if and when they prove to be useful in hepatocarcinomas, they will

generally recommended.

be tried in CRC-LM [138]

macroscopic surgical clearance greater than 65% have been reported [131].

236 Colorectal Cancer - Surgery, Diagnostics and Treatment

One of the problems in treating CRC-LM is the low tolerance of the liver parenchyma to radiation [140]. An elegant solution to overcome this limitation is known as *selective internal radiation therapy* and consists in the administration of 90Y-resin microspheres through the arterial branches supplying the tumour. First applied to non-resectable hepatocarcinoma patients, achieving a reduction in tumour burden, relief of symptoms and increase in survival, it is now being tested in CLR-LM with promising results. However, the type of radiolabelled microspheres, indications and dosing schedules have to be better defined [141].

A novel approach has been the use of precharged particles to chemoembolise liver tumours. Smaller (50- to 100-μm) electrically-activated microspheres are exposed to a chemotherapeutic agent which binds to them by electrostatic forces. These spheres are delivered to the vascular tumour bed where they are widely and uniformly seeded; then the drug is released and exerts its effect specifically on the tumour tissue, while the spheres block further blood supply. Preliminary reports have been quite promising, and may lead to the procedure being applied in CRC-LM [142].

All these techniques can, however, only be applied to selected macroscopic liver metastases, leaving untreated residual microfoci responsible for tumour recurrence. We need therapeutic tools to attack individual cancer cells seeded throughout the whole liver parenchyma from the primary colorectal tumour. Currently, one of the most promising avenues is radioimmuno‐ therapy, with ongoing preclinical and clinical studies in CRC. This type of therapy involves the administration of radiolabeled mAbs that are directed specifically against tumourassociated antigens or against the tumour microenvironment. Some phase II trials have suggested that radioiodinated antibodies against CEA, as an adjuvant treatment after R0 resection of CRC-LM, improve overall survival [143]. More recently, new studies are being undertaken to assess the safety and efficacy of combining anti-CEA-RIT and kinase inhibitors, such as imatinib, to increase antibody distribution in CRC tumours [144].

On the other hand, the new field of nanosystems for cancer diagnostics and treatment is highly promising [145]. NPs, which easily escape detection and destruction by our immune system, are being used to deliver drugs directly to the tumour bed and selectively destroy cancer cells. It has been suggested that this strategy may be able to overcome tumour resistance and reduce toxicity in healthy organs. Tumour tissue tends to retain NPs, probably due to its particular characteristics (abnormally leaky endothelium and underdeveloped lymphatic drainage) [146], and this could explain the tendency of NPs to accumulate in liver metastases more than in normal liver parenchyma when administered through the hepatic artery, as we have recently shown [147]. Further, in order to decrease the severe dose-limiting toxicity of 5-FU and to enhance the concentration of this agent in the tumour mass, some researchers are investigating the use of 5-FU-loaded biodegradable NPs, and have already shown a significant improvement in the anticancer activity of the drug in an *in vitro* CRC model [148]. Finally, magnetic NPs are being investigated in combination with high-frequency magnetic fields to induce local hyperthermia in the tumour, promising results having been obtained in experimental settings (CRC-LM in rats) [149].

**Acknowledgements**

**Author details**

que Country, Leioa, Spain

e97-e103.

col 2011;7(11): 1299-1323.

**References**

Teodoro Palomares1\*, Ana Alonso-Varona2

University of the Basque Country, Leioa, Spain

CA Cancer J Clin 2011;61(2): 69-90.

prognostic factors. Clin Epidemiol 2012;4: 283-301.

\*Address all correspondence to: teodoro.palomares@ehu.es

Our ongoing research effort in this field is supported by research grants from the University

1 Dpt. of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Dentistry,

2 Dpt. of Biology and Histology, Faculty of Medicine and Dentistry, University of the Bas‐

[1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics.

[2] Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, et al. Surviv‐ al after liver resection in metastatic colorectal cancer: review and meta-analysis of

[3] Lopez P, Marzano E, Piardi T, Pessaux P. Repeat hepatectomy for liver metastases from colorectal primary cancer: a review of the literature. J Visc Surg 2012;149(2):

[4] Stein A, Glockzin G, Wienke A, Arnold D, Edelmann T, Hildebrandt B, et al. Treat‐ ment with bevacizumab and FOLFOXIRI in patients with advanced colorectal can‐ cer: presentation of two novel trials (CHARTA and PERIMAX) and review of the

[5] Masi G, Fornaro L, Caparello C, Falcone A. Liver Metastases from Colorectal Cancer. How to Best Complement Medical Treatment With Surgical Approaches. Future On‐

literature. BioMed Central Cancer 2012;12: 356. doi: 10.1186/1471-2407-12-356.

3 Unit of Colorectal Surgery, Hospital Galdakao-Usansolo, Galdakao, Spain

, Ignacio García-Alonso1

New Strategies to Enhance the Efficacy of Surgical Treatment for Colorectal Liver Metastasis

and Vicente Portugal3

http://dx.doi.org/10.5772/57326

239

of the Basque Country (Project GIU 10/16) and the Gangoiti Barrera Foundation.

## **6. Conclusion**

Liver metastases are a common undesirable development in CRC and represent the leading cause of death in this high-prevalence disease. The management of CRC-LM has significantly changed over the past two decades, with dramatic improvements in patient outcomes. This has been made possible by the application of several key concepts when implementing different therapeutic approaches for subsets of patients with mCRC. Firstly, there is a clear consensus that the best management is achieved with a multimodality approach, including surgery, perioperative chemotherapy, biological agents and/or radiotherapy. Secondly, the therapeutic option with the best potential for cure in patients with CRC-LM remains complete resection of the metastases. Strategies to facilitate liver resection are allowing significantly increases in overall survival in this complex disease. In relation to this, the use of optimal firstline chemotherapy doublet (FOLFOX, FOLFIRI, XELOX) or triplet regimens (FOLFOXIRI) in combination with targeted therapy is now recognised as a good therapeutic approach in potentially resectable patients. In particular, the development of new biological molecules for targeted therapy (bevacizumab, cetuximab, and panatimumab) has been a key factor in the most important advances in mCRC treatment.

Nevertheless, much remains to be done. The fact that these current targeted biological agents are only effective in small subsets of patients with mCRC, and that their overall impact in the management of the disease is still relatively modest, has encouraged researchers to search for novel molecules that selectively target specific molecular pathways. This has resulted in a plethora of new antiangiogenic agents (aflibercept, ramucirumab, regorafenib, etc.) and novel molecules directed against new biological targets (such as, autophagy or CSCs) or various different signalling pathways (Wnt and PI3K/AKT/mTOR, among others); these are currently being tested in preclinical studies or in phase II and III trials.

Additionally, new therapeutic techniques, such as surgical approaches focused on increasing the size of the liver lobes, SIRT, radiofrequency ablations and, more recently, NPs to selectively deliver drugs or to induce local hyperthermia in the tumour bed, promise to increase overall outcome in patients with advanced mCRC, in particular, in those with special characteristics that complicate treatment of their disease (inadequate FLR and others).

Finally, it is important not to forget the need to continue the search for new biomarkers to enable better patient stratification for each treatment option. Based on a better understanding of the process involved in the development and progression of CRC, biomarker panels will be developed and this will greatly facilitate the design of personalized medicine for CRC patients.

## **Acknowledgements**

being investigated in combination with high-frequency magnetic fields to induce local hyperthermia in the tumour, promising results having been obtained in experimental settings

Liver metastases are a common undesirable development in CRC and represent the leading cause of death in this high-prevalence disease. The management of CRC-LM has significantly changed over the past two decades, with dramatic improvements in patient outcomes. This has been made possible by the application of several key concepts when implementing different therapeutic approaches for subsets of patients with mCRC. Firstly, there is a clear consensus that the best management is achieved with a multimodality approach, including surgery, perioperative chemotherapy, biological agents and/or radiotherapy. Secondly, the therapeutic option with the best potential for cure in patients with CRC-LM remains complete resection of the metastases. Strategies to facilitate liver resection are allowing significantly increases in overall survival in this complex disease. In relation to this, the use of optimal firstline chemotherapy doublet (FOLFOX, FOLFIRI, XELOX) or triplet regimens (FOLFOXIRI) in combination with targeted therapy is now recognised as a good therapeutic approach in potentially resectable patients. In particular, the development of new biological molecules for targeted therapy (bevacizumab, cetuximab, and panatimumab) has been a key factor in the

Nevertheless, much remains to be done. The fact that these current targeted biological agents are only effective in small subsets of patients with mCRC, and that their overall impact in the management of the disease is still relatively modest, has encouraged researchers to search for novel molecules that selectively target specific molecular pathways. This has resulted in a plethora of new antiangiogenic agents (aflibercept, ramucirumab, regorafenib, etc.) and novel molecules directed against new biological targets (such as, autophagy or CSCs) or various different signalling pathways (Wnt and PI3K/AKT/mTOR, among others); these are currently

Additionally, new therapeutic techniques, such as surgical approaches focused on increasing the size of the liver lobes, SIRT, radiofrequency ablations and, more recently, NPs to selectively deliver drugs or to induce local hyperthermia in the tumour bed, promise to increase overall outcome in patients with advanced mCRC, in particular, in those with special characteristics

Finally, it is important not to forget the need to continue the search for new biomarkers to enable better patient stratification for each treatment option. Based on a better understanding of the process involved in the development and progression of CRC, biomarker panels will be developed and this will greatly facilitate the design of personalized medicine for CRC patients.

(CRC-LM in rats) [149].

238 Colorectal Cancer - Surgery, Diagnostics and Treatment

most important advances in mCRC treatment.

being tested in preclinical studies or in phase II and III trials.

that complicate treatment of their disease (inadequate FLR and others).

**6. Conclusion**

Our ongoing research effort in this field is supported by research grants from the University of the Basque Country (Project GIU 10/16) and the Gangoiti Barrera Foundation.

## **Author details**

Teodoro Palomares1\*, Ana Alonso-Varona2 , Ignacio García-Alonso1 and Vicente Portugal3

\*Address all correspondence to: teodoro.palomares@ehu.es

1 Dpt. of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain

2 Dpt. of Biology and Histology, Faculty of Medicine and Dentistry, University of the Bas‐ que Country, Leioa, Spain

3 Unit of Colorectal Surgery, Hospital Galdakao-Usansolo, Galdakao, Spain

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**Chapter 11**

**Rare Tumors of the Colon and Rectum**

Malignant tumors of the colon and rectum represent a separate entity, due to their early clinical manifestation, specific methods of examination and, particularly, due to treat‐ ment, which is predominantly based on the need for conservation of the sphincter mechanism, without disturbing the oncological principles of surgical treatment and the necessary radicalism. In spite of introduction of the new surgical procedures, and the significant improvements in radio, i.e. chemotherapy, the prognosis of these tumors remains

Adenocarcinomas account for 95-97% of all malignant tumors, while the remaining 3-5% belongs to, so called, rare tumors of colon and rectum. The annual percent change in incidence for each rare tumor increased significantly during the 10 years (range: 3.1–9.4%, p<0.05), except squamous cell carcinoma (5.9%, p>0.05) [1]. With regard to the incidence,

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Goran Stanojević and Zoran Krivokapić

http://dx.doi.org/10.5772/56937

**1. Introduction**

**1.** Adenocarcinomas,

**5.** Squamous cell carcinoma

**2.** Carcinoids,

**3.** Lymphomas,

**6.** Melanomas

serious.

Additional information is available at the end of the chapter

With regard to the histological structure, tumors can be:

**7.** Other (extremely rare forms of malignant tumors)

all rare tumors of the large bowel can be divided into 2 groups:

**4.** Gastrointestinal stromal tumors (GISTs),

## **Rare Tumors of the Colon and Rectum**

Goran Stanojević and Zoran Krivokapić

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56937

**1. Introduction**

Malignant tumors of the colon and rectum represent a separate entity, due to their early clinical manifestation, specific methods of examination and, particularly, due to treat‐ ment, which is predominantly based on the need for conservation of the sphincter mechanism, without disturbing the oncological principles of surgical treatment and the necessary radicalism. In spite of introduction of the new surgical procedures, and the significant improvements in radio, i.e. chemotherapy, the prognosis of these tumors remains serious.

With regard to the histological structure, tumors can be:


Adenocarcinomas account for 95-97% of all malignant tumors, while the remaining 3-5% belongs to, so called, rare tumors of colon and rectum. The annual percent change in incidence for each rare tumor increased significantly during the 10 years (range: 3.1–9.4%, p<0.05), except squamous cell carcinoma (5.9%, p>0.05) [1]. With regard to the incidence, all rare tumors of the large bowel can be divided into 2 groups:


In the first group the most common ones are: carcinoids 1,8%, primary lymphomas 0,1-1%, GISTs 0,9%, melanomas 0,5-1%, and squamous cell carcinoma 0,1% (without the anal canal). The second group or extremely rare forms of malignant tumors consist of: teratoma, plasmo‐ cytoma, schwannomas, metastatic tumor. Literature data are limited and mostly concern series of operated patients of some institutions or several published national studies, but there are no randomized studies or meta-analyses which have higher degree of scientific verification because these tumours are very rare [2].

[1]. Their secretion is active and secrete around 30 vasoactive substances, the most important of which are serotonin, histamine and substance P. In 1867, Langhans [1] first described a gut carcinoid tumor, but the first detailed description of the tumor, similar to carcinoid, was given by Lubrasch 1888, after performing the autopsy on two persons, previously treated due to having multiple tumors of ileum. A German pathologist Oberndorfer first mentioned the term "carcinoid" in 1907, while Siburg published the first data about the rectum carcinoid in 1929 [4-5]. The term "carcinoid" indicates that the tumor, according to some histological character‐ istics, is similar to carcinoma, but it behaves in a more benign way and less aggressive. They have often been discovered accidently, during the colonoscopy, or by examination of the clinical symptoms, such as rectoragia or diarrhea. During the primary diagnosing, 60-90% of carcinoids are less than 1 cm of size.These tumors have a variable malignant potential, which depends on: size, localization, depth of invasion and way of growth of the tumor itself.

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 255

According to the data from literature, the colon and rectum carcinoids less than 1 cm of size have metastases in about 5,5% of cases. The bigger sized tumors, 1-1.9 cm, have metastasis within the range of 4 to 30%, while those above 2 cm, within the range of 70-80%. With regard to localization, the rectum carcinoids have metastasis in 18% on average, unlike the colon ones in 60%, jejunoileal localization in 34%, stomach in 23% and lungs in 21% [2]. The depth of invasion, particularly the tumors, which are less than 2 cm in size, represents a very important predictive factor in the method and outcome of treatment. Invasion of muscularis propria and lymphovascular, i.e. perineural invasion, anaplastic reaction, positive Ki-67 mutations and frequent mitosis increase the risk of metastasis of tumors, which are less than 2 cm in size. Macroscopically, these are small tumors in the nodular form, covered with the normal mucosa, with intensive fibrosis of the intestine wall. Ulcerous forms with a tendency of bleeding, have metastasis in larger percent and represent a significant risk factor. Histologically, the tumor cells look similar, rounded or polygonal with expressed nucleus and acidophilic cytoplasmic granules. Immunohistochemically, they show focal or diffuse existence of chromaganin A and/ or neuron-specific enolase, synaptophysina, CD 56 and pancreatic polypeptide. There is no clear histological difference between benign and malignant large bowel carcinoids, except the

(a) (b)

size of the tumor itself and invasion of muscularis proprie.

**Figure 1.** a) colon carcinoid (H&E 10x); b) colon carcinoid (chromogranin A 10x)

The aims of studying the rare tumors of the colon and rectum are:

– determination of the incidence among population,

– determination of the clinical characteristics

– comparative analysis of the treatment outcome in different parts of the gastrointestinal tract and

– overall and five-year survival of patients.

### **2. Carcinoids**

Carcinoid tumors represents rare, slow growing tumors and they occur in 1,8% of all malignant tumors of the large bowel. There is no clear predominance related to sex and, in the most of cases, the patients are in their sixties or seventies. They originate from the enterochromaffin (argentafil, Kulchitsky) cells, as a part of the diffuse endocrine system and they belong to the group of neuroendocrine tumors, so called well-differentiated "NET's". They are also called APUDomas, which is an abbreviation for "amine precursor uptake and decarboxylation", due to their ability to take over and decarboxylase amines, originally described by Pearse in 1969 [3]. They can occur in all parts of gastrointestinal tract as well as outside of the tract. Therefore with regard to the place of occurrence and according to the division of the primitive intestine during the embryological development, carcinoids are divided into:


Data from literature indicate that the incidence of carcinoids in certain locations is different, although it is considered to be most often localized on the appendix vermiformis, in about 40% of cases, on ileum about 25%, on rectum 15-20% and on respiratory system around 10%. On the other hand, the Japanese National Study has identified, in 90 057 operated patients during the period of 15 years, 345 cases of carcinoids on the small and large bowel, out of which 0,9% was localized on the ileum, 2,3% on the appendix, 8,2% on the colon and 88,6% on the rectum [1]. Their secretion is active and secrete around 30 vasoactive substances, the most important of which are serotonin, histamine and substance P. In 1867, Langhans [1] first described a gut carcinoid tumor, but the first detailed description of the tumor, similar to carcinoid, was given by Lubrasch 1888, after performing the autopsy on two persons, previously treated due to having multiple tumors of ileum. A German pathologist Oberndorfer first mentioned the term "carcinoid" in 1907, while Siburg published the first data about the rectum carcinoid in 1929 [4-5]. The term "carcinoid" indicates that the tumor, according to some histological character‐ istics, is similar to carcinoma, but it behaves in a more benign way and less aggressive. They have often been discovered accidently, during the colonoscopy, or by examination of the clinical symptoms, such as rectoragia or diarrhea. During the primary diagnosing, 60-90% of carcinoids are less than 1 cm of size.These tumors have a variable malignant potential, which depends on: size, localization, depth of invasion and way of growth of the tumor itself.

**1.** tumors with the incidence 0,1-2% and **2.** rare tumors with the incidence <0,1%.

254 Colorectal Cancer - Surgery, Diagnostics and Treatment

because these tumours are very rare [2].

The aims of studying the rare tumors of the colon and rectum are:

during the embryological development, carcinoids are divided into: **1.** foregut carcinoid tumors start in the lungs, bronchi, or stomach;

**3.** hindgut carcinoid tumors start in the distal colon or rectum.

– determination of the incidence among population,

– determination of the clinical characteristics

– overall and five-year survival of patients.

and

**2. Carcinoids**

In the first group the most common ones are: carcinoids 1,8%, primary lymphomas 0,1-1%, GISTs 0,9%, melanomas 0,5-1%, and squamous cell carcinoma 0,1% (without the anal canal). The second group or extremely rare forms of malignant tumors consist of: teratoma, plasmo‐ cytoma, schwannomas, metastatic tumor. Literature data are limited and mostly concern series of operated patients of some institutions or several published national studies, but there are no randomized studies or meta-analyses which have higher degree of scientific verification

– comparative analysis of the treatment outcome in different parts of the gastrointestinal tract

Carcinoid tumors represents rare, slow growing tumors and they occur in 1,8% of all malignant tumors of the large bowel. There is no clear predominance related to sex and, in the most of cases, the patients are in their sixties or seventies. They originate from the enterochromaffin (argentafil, Kulchitsky) cells, as a part of the diffuse endocrine system and they belong to the group of neuroendocrine tumors, so called well-differentiated "NET's". They are also called APUDomas, which is an abbreviation for "amine precursor uptake and decarboxylation", due to their ability to take over and decarboxylase amines, originally described by Pearse in 1969 [3]. They can occur in all parts of gastrointestinal tract as well as outside of the tract. Therefore with regard to the place of occurrence and according to the division of the primitive intestine

**2.** midgut carcinoid tumors start in the small intestine, appendix,or proximal large bowel;

Data from literature indicate that the incidence of carcinoids in certain locations is different, although it is considered to be most often localized on the appendix vermiformis, in about 40% of cases, on ileum about 25%, on rectum 15-20% and on respiratory system around 10%. On the other hand, the Japanese National Study has identified, in 90 057 operated patients during the period of 15 years, 345 cases of carcinoids on the small and large bowel, out of which 0,9% was localized on the ileum, 2,3% on the appendix, 8,2% on the colon and 88,6% on the rectum

According to the data from literature, the colon and rectum carcinoids less than 1 cm of size have metastases in about 5,5% of cases. The bigger sized tumors, 1-1.9 cm, have metastasis within the range of 4 to 30%, while those above 2 cm, within the range of 70-80%. With regard to localization, the rectum carcinoids have metastasis in 18% on average, unlike the colon ones in 60%, jejunoileal localization in 34%, stomach in 23% and lungs in 21% [2]. The depth of invasion, particularly the tumors, which are less than 2 cm in size, represents a very important predictive factor in the method and outcome of treatment. Invasion of muscularis propria and lymphovascular, i.e. perineural invasion, anaplastic reaction, positive Ki-67 mutations and frequent mitosis increase the risk of metastasis of tumors, which are less than 2 cm in size. Macroscopically, these are small tumors in the nodular form, covered with the normal mucosa, with intensive fibrosis of the intestine wall. Ulcerous forms with a tendency of bleeding, have metastasis in larger percent and represent a significant risk factor. Histologically, the tumor cells look similar, rounded or polygonal with expressed nucleus and acidophilic cytoplasmic granules. Immunohistochemically, they show focal or diffuse existence of chromaganin A and/ or neuron-specific enolase, synaptophysina, CD 56 and pancreatic polypeptide. There is no clear histological difference between benign and malignant large bowel carcinoids, except the size of the tumor itself and invasion of muscularis proprie.

**Figure 1.** a) colon carcinoid (H&E 10x); b) colon carcinoid (chromogranin A 10x)

#### **2.1. Clinical presentation and diagnosis**

The clinical presentation is characterized by the existence of symptoms resulting from the secretion of different biochemical substances and growth of the tumor itself. Occasional abdominal pains, followed by facial flushing, diarrhea, bronchospasm, arrhythmia, hyper‐ thermia, - blood pressure variations and vasomotor collapse, which, based on the intensity can lead to a life dangerous condition, or so called "carcinoid crisis". Various daily activities and psychological conditions, such as alcohol drinking, emotional stress, increased body temper‐ ature and difficult defecation potentiate the intensity of symptoms.

**2.2. Treatment**

**b.** laparatomy

*2.2.1. Laparatomy*

**a.** minimally invasive procedure

– transanal tumor extirpation

The treatment of the colon carcinoid can be divided into two groups:

– endoscopic mucosectomy or submucosectomy

– TEM (transanal endoscopic microsurgery)

– laparoscopic resections of colon and rectum

by the invasive procedure, on the other [7-9].

**c.** Minimally invasive procedure includes several types of interventions:

Endoscopic mucosectomy or submucosectomy represent one of the possible methods in the conditions of the initial stadium of disease, without penetration into muscularis mucosae, and up to 1 cm of size. The literature data show that endoscopic mucosetomy or submucosetomy are performed in 54% of patients suffering from rectum carcinoid, transanal extirpation of tumor /TEM in 27% of the operated patients, on one hand, as well as in 6% of patients treated

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 257

The results of the treatment indicate that, in patients treated by the endoscopic methods, in 83% of cases, it was about the positive limits (R1 status), in 16% it was the residual tumor (R2 status) with 2% of acute complications in terms of the occurrence of post-operative bleeding. In 12 patients (14%), a sub-mucosectomy was done, with 42% of the positive margins present.

The advantage of the endoscopic approach is a minimally invasive procedure, faster recovery of a patient and smaller operative trauma, but there are also disadvantages in terms of the high

Transanal exstirpation/TEM is indicated in the conditions of rectal carcinoid invasion to the submucose and muscularis proprie. They are mainly performed after the unsuccessful, previously done mucosectomy i.e. sub-mucosectomy. The results of treatment indicate that in 43% of the operated patients, RO resection was done, while in 52% of cases R1, i.e. R2 resection was done. The post-operative complications occurred in about 9% of patients. The disadvant‐

Laparoscopic resections of colon and rectum represent a trend in the modern colorectal surgery, with all characteristics of the minimally invasive procedure. It is indicated in tumors, which spread to the structures deeper than lamina muscularis mucosa (T2 stadium), most often to the upper third of rectum, but the other parts of rectum as well, where performing the

percent of R1 or R2 procedure, (positive margins or residual tumor).

age of the procedure is still a high percentage of R1 and R2 operations.

endoscopic procedure would lead to a high percent of R1 and R2 operations.

– resection of colon (according to the type of segmental or right/left hemicolectomies)

The diagnosis of the large bowell carcinoids was usually made by detailed anamnesis and clinical examination of the abdomen and digital rectal examination. Very often, it is an unclear finding, due to the intact mucosa, so it is necessary to take biopsy from the part of the tumor surface, as well as, from the deeper structures. It is also necessary to include a colonoscopy in clinical examination, due to the possible existence of the synchronous lesion, and magnetic resonance imaging or endoluminal ultrasound of the small pelvis, because of the pre-operative staging. The examination of the liver metastatsis, should be completed with an ultra-sound and CT scan. The modern diagnostics of carcinoids understands also the, so called, functional or biochemical examinations based on taking over of the certain substances by the tumor cells, which makes them different from the normal tissue. The biochemical properties of carcinoid tumors reflect the presence of neurosecretory granules. They are classified as biochemically typical or atypical based on the presence of high levels of serotonin in so-called typical tumors. The best known metabolite of serotonin in carcinoid tumors is 5-HIAA( hydroxyl indole acetic acid). In a 24-hour sample, the urinary level of 5-HIAA is the test most commonly used in the endocrine work-up of carcinoid tumors. Despite its popularity, it lacks the sensitivity and specificity for the diagnosis of carcinoid tumors because 5-HIAA may not be elevated in atypical carcinoids and can be elevated in other conditions such as tropical sprue, celiac disease, Whipple's disease, and small bowel obstruction, and can be caused by ingestion of food high in serotonin, or certain medications.

Although a number of other tumor markers have been investigated for carcinoid tumor overproduction, serum analysis of chromogranin A, a glycoprotein that is secreted with other hormones by neuroendocrine tumors, appears to be the most promising, with specificity approaching 95% and sensitivity for carcinoid tumors approaching 80 percent. A 40 percent false-positive rate has been seen in patients with multiple myeloma[6].

For this purpose, the scintigraphy of the somatostin receptors on the surface of tumor cells is applied, or SRS and PET scan, which uses a metabolic taking over of FDG Fluorin- 18 fluoro‐ deoxyglucose, by the tumor cells. The results of the research indicate that, Octreoscan is the most optimal for identification of the primary tumor and existence of the positive lymph nodes, while in the case of distant metastasis, it is CT or NMR. Within the frame of the biochemical analyses, in case of doubt that there is a carcinoid present, it is necessary to determine the level of 5 hydroxy-indole acetic acid in urine.

#### **2.2. Treatment**

**2.1. Clinical presentation and diagnosis**

256 Colorectal Cancer - Surgery, Diagnostics and Treatment

food high in serotonin, or certain medications.

of 5 hydroxy-indole acetic acid in urine.

The clinical presentation is characterized by the existence of symptoms resulting from the secretion of different biochemical substances and growth of the tumor itself. Occasional abdominal pains, followed by facial flushing, diarrhea, bronchospasm, arrhythmia, hyper‐ thermia, - blood pressure variations and vasomotor collapse, which, based on the intensity can lead to a life dangerous condition, or so called "carcinoid crisis". Various daily activities and psychological conditions, such as alcohol drinking, emotional stress, increased body temper‐

The diagnosis of the large bowell carcinoids was usually made by detailed anamnesis and clinical examination of the abdomen and digital rectal examination. Very often, it is an unclear finding, due to the intact mucosa, so it is necessary to take biopsy from the part of the tumor surface, as well as, from the deeper structures. It is also necessary to include a colonoscopy in clinical examination, due to the possible existence of the synchronous lesion, and magnetic resonance imaging or endoluminal ultrasound of the small pelvis, because of the pre-operative staging. The examination of the liver metastatsis, should be completed with an ultra-sound and CT scan. The modern diagnostics of carcinoids understands also the, so called, functional or biochemical examinations based on taking over of the certain substances by the tumor cells, which makes them different from the normal tissue. The biochemical properties of carcinoid tumors reflect the presence of neurosecretory granules. They are classified as biochemically typical or atypical based on the presence of high levels of serotonin in so-called typical tumors. The best known metabolite of serotonin in carcinoid tumors is 5-HIAA( hydroxyl indole acetic acid). In a 24-hour sample, the urinary level of 5-HIAA is the test most commonly used in the endocrine work-up of carcinoid tumors. Despite its popularity, it lacks the sensitivity and specificity for the diagnosis of carcinoid tumors because 5-HIAA may not be elevated in atypical carcinoids and can be elevated in other conditions such as tropical sprue, celiac disease, Whipple's disease, and small bowel obstruction, and can be caused by ingestion of

Although a number of other tumor markers have been investigated for carcinoid tumor overproduction, serum analysis of chromogranin A, a glycoprotein that is secreted with other hormones by neuroendocrine tumors, appears to be the most promising, with specificity approaching 95% and sensitivity for carcinoid tumors approaching 80 percent. A 40 percent

For this purpose, the scintigraphy of the somatostin receptors on the surface of tumor cells is applied, or SRS and PET scan, which uses a metabolic taking over of FDG Fluorin- 18 fluoro‐ deoxyglucose, by the tumor cells. The results of the research indicate that, Octreoscan is the most optimal for identification of the primary tumor and existence of the positive lymph nodes, while in the case of distant metastasis, it is CT or NMR. Within the frame of the biochemical analyses, in case of doubt that there is a carcinoid present, it is necessary to determine the level

false-positive rate has been seen in patients with multiple myeloma[6].

ature and difficult defecation potentiate the intensity of symptoms.

The treatment of the colon carcinoid can be divided into two groups:

	- endoscopic mucosectomy or submucosectomy
	- transanal tumor extirpation
	- TEM (transanal endoscopic microsurgery)
	- laparoscopic resections of colon and rectum

Endoscopic mucosectomy or submucosectomy represent one of the possible methods in the conditions of the initial stadium of disease, without penetration into muscularis mucosae, and up to 1 cm of size. The literature data show that endoscopic mucosetomy or submucosetomy are performed in 54% of patients suffering from rectum carcinoid, transanal extirpation of tumor /TEM in 27% of the operated patients, on one hand, as well as in 6% of patients treated by the invasive procedure, on the other [7-9].

The results of the treatment indicate that, in patients treated by the endoscopic methods, in 83% of cases, it was about the positive limits (R1 status), in 16% it was the residual tumor (R2 status) with 2% of acute complications in terms of the occurrence of post-operative bleeding. In 12 patients (14%), a sub-mucosectomy was done, with 42% of the positive margins present.

The advantage of the endoscopic approach is a minimally invasive procedure, faster recovery of a patient and smaller operative trauma, but there are also disadvantages in terms of the high percent of R1 or R2 procedure, (positive margins or residual tumor).

Transanal exstirpation/TEM is indicated in the conditions of rectal carcinoid invasion to the submucose and muscularis proprie. They are mainly performed after the unsuccessful, previously done mucosectomy i.e. sub-mucosectomy. The results of treatment indicate that in 43% of the operated patients, RO resection was done, while in 52% of cases R1, i.e. R2 resection was done. The post-operative complications occurred in about 9% of patients. The disadvant‐ age of the procedure is still a high percentage of R1 and R2 operations.

Laparoscopic resections of colon and rectum represent a trend in the modern colorectal surgery, with all characteristics of the minimally invasive procedure. It is indicated in tumors, which spread to the structures deeper than lamina muscularis mucosa (T2 stadium), most often to the upper third of rectum, but the other parts of rectum as well, where performing the endoscopic procedure would lead to a high percent of R1 and R2 operations.

#### *2.2.1. Laparatomy*

– resection of colon (according to the type of segmental or right/left hemicolectomies)

– (resections of rectum with different forms of reconstructions T-T anastomosis, L-T anasto‐ mosis, colonic J pouch, etc.)

End Results) database identified 2459 with colon tumors and 4701 patients with rectal carcinoid tumors from 1973 to 2004. Patients were analyzed according to various clinicopathologic factors and a tumor (T1, T2, T3), lymph node (N0, N1), and metastasis (M0, M1) staging system

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 259

Lymphomas of colon and rectum are the rare tumors that make 1,4% of human lymphomas, 10-20% of gastrointestinal lymphomas, 0,2-0,6% of all malignant tumors of colon, that is, 0,1-1% of all tumors of the large bowel. According to the incidence in the gastrointestinal system in adults, they take a third place, following the stomach and small intestine, unlike with the age of up to seventeen, where the intestinal localization is predominant. In relation to the incidence of all malignant colon and rectum diseases, they take a third place, following adenocarcinoma and carcinoids [17,18]. The predilection places of occurrence are cecum and rectum, due to

It occurs more often in male patients, older than 50. With regard to the degree of spreading, diseases can be: primary (localized) and secondary (diffuse form). The primary lymphomas of the large bowel are characterized by the existence of the so-called Dawson's criteria [19]:

was created according to these parameters. Results is shown in Table 1.

large amount of lymph tissue in these regions of the large bowel.

**3. Primary non-Hodgkin lymphomas**

**Figure 2.** Primary non-Hodgkin lymphoma of the cekum

**1.** no palpable, superficial lymph nodes at presentation;l

**2.** no enlarged mediastinal lymph nodes on chest x-ray;

**4.** at surgery, only the regional lymph nodes are involved;

**3.** normal range for white blood cell count including total and differential

– incontinence operations (abdominoperineal amputation of rectum, etc.)

– in case of inoperability of tumor, the performance of colostomy.

Laparotomy is indicated in carcinoids of greater median size, so-called bulky tumors, with infiltration to the surrounding organs, as well as, with the potential risk of the colon obstruc‐ tion. In relation to the outcome of treatment, the resection procedures are loaded with a higher percent of the local recurrence rate, which is explained by the existence of the more invasive and bigger tumors, treated in this way [10-13].

Systemic therapy in carcinoid treatment has two aims

– to reduce intensity of the systemic effects of disease and

– treatment of metastasis.

Reducing intensity of the systemic effects means the use of various medicaments, such as: H2 blockers, Phenothiazin, corticosteroids, serotonin blockers serotonin, bronchodilators etc. The analogues of Somatostatin have a significant effect that, by blocking the receptors reduce the production and systemic effects, primarily the intensity of flushing and diarrhea, in 80% of patients.


**Table 1.** Staging system and 5- year survival rate [14-16]

In treatment of metastasis, the effect of chemotherapy application ( 5-fluorouracil, strreptozo‐ tocin, doxorubicin,, etoposide, cisplatin, carboplatin, etc. ) is insignificant, with a clinical response ( Response Rate- RR) from 0 to 30%. In some cases, Interferon is used, in duration of up to 2,5 years, but due the numerous unfavorable effects, its use is limited [6].

The prognosis of the disease, depending on TNM stadium. A search of 15,983 patients with carcinoid tumors from the National Cancer Institute's SEER (Surveillance Epidemiology and End Results) database identified 2459 with colon tumors and 4701 patients with rectal carcinoid tumors from 1973 to 2004. Patients were analyzed according to various clinicopathologic factors and a tumor (T1, T2, T3), lymph node (N0, N1), and metastasis (M0, M1) staging system was created according to these parameters. Results is shown in Table 1.

## **3. Primary non-Hodgkin lymphomas**

– (resections of rectum with different forms of reconstructions T-T anastomosis, L-T anasto‐

Laparotomy is indicated in carcinoids of greater median size, so-called bulky tumors, with infiltration to the surrounding organs, as well as, with the potential risk of the colon obstruc‐ tion. In relation to the outcome of treatment, the resection procedures are loaded with a higher percent of the local recurrence rate, which is explained by the existence of the more invasive

Reducing intensity of the systemic effects means the use of various medicaments, such as: H2 blockers, Phenothiazin, corticosteroids, serotonin blockers serotonin, bronchodilators etc. The analogues of Somatostatin have a significant effect that, by blocking the receptors reduce the production and systemic effects, primarily the intensity of flushing and diarrhea, in 80% of

In treatment of metastasis, the effect of chemotherapy application ( 5-fluorouracil, strreptozo‐ tocin, doxorubicin,, etoposide, cisplatin, carboplatin, etc. ) is insignificant, with a clinical response ( Response Rate- RR) from 0 to 30%. In some cases, Interferon is used, in duration of

The prognosis of the disease, depending on TNM stadium. A search of 15,983 patients with carcinoid tumors from the National Cancer Institute's SEER (Surveillance Epidemiology and

up to 2,5 years, but due the numerous unfavorable effects, its use is limited [6].

**Rectal carcinoids % patient. 5-year surv.%**

**% patien. 5-year surv.%**

I 13 97 83 97 II 32 69 6,5 84 III 12 21 2,8 27 IV 43 17 7,4 20

N 0 52 96 1 48 4 M 0 76 97,6 1 24 2,4

– incontinence operations (abdominoperineal amputation of rectum, etc.)

– in case of inoperability of tumor, the performance of colostomy.

and bigger tumors, treated in this way [10-13].

**Staging system Colon carcinoids**

**Table 1.** Staging system and 5- year survival rate [14-16]

Systemic therapy in carcinoid treatment has two aims

– to reduce intensity of the systemic effects of disease and

mosis, colonic J pouch, etc.)

258 Colorectal Cancer - Surgery, Diagnostics and Treatment

– treatment of metastasis.

patients.

Lymphomas of colon and rectum are the rare tumors that make 1,4% of human lymphomas, 10-20% of gastrointestinal lymphomas, 0,2-0,6% of all malignant tumors of colon, that is, 0,1-1% of all tumors of the large bowel. According to the incidence in the gastrointestinal system in adults, they take a third place, following the stomach and small intestine, unlike with the age of up to seventeen, where the intestinal localization is predominant. In relation to the incidence of all malignant colon and rectum diseases, they take a third place, following adenocarcinoma and carcinoids [17,18]. The predilection places of occurrence are cecum and rectum, due to large amount of lymph tissue in these regions of the large bowel.

**Figure 2.** Primary non-Hodgkin lymphoma of the cekum

It occurs more often in male patients, older than 50. With regard to the degree of spreading, diseases can be: primary (localized) and secondary (diffuse form). The primary lymphomas of the large bowel are characterized by the existence of the so-called Dawson's criteria [19]:


#### **5.** the liver and spleen are without disease

Primary lymphoma of the colon is a predominantly extranodal form of non-Hodgkin lym‐ phoma, while Hodgkin type is much rarer, present in less than 5% of all patients autopsied due to this disease [20-22]. Devin and his coworkers from the Mayo Clinic, published the largest study of patients with rectum lymphomas,which shows that, out of 61 patients treated in the period of 27 years, 49 of them had a diffuse form and only 12 had a localized disease [23]. The tumors usually have a form of polypoid and ulceriform mass, and sometimes, they form excrescent on mucosa, similar to multiple adenomatous polyposis.

The degree of disease spreading to the surrounding structures was the best presented by the, so-called, Ann-Arbor staging, modification according to Musshoffu [28,29]. The aim of the successful treatment is the early detection of the disease in IE or IIE stage where still there is a possibility of curative resection. The data from literature are significantly different in relation to the stage of a disease in treated patients, which is a consequence of the various criteria according to which the patients were included into the study, different methodologies of

III Involvement of the large bowel and lymph nodes on both

IV Involvement of distant organs (large bowel and one or

The clinical presentation is characterized by the existence of rectoragia and the changed bowel habits. By analyzing the symptoms of the disease, Cho and his associates, presented the study data, which showed that, out of 23 patients, 56% had a non-specific symptoms, abdominal pain and weight loss or anorexia, that is, 35% the of tested patients were operated in the advanced stage of the disease [30]. The data from the research made by Fan and associates, showed that, out of 37 tested patients, 59% had only abdominal pain and 75,7% were operated in the stage of the disease where positive lymphoma nodes were present in the mesenterium of colon and mesorectum. The specific symptoms, such as bleeding per rectum, were present in only 12,5% of patients [17]. Non-specificity of symptoms often postpones timely visit to a doctor and timely diagnosing, which leads to a much higher incidence of the advanced stages of the disease. A special problem is primary colorectal lymphomas - present as surgical emergency, caused by tumors of the IIIE and IVE stages[31]. Surgical emergencies, caused by the obstruc‐ tion of the large bowel, or perforation, initiate a need for urgent surgical intervention, which leads to significantly higher rate of mortality of 58% and more frequent disease recurrence [32-36]. The diagnosis can be made - by taking the anamnestic data and clinical examination including digito rectal examination and colonoscopy with biopsy. There are data from literature, which show that it is not always possible to establish the diagnosis by endoscopic procedures, due to inadequately made biopsy of the tumor, as well as the need for timely performance of an adequate immunohistochemical staining during histopathological exami‐ nation, which is done by a pathologist. It very often leads to inability to give correct interpre‐

sides of diaphragm

more extralymphatic organs or tissue)

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 261

performance and the level of health culture among the tested population.

IE Limited to the colonic/rectal wall IIE 1 Involvement of paracolic lymph nodes IIE 2 Involvement of intermedial lymph nodes.

**Table 2.** Ann-Arbor staging- Musshoff modifications of primary colorectal lymphoma[29].

**3.1. Clinical presentation and diagnosis**

tation of the pathologic finding [37].

**Stage Characteristics**

Etiological factors in formation of the large bowel lymphoma are unknown, as well as for the other types of malignant diseases. However, the higher incidence was noticed in the conditions of immunosuppression, such as the inflammatory disease – ulcerative colitis, HIV virus infections and conditions after organ transplantations, although there are no clear scientific proofs about the connections among these diseases.

More than two-thirds of intestinal lymphomas are supposed to be of B cell lineage, while T cell intestinal lymphomas are rather infrequent and often multifocal and most frequently localized in the small bowel. In relation to the histological type of B cell, non-Hodgkin lymphomas can be: diffuse B cell type, MALT lymphoma, mantle type, Burkitt type and follicular lymphoma. The incidence of some histopathological forms differs from study to study, so Anderson and his associates presented the data of the, so-called, International Study Group about Lymphomas, which included 1378 patients from 8 different cities from 4 continents. Out of the total number of the histopathological findings, in 80% of cases B-cell lymphoma was diagnosed, where the most common form was the one with the large cells, while the other forms, such as mantle, Burkitt and MALT types were significantly rare. In relation to the histological grades, in 75% of tumors, a moderate and intermediately type of diffuse lymphoma of the large cells was established [24-27].

**Figure 3.** Mantle type of primary non-Hodgkin lymphoma

The degree of disease spreading to the surrounding structures was the best presented by the, so-called, Ann-Arbor staging, modification according to Musshoffu [28,29]. The aim of the successful treatment is the early detection of the disease in IE or IIE stage where still there is a possibility of curative resection. The data from literature are significantly different in relation to the stage of a disease in treated patients, which is a consequence of the various criteria according to which the patients were included into the study, different methodologies of performance and the level of health culture among the tested population.


**Table 2.** Ann-Arbor staging- Musshoff modifications of primary colorectal lymphoma[29].

#### **3.1. Clinical presentation and diagnosis**

**5.** the liver and spleen are without disease

260 Colorectal Cancer - Surgery, Diagnostics and Treatment

excrescent on mucosa, similar to multiple adenomatous polyposis.

proofs about the connections among these diseases.

diffuse lymphoma of the large cells was established [24-27].

**Figure 3.** Mantle type of primary non-Hodgkin lymphoma

Primary lymphoma of the colon is a predominantly extranodal form of non-Hodgkin lym‐ phoma, while Hodgkin type is much rarer, present in less than 5% of all patients autopsied due to this disease [20-22]. Devin and his coworkers from the Mayo Clinic, published the largest study of patients with rectum lymphomas,which shows that, out of 61 patients treated in the period of 27 years, 49 of them had a diffuse form and only 12 had a localized disease [23]. The tumors usually have a form of polypoid and ulceriform mass, and sometimes, they form

Etiological factors in formation of the large bowel lymphoma are unknown, as well as for the other types of malignant diseases. However, the higher incidence was noticed in the conditions of immunosuppression, such as the inflammatory disease – ulcerative colitis, HIV virus infections and conditions after organ transplantations, although there are no clear scientific

More than two-thirds of intestinal lymphomas are supposed to be of B cell lineage, while T cell intestinal lymphomas are rather infrequent and often multifocal and most frequently localized in the small bowel. In relation to the histological type of B cell, non-Hodgkin lymphomas can be: diffuse B cell type, MALT lymphoma, mantle type, Burkitt type and follicular lymphoma. The incidence of some histopathological forms differs from study to study, so Anderson and his associates presented the data of the, so-called, International Study Group about Lymphomas, which included 1378 patients from 8 different cities from 4 continents. Out of the total number of the histopathological findings, in 80% of cases B-cell lymphoma was diagnosed, where the most common form was the one with the large cells, while the other forms, such as mantle, Burkitt and MALT types were significantly rare. In relation to the histological grades, in 75% of tumors, a moderate and intermediately type of

The clinical presentation is characterized by the existence of rectoragia and the changed bowel habits. By analyzing the symptoms of the disease, Cho and his associates, presented the study data, which showed that, out of 23 patients, 56% had a non-specific symptoms, abdominal pain and weight loss or anorexia, that is, 35% the of tested patients were operated in the advanced stage of the disease [30]. The data from the research made by Fan and associates, showed that, out of 37 tested patients, 59% had only abdominal pain and 75,7% were operated in the stage of the disease where positive lymphoma nodes were present in the mesenterium of colon and mesorectum. The specific symptoms, such as bleeding per rectum, were present in only 12,5% of patients [17]. Non-specificity of symptoms often postpones timely visit to a doctor and timely diagnosing, which leads to a much higher incidence of the advanced stages of the disease. A special problem is primary colorectal lymphomas - present as surgical emergency, caused by tumors of the IIIE and IVE stages[31]. Surgical emergencies, caused by the obstruc‐ tion of the large bowel, or perforation, initiate a need for urgent surgical intervention, which leads to significantly higher rate of mortality of 58% and more frequent disease recurrence [32-36]. The diagnosis can be made - by taking the anamnestic data and clinical examination including digito rectal examination and colonoscopy with biopsy. There are data from literature, which show that it is not always possible to establish the diagnosis by endoscopic procedures, due to inadequately made biopsy of the tumor, as well as the need for timely performance of an adequate immunohistochemical staining during histopathological exami‐ nation, which is done by a pathologist. It very often leads to inability to give correct interpre‐ tation of the pathologic finding [37].

#### **3.2. Treatment**

Modern treatment of the primary lymphoma of colon and rectum implies a multi-modal approach, that is, a surgical intervention, chemotherapy and radiotherapy in selected cases. Beside the doubtless improvements achieved in surgical technique, as well as in anesthesiology and chemotherapy, during the last three decades, there is still a low level of the five-year survival among the operated patients, which is 42% [29, 37]. The treatment of the large bowel Non-Hodgkin lymphoma is characterized by the existence of different attitudes about it, from applying only chemo and radiotherapy on one side, to the performance of surgical procedures, on the other. Bilsel and his associates published a review of the case from 2005, which gave a complete clinical response of the primary rectal lymphoma, after the treatment with chemo and radiotherapy [24]. The other authors also presented similar data [ 38,39]. Pricolo and his associates, in their analysis of the case presentation from 2002, describe the treatment of rectum lymphoma using the resection procedures and then chemo and radio therapy, while Shimono from Japan recommends a pre-operative radiotherapy first, and then a surgical intervention [40,41]. Regarding the type of operation, there are recommendations that, with small dimen‐ sion primary rectal lymphoma and low malignant potential – MALT or mantle type lympho‐ ma, it is enough to perform a limited resection or transanal extirpation of tumor [42,43]. The differences in attitude are the consequence of the results achieved based on the presentations of cases or studies about a small number of patients and a heterogeneous groups of the treated tumors, in various stages of the disease, with different histopathological diagnosis etc. Nevertheless, based on the modest experience of the authors, the resection of the large bowel is recommended whenever possible, together with neo or adjuvant therapy [44, 45].

the metastasis risk assessment of the GISTs on various locations, determined by the size of

**Mitotic count Size Gastric GIST Duodenal GIST Jejunal & ileal GIST Rectal GIST**

>10 12% 52%

>10 86% 90%

GISTs are symptomatic in about 70%, - in about 10% asymptomatic and in 20% they are discovered during the autopsy, which shows that 1/3 of the large bowel stromal tumors are clinically completely silent. The symptomatology is very similar to the other colon tumors, and is characterized by hematochezia, abdominal or rectal pain, occurrence of complete rectum prolapse etc.[49]. Depending on the tumor size, it is possible to get the clinical presentation of the obstruction or ileus, caused by the growth of GISTs. The diagnosis - can be made by taking the anamnestic data, clinical examination including a digital rectal exam, which should be completed with rectoscopy, colonoscopy, endorectal ultrasound and NMR. It is necessary to do a biopsy of tumor with immunohistochemical analysis, for definite confirmation of the GIST existence in the large bowel. In the case of any doubt that there is metastasis in the liver, it is also necessary to perform the ultrasound and CT scan, within the complete staging of tumor.

Surgical intervention is a method of choice in treatment of large bowel GISTs, and is applied

The main aims of surgical treatment of the primary disease are the complete resection, so-called R0 resection and preservation of the tumor pseudocapsule, without wide resection margins and lymphadenectomy. This is very important in treatment of the rectum GISTs, due to the

<2 cm 0% 0% 0% 0% >2 ≤5 1.9% 8.3% 4.3% 8.5% >5 ≤10 3.6% 34% 24% 57%

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 263

≤2 0% N/A 50% 54% >2 ≤5 16% 50% 73% 52% >5 ≤10 55% 86% 85% 71%

tumor and mitotic index, as shown in table 4 [47].

**Table 3.** Metastasis risk assessment of GISTs in different parts of GI tract [48].

PET scan is indicated in the operated patients in order to follow up.

**4.1. Clinical presentation and diagnosis**

≤5/50

>5/50

**4.2. Treatment**

**3.** Recurrence

in the following cases: **1.** Primary disease; **2.** Metastatic diseases

## **4. GISTs**

Gastrointestinal stromal tumors or, shortly GISTs, are the most common mesenchymal tumors, which are characterized by positive c-KIT, that is, CD117, CD 34 antigens, and they make 0,1-1% of all gastrointestinal tract tumors. They occur most commonly in the stomach 60-70% and small intestine 20-25%, while they are the least present in the large bowel, around 5%, and 0,9% of all tumors in the rectum. In relation to the incidence of occurrence only in the large bowel, they occur in 80% of all patients in the rectum, while in 20% of cases it is in the colon. They occur in middle-aged persons between 40-60 and between both sexes equally, with the incidence of 6,8 / 1 000 000 [46].

At the beginning of XXth century, Theodor Bilroth provided the first descriptions of the stromal tumors. However, the term "stromal tumor" was introduced bay Mazur and Clark only in 1983, following the development of immunohistochemistry. One year later, in 1984, Henry Appelman introduced the term "GIST-gastrointestinal stromal tumors" for the first time, while Kindblom and his associates proved that GISTs originate from the interstitial Cajal cells, which represent the so called, pace maker cells of the gastrointestinal tract. Due to the similar structural and immunohistochemical characteristics of GISTs and Cajal cells, many authors are of the opinion that they originate from the same mesenchimal cell [45]. Invasiveness, or


the metastasis risk assessment of the GISTs on various locations, determined by the size of tumor and mitotic index, as shown in table 4 [47].

**Table 3.** Metastasis risk assessment of GISTs in different parts of GI tract [48].

#### **4.1. Clinical presentation and diagnosis**

GISTs are symptomatic in about 70%, - in about 10% asymptomatic and in 20% they are discovered during the autopsy, which shows that 1/3 of the large bowel stromal tumors are clinically completely silent. The symptomatology is very similar to the other colon tumors, and is characterized by hematochezia, abdominal or rectal pain, occurrence of complete rectum prolapse etc.[49]. Depending on the tumor size, it is possible to get the clinical presentation of the obstruction or ileus, caused by the growth of GISTs. The diagnosis - can be made by taking the anamnestic data, clinical examination including a digital rectal exam, which should be completed with rectoscopy, colonoscopy, endorectal ultrasound and NMR. It is necessary to do a biopsy of tumor with immunohistochemical analysis, for definite confirmation of the GIST existence in the large bowel. In the case of any doubt that there is metastasis in the liver, it is also necessary to perform the ultrasound and CT scan, within the complete staging of tumor. PET scan is indicated in the operated patients in order to follow up.

#### **4.2. Treatment**

**3.2. Treatment**

262 Colorectal Cancer - Surgery, Diagnostics and Treatment

**4. GISTs**

incidence of 6,8 / 1 000 000 [46].

Modern treatment of the primary lymphoma of colon and rectum implies a multi-modal approach, that is, a surgical intervention, chemotherapy and radiotherapy in selected cases. Beside the doubtless improvements achieved in surgical technique, as well as in anesthesiology and chemotherapy, during the last three decades, there is still a low level of the five-year survival among the operated patients, which is 42% [29, 37]. The treatment of the large bowel Non-Hodgkin lymphoma is characterized by the existence of different attitudes about it, from applying only chemo and radiotherapy on one side, to the performance of surgical procedures, on the other. Bilsel and his associates published a review of the case from 2005, which gave a complete clinical response of the primary rectal lymphoma, after the treatment with chemo and radiotherapy [24]. The other authors also presented similar data [ 38,39]. Pricolo and his associates, in their analysis of the case presentation from 2002, describe the treatment of rectum lymphoma using the resection procedures and then chemo and radio therapy, while Shimono from Japan recommends a pre-operative radiotherapy first, and then a surgical intervention [40,41]. Regarding the type of operation, there are recommendations that, with small dimen‐ sion primary rectal lymphoma and low malignant potential – MALT or mantle type lympho‐ ma, it is enough to perform a limited resection or transanal extirpation of tumor [42,43]. The differences in attitude are the consequence of the results achieved based on the presentations of cases or studies about a small number of patients and a heterogeneous groups of the treated tumors, in various stages of the disease, with different histopathological diagnosis etc. Nevertheless, based on the modest experience of the authors, the resection of the large bowel

is recommended whenever possible, together with neo or adjuvant therapy [44, 45].

Gastrointestinal stromal tumors or, shortly GISTs, are the most common mesenchymal tumors, which are characterized by positive c-KIT, that is, CD117, CD 34 antigens, and they make 0,1-1% of all gastrointestinal tract tumors. They occur most commonly in the stomach 60-70% and small intestine 20-25%, while they are the least present in the large bowel, around 5%, and 0,9% of all tumors in the rectum. In relation to the incidence of occurrence only in the large bowel, they occur in 80% of all patients in the rectum, while in 20% of cases it is in the colon. They occur in middle-aged persons between 40-60 and between both sexes equally, with the

At the beginning of XXth century, Theodor Bilroth provided the first descriptions of the stromal tumors. However, the term "stromal tumor" was introduced bay Mazur and Clark only in 1983, following the development of immunohistochemistry. One year later, in 1984, Henry Appelman introduced the term "GIST-gastrointestinal stromal tumors" for the first time, while Kindblom and his associates proved that GISTs originate from the interstitial Cajal cells, which represent the so called, pace maker cells of the gastrointestinal tract. Due to the similar structural and immunohistochemical characteristics of GISTs and Cajal cells, many authors are of the opinion that they originate from the same mesenchimal cell [45]. Invasiveness, or

Surgical intervention is a method of choice in treatment of large bowel GISTs, and is applied in the following cases:


The main aims of surgical treatment of the primary disease are the complete resection, so-called R0 resection and preservation of the tumor pseudocapsule, without wide resection margins and lymphadenectomy. This is very important in treatment of the rectum GISTs, due to the aims of sphincter saving procedure and improve the patient's quality of life. With regard to the size and localization of the large bowel stromal tumors, it is possible to use various surgical procedures: segmental resection, local excision, anterior and abdominoperineal resection. The performance of the anterior resection (high or low), means the observance of the partial or total mesorectal excision principles, in order to prevent sacral nerves injury, bleeding or local recurrence.

**4.3. Treatment outcomes**

**5. Squamous cell carcinoma**

the formation of this neoplasm:

undergo a malignant transformation

**5.1. Clinical presentation and diagnosis**

differentiation of the stem cells,

– The influence of differentiation of stem cells,

The outcome of the large bowel GISTs treatment is troubled with a high percentage of local and distant recurrences, so after the R0 resection, it occurs in 45-50% of cases, 20-25 months after the surgical intervention. The average five-year survival rate is 50%, 73% after the R0 and in 26% after R1 and R2 resections. In the case of the advanced disease with local recurrence

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 265

Squamous cell Carcinoma of the large bowel is a very rare disease, unlike its localizations on the esophagus and the anal canal. The data from literature are based on the reviews of the clinical cases and series with a small number of patients. Schmidtmann first described the squamous cell carcinoma of the large bowel, actually cecum in 1919, and Reiford described the same disease on the rectum in 1933. Currently, there are about 100 cases of the squamous cell carcinoma of the large bowel described in literature, and the incidence of the disease is 0,1-0,25

Due to a very rare occurrence of the tumor, there is a lack of prospective studies, or meta analyses, which would offer data about the demographic characteristics of the patients, risk factors, the nature of the disease behavior, as well as the optimal treatment.It mainly occurs in patients of the average age of 60, more often among women 66% than among men 34% [56].Etiology of the occurrence of colorectal squamous cell carcinoma is still unknown, as well as of the other kinds of malignant diseases, although there are several theories trying to explain

– Proliferation of uncommitted mucosal basal cells into squamous cells which subsequently

– Oncogenic influence of the chronicle kidney insufficiency, as well as, the application of the immunosuppressive therapy in terms of development of some cancerous viruses or oncogenic

– Special influences of irradiation, colocutaneous fistula, ulcerous colitis, Entamoeba histoli‐ tyca colitis, homosexuality, immunosuppression, schistosomiasis, and still unclear influence

The symptoms of the disease are very similar to the symptoms of colon carcinoma, such as bleeding, abdominal pain, change in bowel habits with the episodes of diarrhea and obstipa‐ tion and weight loss.The diagnosis is established by taking the anamnestic data, clinical

and metastatic disease, a five-year survival rate is 28-35% [54].

on 1000 patients suffering from the colorectal carcinoma [55].

– Squamous metaplasia at the place of existence of colorectal adenoma,

of HIV (human papilloma viruses types 16, 18, 31, 33) [57- 59].

**Figure 4.** Rectal GIST

When GIST adheres to contiguous organs, consideration should be given to an en bloc resection. The modern aspects of the GISTs treatment also mean the use of Imatinib, a medicament, which revolutionary contributed to the significantly better results in treatment in GISTs. Joensuua, Heinrick van Oosterona and Tuveson made the first reports about the use of Imatinib in 2001. An immediate cause for the invention of this medicament was the discovery of Hirot about the existence of the abnormal activation of KIT oncoprotein or transmembrane receptor tyrosine kinase and the following mutation of C-kit gene, with exceptional cellular proliferation. Imatinib selectively inhibits the receptors of the transmembrane tyrosin kinese, thus blocking the abnormal growth of tumor. Van Oosteron and his associates published the results from 70% of clinical responses in KIT-positive metastatic GISTs [50,51]. Primary unresectable GISTs of the large bowel are initially treated with Imatinib, with an aim to reduce the size of a tumor – "downsizing". In the case of the existence of a metastatic disease, a nonadjuvant use of Imanitib is indicated, in order to secure good clinical response, meaning a disease without progression, with the possibility of performing R0 resection [52]. When there is a small volume metastasis in liver, some authors recommend the simultaneous resection of the large bowel and liver, and then the application of Imatinib[53]. Distant metastasis occur on the liver in over 50%, and they are treated with the initial application of Imatinib, followed by the various resection procedures.

The treatment of GISTs using chemotherapy has a minimum effect, RR<10%, and has no significance for the overall survival, as well as the application of radiotherapy, since the tumor is radio resistant.

#### **4.3. Treatment outcomes**

aims of sphincter saving procedure and improve the patient's quality of life. With regard to the size and localization of the large bowel stromal tumors, it is possible to use various surgical procedures: segmental resection, local excision, anterior and abdominoperineal resection. The performance of the anterior resection (high or low), means the observance of the partial or total mesorectal excision principles, in order to prevent sacral nerves injury, bleeding or local

When GIST adheres to contiguous organs, consideration should be given to an en bloc resection. The modern aspects of the GISTs treatment also mean the use of Imatinib, a medicament, which revolutionary contributed to the significantly better results in treatment in GISTs. Joensuua, Heinrick van Oosterona and Tuveson made the first reports about the use of Imatinib in 2001. An immediate cause for the invention of this medicament was the discovery of Hirot about the existence of the abnormal activation of KIT oncoprotein or transmembrane receptor tyrosine kinase and the following mutation of C-kit gene, with exceptional cellular proliferation. Imatinib selectively inhibits the receptors of the transmembrane tyrosin kinese, thus blocking the abnormal growth of tumor. Van Oosteron and his associates published the results from 70% of clinical responses in KIT-positive metastatic GISTs [50,51]. Primary unresectable GISTs of the large bowel are initially treated with Imatinib, with an aim to reduce the size of a tumor – "downsizing". In the case of the existence of a metastatic disease, a nonadjuvant use of Imanitib is indicated, in order to secure good clinical response, meaning a disease without progression, with the possibility of performing R0 resection [52]. When there is a small volume metastasis in liver, some authors recommend the simultaneous resection of the large bowel and liver, and then the application of Imatinib[53]. Distant metastasis occur on the liver in over 50%, and they are treated with the initial application of Imatinib, followed

The treatment of GISTs using chemotherapy has a minimum effect, RR<10%, and has no significance for the overall survival, as well as the application of radiotherapy, since the tumor

recurrence.

264 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Figure 4.** Rectal GIST

by the various resection procedures.

is radio resistant.

The outcome of the large bowel GISTs treatment is troubled with a high percentage of local and distant recurrences, so after the R0 resection, it occurs in 45-50% of cases, 20-25 months after the surgical intervention. The average five-year survival rate is 50%, 73% after the R0 and in 26% after R1 and R2 resections. In the case of the advanced disease with local recurrence and metastatic disease, a five-year survival rate is 28-35% [54].

## **5. Squamous cell carcinoma**

Squamous cell Carcinoma of the large bowel is a very rare disease, unlike its localizations on the esophagus and the anal canal. The data from literature are based on the reviews of the clinical cases and series with a small number of patients. Schmidtmann first described the squamous cell carcinoma of the large bowel, actually cecum in 1919, and Reiford described the same disease on the rectum in 1933. Currently, there are about 100 cases of the squamous cell carcinoma of the large bowel described in literature, and the incidence of the disease is 0,1-0,25 on 1000 patients suffering from the colorectal carcinoma [55].

Due to a very rare occurrence of the tumor, there is a lack of prospective studies, or meta analyses, which would offer data about the demographic characteristics of the patients, risk factors, the nature of the disease behavior, as well as the optimal treatment.It mainly occurs in patients of the average age of 60, more often among women 66% than among men 34% [56].Etiology of the occurrence of colorectal squamous cell carcinoma is still unknown, as well as of the other kinds of malignant diseases, although there are several theories trying to explain the formation of this neoplasm:

– The influence of differentiation of stem cells,

– Squamous metaplasia at the place of existence of colorectal adenoma,

– Proliferation of uncommitted mucosal basal cells into squamous cells which subsequently undergo a malignant transformation

– Oncogenic influence of the chronicle kidney insufficiency, as well as, the application of the immunosuppressive therapy in terms of development of some cancerous viruses or oncogenic differentiation of the stem cells,

– Special influences of irradiation, colocutaneous fistula, ulcerous colitis, Entamoeba histoli‐ tyca colitis, homosexuality, immunosuppression, schistosomiasis, and still unclear influence of HIV (human papilloma viruses types 16, 18, 31, 33) [57- 59].

#### **5.1. Clinical presentation and diagnosis**

The symptoms of the disease are very similar to the symptoms of colon carcinoma, such as bleeding, abdominal pain, change in bowel habits with the episodes of diarrhea and obstipa‐ tion and weight loss.The diagnosis is established by taking the anamnestic data, clinical examination including digital rectal exam, which should be completed with rectoscopy, colonoscopy, MSCT, endorectal ultrasound andd NMR.Williams and his associates published the following criteria for diagnosing the squamous cell carcinoma of the large bowel, in 1979:

were made based on the application of the identical treatment protocol in anal squamous cell carcinoma - (combination of the chemo and radio therapy 5-FU +mitomycin-C and radio 45 Gy), did not give the expected results in localization of the proximal parts of the rectum and colon. There are data in literature, which recommend only application of the chemo and radio therapy, as well as, the simultaneous chemo-radiation. However, the majority of authors agree that, for the time being and based on the experiences acquired in treatment of a small number of patients, the optimal therapy means surgical intervention and the adjuvant chemo radiation [52]. Surgical treatment of the advanced disease means the application of the resection procedures (colectomy, high and low resection of rectum) and abdominoperineal amputations of rectum. The resections of rectum, as a sphincter preserving operation, enable better quality of life of the patient on one hand, and compliance with the oncological principles on the other. Regardless of the advantages of the resection procedures in relation to the amputation surgery of rectum, the data from literature show that Miles's operation has been performed twice as much in treatment of the squamous cell carcinoma of rectum, which has been explained by a

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 267

The disease prognosis is based on determination of the TNM stage, the most important prognostic factor, identical to the one in anal squamous cell carcinoma. The TNM stage is

By comparing the disease prognosis from adenocarcinoma of the colon and rectum of the same stage, it has been established that stages of the disease I and II have a similar prognosis, unlike the advanced ones (stages III and IV), where squamous cell carcinoma has worse prognosis. The average five-year survival is 32%, with variations, which are related to the certain stages: Dukes B 50%, Dukes C 33% & Dukes D 0%. Application of the adjuvant therapy improves the overall survival of a patient, on one hand, while the pre-operative radiotherapy increases the

T2 N0 M0

large number of advanced tumors at the time of diagnosing [61].

**Stadium T N M** 0 Tis N0 M0 I T1 N0 M0

IIA T3 N0 M0 IIB T4 N0 M0 IIIA T1-T2 N1 M0 IIIB T3-T4 N1 M0 IIIC Any T N2 M0 IV Any T Any N M1

**Table 4.** TNM staging system of squamous cell carcinoma of the large bowel [56].

percent of the sphincter preserving operation, on the other [58,59].

shown in Table 4.


These criteria should be completed with the excision biopsy of tumor, as well as, the PH, or immunohistochemical confirmation (presence of cytokeratin CAM 5.2, AE1/AE3 i 34B12. CAM 5.2). Sub-mucous localizations of the squamous cell carcinoma represent a separate problem, due to difficult identification during standard examinations, so, in these cases, it is recom‐ mended to use endoluminal ultrasound guided needle biopsy of tumor. Determination of values of the tumor markers represents one of the possible auxiliary diagnostic procedures for determination of the disease, under the condition that the marker is specific for a particular tumor. In the case of the squamous cell carcinoma of the colon and rectum, there are no specific tumor markers, so those, usually used for the anal squamous cell carcinoma or for the so called layer plate cells of carcinoma antigen ( Squamous cell carcinoma antigen "-SCC Ag)", are used. According to the opinions of some authors, SCC Ag is not specific for the initial diagnosis, but for the follow up of the occurance of local and distant recurrence after treatment [60].

#### **5.2. Treatment**

Surgical intervention is a method of choice in treatment of the squamous cell carcinoma of the large bowel. The type of surgical intervention depends on the size of tumor, its localization, depth of invasion into the colon wall, presence of local and distant metastasis, BMI (Body Mass Index), general condition of the patient and presence of comorbidity. The types of surgical intervention are similar to those used with the colon carcinoma: endoscopic mucosa/submucosa resection, segmental or hemi colectomy, local excision, resection procedures on the rectum, as well as abdominoperineal amputation of the rectum. Endoscopic mucosa/submucosa resection is applied based on the experience acquired in treatment of adenocarcinoma, and is indicated in patients with superficial tumors – T1 stage and with an expressed comor‐ bidity. Endoscopic mucosa/sub-mucosa resection, local excision (trans-anal or trans-anal endoscopic microsurgery-TEM) is a method of choice with T1 stage of the disease, which means a tumor spreading to mucosa/sub-mucosa. There are some dilemmas about the type of treatment in T2 stage (spreading to muscularis proprie), because after application of the local excision, a recurrence rate is present in 20% of the operated patients. In these cases, it is necessary to make a good pre-operative staging of tumor in relation to the existence of the positive lymph nodes and the range of spreading to the large bowel wall.In the cases of the transmural spreading to the wall, up to the pericolic/rectal fat tissue – T3 stage, as well as the infiltration into the surrounding organs T4-stage, there are dilemmas whether it is better to do a surgical intervention first, and then the chemotherapy, or vice versa. The researches, which

were made based on the application of the identical treatment protocol in anal squamous cell carcinoma - (combination of the chemo and radio therapy 5-FU +mitomycin-C and radio 45 Gy), did not give the expected results in localization of the proximal parts of the rectum and colon. There are data in literature, which recommend only application of the chemo and radio therapy, as well as, the simultaneous chemo-radiation. However, the majority of authors agree that, for the time being and based on the experiences acquired in treatment of a small number of patients, the optimal therapy means surgical intervention and the adjuvant chemo radiation [52]. Surgical treatment of the advanced disease means the application of the resection procedures (colectomy, high and low resection of rectum) and abdominoperineal amputations of rectum. The resections of rectum, as a sphincter preserving operation, enable better quality of life of the patient on one hand, and compliance with the oncological principles on the other. Regardless of the advantages of the resection procedures in relation to the amputation surgery of rectum, the data from literature show that Miles's operation has been performed twice as much in treatment of the squamous cell carcinoma of rectum, which has been explained by a large number of advanced tumors at the time of diagnosing [61].

examination including digital rectal exam, which should be completed with rectoscopy, colonoscopy, MSCT, endorectal ultrasound andd NMR.Williams and his associates published the following criteria for diagnosing the squamous cell carcinoma of the large bowel, in 1979: **1.** non-existence of the squamous cell carcinoma and its metastasis on the other locations

**2.** careful anoscopy and rectoscopy in order to exclude the existence proximal extension of

These criteria should be completed with the excision biopsy of tumor, as well as, the PH, or immunohistochemical confirmation (presence of cytokeratin CAM 5.2, AE1/AE3 i 34B12. CAM 5.2). Sub-mucous localizations of the squamous cell carcinoma represent a separate problem, due to difficult identification during standard examinations, so, in these cases, it is recom‐ mended to use endoluminal ultrasound guided needle biopsy of tumor. Determination of values of the tumor markers represents one of the possible auxiliary diagnostic procedures for determination of the disease, under the condition that the marker is specific for a particular tumor. In the case of the squamous cell carcinoma of the colon and rectum, there are no specific tumor markers, so those, usually used for the anal squamous cell carcinoma or for the so called layer plate cells of carcinoma antigen ( Squamous cell carcinoma antigen "-SCC Ag)", are used. According to the opinions of some authors, SCC Ag is not specific for the initial diagnosis, but

for the follow up of the occurance of local and distant recurrence after treatment [60].

Surgical intervention is a method of choice in treatment of the squamous cell carcinoma of the large bowel. The type of surgical intervention depends on the size of tumor, its localization, depth of invasion into the colon wall, presence of local and distant metastasis, BMI (Body Mass Index), general condition of the patient and presence of comorbidity. The types of surgical intervention are similar to those used with the colon carcinoma: endoscopic mucosa/submucosa resection, segmental or hemi colectomy, local excision, resection procedures on the rectum, as well as abdominoperineal amputation of the rectum. Endoscopic mucosa/submucosa resection is applied based on the experience acquired in treatment of adenocarcinoma, and is indicated in patients with superficial tumors – T1 stage and with an expressed comor‐ bidity. Endoscopic mucosa/sub-mucosa resection, local excision (trans-anal or trans-anal endoscopic microsurgery-TEM) is a method of choice with T1 stage of the disease, which means a tumor spreading to mucosa/sub-mucosa. There are some dilemmas about the type of treatment in T2 stage (spreading to muscularis proprie), because after application of the local excision, a recurrence rate is present in 20% of the operated patients. In these cases, it is necessary to make a good pre-operative staging of tumor in relation to the existence of the positive lymph nodes and the range of spreading to the large bowel wall.In the cases of the transmural spreading to the wall, up to the pericolic/rectal fat tissue – T3 stage, as well as the infiltration into the surrounding organs T4-stage, there are dilemmas whether it is better to do a surgical intervention first, and then the chemotherapy, or vice versa. The researches, which

**3.** non-existence of a fistulous tract lined by squamous cells [55, 58].

(particularly the skin),

**5.2. Treatment**

anal squamous cell carcinoma,

266 Colorectal Cancer - Surgery, Diagnostics and Treatment

The disease prognosis is based on determination of the TNM stage, the most important prognostic factor, identical to the one in anal squamous cell carcinoma. The TNM stage is shown in Table 4.


**Table 4.** TNM staging system of squamous cell carcinoma of the large bowel [56].

By comparing the disease prognosis from adenocarcinoma of the colon and rectum of the same stage, it has been established that stages of the disease I and II have a similar prognosis, unlike the advanced ones (stages III and IV), where squamous cell carcinoma has worse prognosis. The average five-year survival is 32%, with variations, which are related to the certain stages: Dukes B 50%, Dukes C 33% & Dukes D 0%. Application of the adjuvant therapy improves the overall survival of a patient, on one hand, while the pre-operative radiotherapy increases the percent of the sphincter preserving operation, on the other [58,59].

#### **6. Melanoma**

Melanoma of the gastrointestinal tract is a rare mucosal melanoma with a particularly aggressive biology compared with cutaneous one of equal stage. They most often occur as a metastatic tumor, while the primary localization is rare and possible in esophagus, stomach, small intestine and anorectum, that is, at the places where melanocyte normally exist. The colon melanoma is an extremely rare tumor with regard to the fact that, embryologically, melanocytes do not exist in this part of colon and that, up to now, only 12 cases have been describes in the English literature. There are several theories, which describe the formation of the colon melanoma: relation to neural crest cells, model of tumor regression and ectodermal differentiation, but none of them has been completely proved so far. Localization in the anorectum takes the third place regarding the incidence of localization, behind the rest of skin and eyes surfaces and it makes 1-1,5% of all melanomas in the human body, and 3-15% of all tumors of the colon and rectum [62,63]. Moore described it for the first time in 1857 and, until now, the total of 500 cases was described in the literature. The most often it occurs on the skin, under the dental line, and rarely at the level of cuboidal epithelium of the transition zone and mucosae of the distal rectum. It is more common in women (twice as much than in men), between 60 and 70 years of age [64]. The melanoma represents a disease of the neuroectodermal origin, which the most often originates from melanocytes and nevus cells of the basal layer of epidermis, and significantly less from mucosa. It has an extremely worse long-term prognosis, because of the disease discovery in the advanced stage, mainly with metastasis in the inguinal nodes. Beside the lymhogenous dissemination, spreading is possible by the local ingrowth and in hematogenous way. The local spread is according to the radial (horizontal) and vertical growth. Radial growth means circular spreading around the primary tumor, through the epithelium of mucosa and the superficial layers of sub-mucosa, without tendency of metasta‐ sizing. Vertical growth means penetration into the deeper layers of the colon wall, with simultaneous metastasizing. Determination of level of the vertical tumor growth, i.e. involve‐ ment of the colon and rectum wall layers, is essential for the choice of surgical intervention. The most important roles here have the MSCT (multi-slice scanner), NMR (magnetic reso‐ nance) and endoluminal ultrasound. Hematogenous dissemination occurs by penetration of the melanoma cells into the blood vessels, with further spreading to the whole body. About 30% of patients, at the moment of diagnosing, are considered to have a disseminated process, while only 17% of the operated ones have a five-year survival. [65,66]. It differs from skin melanoma in the way that 25% of tumors do not contain a pigment of the so called "coloured" tumor, and because ultraviolet radiation is a factor of protection, not a risk. In case of existence of the pigment tumor of the rectum, the macroscopic appearance is very similar to thrombosed external and prolapsing internal hemorrhoids (see figure 5), which can mislead a doctor in setting a diagnosis[67,68].

(NMR), endoluminal ultrasound and tumor biopsy with pathohistological and immunohis‐ tochemical processing. Special attention should be paid to the examination of certain groups of lymph nodes, depending on the primary tumor localization. Taking into account the results made by Kalid and his associates, the most often localization of the primary colon melanoma is cekum ascedens and transversum, while with the metastatic melanoma these are the ascendant and descendant parts of colon [62]. Curative treatment of the large bowel melanoma is exclusively surgical. The main aim of the treatment is to achieve a compromise between the necessity to apply a radical oncological treatment and a need to preserve the patient's quality of living. The contemporary approach to treatment of the primary colon and rectum melanoma

**Figure 5.** a). Prolapsed melanoma recti; b). Histopathological finding of melanoma recti (H&E 40x)

(a) (b)

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 269

**a.** colectomy with wide excisional margins (partial, hemi-colectomy, subtotal and total)

**b.** trans-anal wide local excision with preservation of the anal sphincter (in the case of the

**c.** extensive surgeries according to the type of the rectum resection or abdominoperineal

There are numerous dilemmas about which type of surgical intervention to be applied in certain stages of the disease. The supporters of radical treatment recommend the resection or rectum abdominoperineal amputation, depending on the localization, with dissection of both

– possibility of the detailed exploration of the abdomen and the eventual discovery of distant

On the other hand, some authors recommend a wide local excision of tumor with preservation

implies to the performance of surgical interventions, such as:

initial stage of the rectum tumor)

inguinal regions, stating the following advantages:

– lower percent of the local recurrence rate [69].

– absence of definitive stoma,

– similar five-year survival [70,71].

of the sphincter mechanism, for the following reasons:

amputation.

metastasis;

The symptoms of the disease are different, but the most common ones are the abdominal pain, weight loss and bleeding.The diagnosis of the disease implies to detailed anamnesis, physical examination with special reference to inspection of all parts of skin and eyes, as the most common primary localizations, as well as, taking biochemical laboratory analyses, digito rectal examination, colonoscopy, barium enema, multi-slice scanner (MSCT), magnetic resonance

**Figure 5.** a). Prolapsed melanoma recti; b). Histopathological finding of melanoma recti (H&E 40x)

(NMR), endoluminal ultrasound and tumor biopsy with pathohistological and immunohis‐ tochemical processing. Special attention should be paid to the examination of certain groups of lymph nodes, depending on the primary tumor localization. Taking into account the results made by Kalid and his associates, the most often localization of the primary colon melanoma is cekum ascedens and transversum, while with the metastatic melanoma these are the ascendant and descendant parts of colon [62]. Curative treatment of the large bowel melanoma is exclusively surgical. The main aim of the treatment is to achieve a compromise between the necessity to apply a radical oncological treatment and a need to preserve the patient's quality of living. The contemporary approach to treatment of the primary colon and rectum melanoma implies to the performance of surgical interventions, such as:


There are numerous dilemmas about which type of surgical intervention to be applied in certain stages of the disease. The supporters of radical treatment recommend the resection or rectum abdominoperineal amputation, depending on the localization, with dissection of both inguinal regions, stating the following advantages:

– possibility of the detailed exploration of the abdomen and the eventual discovery of distant metastasis;

– lower percent of the local recurrence rate [69].

On the other hand, some authors recommend a wide local excision of tumor with preservation of the sphincter mechanism, for the following reasons:

– absence of definitive stoma,

**6. Melanoma**

268 Colorectal Cancer - Surgery, Diagnostics and Treatment

setting a diagnosis[67,68].

Melanoma of the gastrointestinal tract is a rare mucosal melanoma with a particularly aggressive biology compared with cutaneous one of equal stage. They most often occur as a metastatic tumor, while the primary localization is rare and possible in esophagus, stomach, small intestine and anorectum, that is, at the places where melanocyte normally exist. The colon melanoma is an extremely rare tumor with regard to the fact that, embryologically, melanocytes do not exist in this part of colon and that, up to now, only 12 cases have been describes in the English literature. There are several theories, which describe the formation of the colon melanoma: relation to neural crest cells, model of tumor regression and ectodermal differentiation, but none of them has been completely proved so far. Localization in the anorectum takes the third place regarding the incidence of localization, behind the rest of skin and eyes surfaces and it makes 1-1,5% of all melanomas in the human body, and 3-15% of all tumors of the colon and rectum [62,63]. Moore described it for the first time in 1857 and, until now, the total of 500 cases was described in the literature. The most often it occurs on the skin, under the dental line, and rarely at the level of cuboidal epithelium of the transition zone and mucosae of the distal rectum. It is more common in women (twice as much than in men), between 60 and 70 years of age [64]. The melanoma represents a disease of the neuroectodermal origin, which the most often originates from melanocytes and nevus cells of the basal layer of epidermis, and significantly less from mucosa. It has an extremely worse long-term prognosis, because of the disease discovery in the advanced stage, mainly with metastasis in the inguinal nodes. Beside the lymhogenous dissemination, spreading is possible by the local ingrowth and in hematogenous way. The local spread is according to the radial (horizontal) and vertical growth. Radial growth means circular spreading around the primary tumor, through the epithelium of mucosa and the superficial layers of sub-mucosa, without tendency of metasta‐ sizing. Vertical growth means penetration into the deeper layers of the colon wall, with simultaneous metastasizing. Determination of level of the vertical tumor growth, i.e. involve‐ ment of the colon and rectum wall layers, is essential for the choice of surgical intervention. The most important roles here have the MSCT (multi-slice scanner), NMR (magnetic reso‐ nance) and endoluminal ultrasound. Hematogenous dissemination occurs by penetration of the melanoma cells into the blood vessels, with further spreading to the whole body. About 30% of patients, at the moment of diagnosing, are considered to have a disseminated process, while only 17% of the operated ones have a five-year survival. [65,66]. It differs from skin melanoma in the way that 25% of tumors do not contain a pigment of the so called "coloured" tumor, and because ultraviolet radiation is a factor of protection, not a risk. In case of existence of the pigment tumor of the rectum, the macroscopic appearance is very similar to thrombosed external and prolapsing internal hemorrhoids (see figure 5), which can mislead a doctor in

The symptoms of the disease are different, but the most common ones are the abdominal pain, weight loss and bleeding.The diagnosis of the disease implies to detailed anamnesis, physical examination with special reference to inspection of all parts of skin and eyes, as the most common primary localizations, as well as, taking biochemical laboratory analyses, digito rectal examination, colonoscopy, barium enema, multi-slice scanner (MSCT), magnetic resonance

– similar five-year survival [70,71].

The authors from MD Anderson Cancer Center present 20-year experience with treatment of 54 patients with localized anorectal melanoma, demonstrating that combined surgical wide local excision and adjuvant radotherapy provides good local disease control with acceptable side effects [72].The existence of such different attitudes in literature is a consequence of, primarily, uneven criteria of the researches made, comparison of different localizations of the anorectal melanoma and stage of the disease. The most significant parameter, based on which a decision about the type of surgical intervention is made, is the thickness of tumor. According to Weynadt and his associates, indication for a wide local excision are melanomas up to 4 mm thick, with the limits of excision up to 2 cm from the primary tumor, without involvement of sphincter, while the extensive surgeries on the rectum are recommended for the melanomas over 4 mm thick [73].In relation to the adjuvant therapy, melanomas are considered hemi resistant tumors, so certain cytostatic medicaments have an effect in 10-25% of the treated ones. The most often used are: dacarbazin, temozolamid, cisplatin, carboplatin, nitrosoureas.The latest research showed that determination of biological markers RAS/RAF/MEK/ERK, represent a significant indicator of the cell growth intensity degree, as well as, the invasion and survival [62]. The adjuvant therapy of anorectum melanoma is not very much successful because all these tumors are radio resistant and scarcely responsive to chemotherapy[74,75].

and a pedicle. The cases of rupture of the ovarian teratoma into the rectal lumen are described, with the similar difficulties. The additional diagnostic procedures, such as the endoluminal ultrasound, multi-slice scanner and NMR give the additional information about the extensity of the tumor itself, as well as, the estimation of operability. Some malignant transformations of teratomas with a tendency of creating squamous cell carcinoma are possible, and due to this, it is not advisable to perform the transanal punctuation because of the danger of malignant cells spreading, on one hand, and the potential infection, on the other. The method of choice

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 271

**The most frequent form of plasma cell neoplasm is a multiple myeloma**. Out of the total number of all multiple myeloma, only 2% are the so-called extramedullary plasmacytoma. More the 75% of extramedullary plasmacytoma occur in the upper part of the respiratory system, while the most common places of occurence in the gastrointestinal tract are the stomach and small intestine. Until now, 22 cases of the occurence of extramedulllary plasma‐ cytoma in the colon, have been reported, where the average age of patients was around 52,3. The most frequent localization on the large bowel are the cecum with 36,4% and rectum with 22,7%. It is essential to make a differential diagnosis differentiation between the primary and secondary plasmacytoma, that is, the metastasis of the multiple myeloma. It is achieved by determination of the Bence-Jones proteins in urine, by serum electrophoresis, as well as, the

in the treatment is the complete elimination of the cystic tumor.

immunohistochemical finding of the collections of monoclonal plasma cells.

– combined application of surgical intervention and radio-therapy in 4,5% of cases [77,78].

**Schwannomas** originate from Schwann cells, which form neural sheath and belong to the group of stromal tumors. In the gastrointestinal tract, they most frequently appear in the stomach, while the primary Schwannomas of the large bowel are extremely rare and, until to now, only 39 clinical cases have been reported. They mainly occur in older patients around 65 years of age, of both sexes equally. They grow slowly and there is a large number of patients who do not have any symptoms at the moment of diagnosing. The symptoms occur depending on the size and localization of tumor, but vague pain in the abdomen, bleeding and change of bowel habitus mainly manifest them. The pre-operative diagnosing, using the standard procedures such as anamnesis, physical examination, colonoscopy MSCT, NMR and endolu‐ minal ultrasound, is possible in determination of the tumor mass, but not the type and kind of tumor because it resembles to the GIST tumors of the colon. The most accurate diagnosis implies the elimination of tumor as a whole, with pathohistologic and immunohistochemical analyisis. It is also difficult to differentiate it from GISTs in respect of immunohistochemical analyisis and some authors classify it the sub-group of GISTs, such as GANT tumors, i.e.

The treatment involves the application of:

– surgical intervention in 81,8% of cases,

gastrointestinal autonomous nerve tumors [79].

– radio-therapy in 9% of cases,

#### **6. Extremely rare tumors**

Other tumors include an extremely rare malignant diseases of the large bowel: primary teratomas, extramedullary plasmacytomas, schwannomas and metastasis of distant tumors.

**Primary teratomas** of the large bowel are very rare diseases and, there are only about 50 cases published in literature until now, mainly the ones in the rectum and in the form of clinical presentation. It occurs more often in women at the average age of 42,5. They are considered to originate as consequence of the ectopic development of the so-called "captured" ectodermal tissue although, in their composition, some structures of mesodermal endodermal origin are possible. Histologically, it is composed of the stratified squamous epithelia, fat cells, hair follicle, cartilage and, partially glandular tissue. They are usually benign tumors, however some malignant transformations are also possible, which create a need for the total elimination of tumor, due to compliance with the oncological principles. Data from literature indicate that teratomas usually occur in the ovary, testicles, mediastinum and the middle lines such as sacrococcygeal region, while they occur less frequently in the gastrointestinal tract (rectum, sigmoid part of colon, appendix and terminal ileum) [76]. The rectal teratomas usually have a polypoid cystic form, with protrusion into the lumen area. The solitary cysts are mainly present, filled in with sebaceous whitish liquid into which the sebaceous glands, hair follicles and teeth are immersed. Beside the cystic form, the existence of the solid tumors is possible, which indicates a mature form of the teratoma.

The clinical presentation is characterized by the presence of pain during defecation, bleeding and change in bowel habits. The diagnosis is established by the anamnesis and digital rectal examination, which confirms the existence of the polypoid tumor mass of mainly smooth edges and a pedicle. The cases of rupture of the ovarian teratoma into the rectal lumen are described, with the similar difficulties. The additional diagnostic procedures, such as the endoluminal ultrasound, multi-slice scanner and NMR give the additional information about the extensity of the tumor itself, as well as, the estimation of operability. Some malignant transformations of teratomas with a tendency of creating squamous cell carcinoma are possible, and due to this, it is not advisable to perform the transanal punctuation because of the danger of malignant cells spreading, on one hand, and the potential infection, on the other. The method of choice in the treatment is the complete elimination of the cystic tumor.

**The most frequent form of plasma cell neoplasm is a multiple myeloma**. Out of the total number of all multiple myeloma, only 2% are the so-called extramedullary plasmacytoma. More the 75% of extramedullary plasmacytoma occur in the upper part of the respiratory system, while the most common places of occurence in the gastrointestinal tract are the stomach and small intestine. Until now, 22 cases of the occurence of extramedulllary plasma‐ cytoma in the colon, have been reported, where the average age of patients was around 52,3. The most frequent localization on the large bowel are the cecum with 36,4% and rectum with 22,7%. It is essential to make a differential diagnosis differentiation between the primary and secondary plasmacytoma, that is, the metastasis of the multiple myeloma. It is achieved by determination of the Bence-Jones proteins in urine, by serum electrophoresis, as well as, the immunohistochemical finding of the collections of monoclonal plasma cells.

The treatment involves the application of:


The authors from MD Anderson Cancer Center present 20-year experience with treatment of 54 patients with localized anorectal melanoma, demonstrating that combined surgical wide local excision and adjuvant radotherapy provides good local disease control with acceptable side effects [72].The existence of such different attitudes in literature is a consequence of, primarily, uneven criteria of the researches made, comparison of different localizations of the anorectal melanoma and stage of the disease. The most significant parameter, based on which a decision about the type of surgical intervention is made, is the thickness of tumor. According to Weynadt and his associates, indication for a wide local excision are melanomas up to 4 mm thick, with the limits of excision up to 2 cm from the primary tumor, without involvement of sphincter, while the extensive surgeries on the rectum are recommended for the melanomas over 4 mm thick [73].In relation to the adjuvant therapy, melanomas are considered hemi resistant tumors, so certain cytostatic medicaments have an effect in 10-25% of the treated ones. The most often used are: dacarbazin, temozolamid, cisplatin, carboplatin, nitrosoureas.The latest research showed that determination of biological markers RAS/RAF/MEK/ERK, represent a significant indicator of the cell growth intensity degree, as well as, the invasion and survival [62]. The adjuvant therapy of anorectum melanoma is not very much successful because all these tumors are radio resistant and scarcely responsive to chemotherapy[74,75].

Other tumors include an extremely rare malignant diseases of the large bowel: primary teratomas, extramedullary plasmacytomas, schwannomas and metastasis of distant tumors.

**Primary teratomas** of the large bowel are very rare diseases and, there are only about 50 cases published in literature until now, mainly the ones in the rectum and in the form of clinical presentation. It occurs more often in women at the average age of 42,5. They are considered to originate as consequence of the ectopic development of the so-called "captured" ectodermal tissue although, in their composition, some structures of mesodermal endodermal origin are possible. Histologically, it is composed of the stratified squamous epithelia, fat cells, hair follicle, cartilage and, partially glandular tissue. They are usually benign tumors, however some malignant transformations are also possible, which create a need for the total elimination of tumor, due to compliance with the oncological principles. Data from literature indicate that teratomas usually occur in the ovary, testicles, mediastinum and the middle lines such as sacrococcygeal region, while they occur less frequently in the gastrointestinal tract (rectum, sigmoid part of colon, appendix and terminal ileum) [76]. The rectal teratomas usually have a polypoid cystic form, with protrusion into the lumen area. The solitary cysts are mainly present, filled in with sebaceous whitish liquid into which the sebaceous glands, hair follicles and teeth are immersed. Beside the cystic form, the existence of the solid tumors is possible,

The clinical presentation is characterized by the presence of pain during defecation, bleeding and change in bowel habits. The diagnosis is established by the anamnesis and digital rectal examination, which confirms the existence of the polypoid tumor mass of mainly smooth edges

**6. Extremely rare tumors**

270 Colorectal Cancer - Surgery, Diagnostics and Treatment

which indicates a mature form of the teratoma.

– combined application of surgical intervention and radio-therapy in 4,5% of cases [77,78].

**Schwannomas** originate from Schwann cells, which form neural sheath and belong to the group of stromal tumors. In the gastrointestinal tract, they most frequently appear in the stomach, while the primary Schwannomas of the large bowel are extremely rare and, until to now, only 39 clinical cases have been reported. They mainly occur in older patients around 65 years of age, of both sexes equally. They grow slowly and there is a large number of patients who do not have any symptoms at the moment of diagnosing. The symptoms occur depending on the size and localization of tumor, but vague pain in the abdomen, bleeding and change of bowel habitus mainly manifest them. The pre-operative diagnosing, using the standard procedures such as anamnesis, physical examination, colonoscopy MSCT, NMR and endolu‐ minal ultrasound, is possible in determination of the tumor mass, but not the type and kind of tumor because it resembles to the GIST tumors of the colon. The most accurate diagnosis implies the elimination of tumor as a whole, with pathohistologic and immunohistochemical analyisis. It is also difficult to differentiate it from GISTs in respect of immunohistochemical analyisis and some authors classify it the sub-group of GISTs, such as GANT tumors, i.e. gastrointestinal autonomous nerve tumors [79].

## **7. Metastases in the colon and rectum from the distant tumors**

The metastasis of distant primary tumors rarely spread to the large bowel, and it is usually related to the carcinoma of the surrounding organs (stomach, pancreas, ovarian etc.) which, due to their growth and size, spread to the surrounding parts of colon, or "fall" on the intraperitoneal rectum with secondary infiltration. The degree of the tumor spreading depends on the length of the primary tumor existence and the histologic type, although the literature data indicate that serosa is infiltrated in 28%, muscles' layer in 31% and mucosa in 14% of patients. The expansion of the prostate cancer is possible, with perforation to Denonvilliers fascia and the secondary spreading to the rectum, according to the type of circumferential, i.e. annular stenosis, without spreading to mucosa in men, as well as the carcinoma portie vaginalis uteri, in women [80,81]. The pouch of Douglas, as the lowest point in the abdomen and in the close vicinity of the rectum, is a place of intraperitoneal spreading of carcinoma of any intraabdominal or retroperitoneal organ, with predomination of the stomach and ovarium. Carcinoma metastasis of retroperitoneal and extra-abdominal organs, pancreas, kidneys and breast, are described in literature [82,83]. The clinical presentation is similar to those of the other colon tumors (bleeding, change in the bowel habitus, pain in the region of anus), supplemented with symptomatology of the primary localization of the malignant process. The diagnosis implicates anamnesis, digital rectal examination, colonoscopy, endoanal ultrasound, multi-slice scanner, NMR, as well as, the biopsy with pathohisiological confirmation.

techniques, especially the development of more sophisticated diagnostic tools including high resolution CT and MRI, capsule endoscopy and somatostatin scintigraphy for NETs. Although the development of specific targeted therapies such as tyrosine kinase inhibitors for GISTs and somatostatin analogs for NETs have improved prognosis, early detection remains the critical variable in determining outcome. Similarly, promising therapeutic data in some subgroups are encouraging although the majority is still diagnosed late and targeted effective therapy is lacking. Difference in survival is the consequence of the difference in biological aggressiveness of tumor, way of the disease spreading and tendency towards metastasis on one hand, and the frequency of appearance and symptomatology on the other. Carcinoid was an indolent tumor with the best prognosis, both non-Hodgkin lymphoma and squamous cell carcinoma of the large bowel showed significantly worse overall survival rate, as compared to adenocarcinoma, while melanoma has the shortest time of survival. The aim of this chapter is to draw our

Rare Tumors of the Colon and Rectum http://dx.doi.org/10.5772/56937 273

We would like to express our gratitude to Mrs. Gorjana Djordjevic, for meticulous proofread‐

attention to the rare tumors in everyday clinical practice.

**Acknowledgements**

**Author details**

**References**

ing and assistance with the English text.

Goran Stanojević1,2 and Zoran Krivokapić3,4

\*Address all correspondence to: stgoran1964@gmail.com

2 Clinic for General Surgery, Clinical Center Niš, Niš, Serbia

4 First Surgery Clinic, Clinical Center Serbia, Belgrade, Serbia

1 Department of Surgery of the Medical Faculty – University of Niš, Niš, Serbia

3 Medical Faculty –University of Belgrade, Department of Surgery, Belgrade, Serbia

[1] Kang H, O'Connell JB, Leonardi MJ, Maggard MA, McGory ML, Ko CY. Rare tumors of the colon and rectum: a national review. Int J Colorectal Dis 2007; 22(2):183-189.

The strategy of treatment depends on:


If the primary tumor localization is in the immediate vicinity of the colon and rectum (pancreas, sigma, prostate, cervix and vagina), it is recommended to use the so called en block resections, with an aim to achieve the oncological principle of radicalism or R0 procedure [84]. Sometimes, it is necessary to perform a non-adjuvant therapy in order to reduce the volume of tumor, so called "downsizing", and the biological aggressiveness of tumor, "down-staging", on one hand, or to supplement the surgical intervention with the adjuvant therapy, on the other. In the case of extra abdominal localization of the primary tumor, it is necessary to assess the effect of successfulness of the surgical intervention in achieving a R0 resection, or the application of the neoadjuvant therapy.

#### **8. Conclusion**

Rare tumors of the colon and rectum represent an important group of neoplasms, due to their specific prognosis secondary to late diagnosis, and resistance to conventional cancer therapy. Over the last 20 years, their overall incidence has increased, due to advent of novel imaging techniques, especially the development of more sophisticated diagnostic tools including high resolution CT and MRI, capsule endoscopy and somatostatin scintigraphy for NETs. Although the development of specific targeted therapies such as tyrosine kinase inhibitors for GISTs and somatostatin analogs for NETs have improved prognosis, early detection remains the critical variable in determining outcome. Similarly, promising therapeutic data in some subgroups are encouraging although the majority is still diagnosed late and targeted effective therapy is lacking. Difference in survival is the consequence of the difference in biological aggressiveness of tumor, way of the disease spreading and tendency towards metastasis on one hand, and the frequency of appearance and symptomatology on the other. Carcinoid was an indolent tumor with the best prognosis, both non-Hodgkin lymphoma and squamous cell carcinoma of the large bowel showed significantly worse overall survival rate, as compared to adenocarcinoma, while melanoma has the shortest time of survival. The aim of this chapter is to draw our attention to the rare tumors in everyday clinical practice.

## **Acknowledgements**

**7. Metastases in the colon and rectum from the distant tumors**

The metastasis of distant primary tumors rarely spread to the large bowel, and it is usually related to the carcinoma of the surrounding organs (stomach, pancreas, ovarian etc.) which, due to their growth and size, spread to the surrounding parts of colon, or "fall" on the intraperitoneal rectum with secondary infiltration. The degree of the tumor spreading depends on the length of the primary tumor existence and the histologic type, although the literature data indicate that serosa is infiltrated in 28%, muscles' layer in 31% and mucosa in 14% of patients. The expansion of the prostate cancer is possible, with perforation to Denonvilliers fascia and the secondary spreading to the rectum, according to the type of circumferential, i.e. annular stenosis, without spreading to mucosa in men, as well as the carcinoma portie vaginalis uteri, in women [80,81]. The pouch of Douglas, as the lowest point in the abdomen and in the close vicinity of the rectum, is a place of intraperitoneal spreading of carcinoma of any intraabdominal or retroperitoneal organ, with predomination of the stomach and ovarium. Carcinoma metastasis of retroperitoneal and extra-abdominal organs, pancreas, kidneys and breast, are described in literature [82,83]. The clinical presentation is similar to those of the other colon tumors (bleeding, change in the bowel habitus, pain in the region of anus), supplemented with symptomatology of the primary localization of the malignant process. The diagnosis implicates anamnesis, digital rectal examination, colonoscopy, endoanal ultrasound,

multi-slice scanner, NMR, as well as, the biopsy with pathohisiological confirmation.

If the primary tumor localization is in the immediate vicinity of the colon and rectum (pancreas, sigma, prostate, cervix and vagina), it is recommended to use the so called en block resections, with an aim to achieve the oncological principle of radicalism or R0 procedure [84]. Sometimes, it is necessary to perform a non-adjuvant therapy in order to reduce the volume of tumor, so called "downsizing", and the biological aggressiveness of tumor, "down-staging", on one hand, or to supplement the surgical intervention with the adjuvant therapy, on the other. In the case of extra abdominal localization of the primary tumor, it is necessary to assess the effect of successfulness of the surgical intervention in achieving a R0 resection, or the application of

Rare tumors of the colon and rectum represent an important group of neoplasms, due to their specific prognosis secondary to late diagnosis, and resistance to conventional cancer therapy. Over the last 20 years, their overall incidence has increased, due to advent of novel imaging

The strategy of treatment depends on:

272 Colorectal Cancer - Surgery, Diagnostics and Treatment

– histological type of the primary tumor

– advancement of the disease,

the neoadjuvant therapy.

**8. Conclusion**

– localization of the primary malignant process,

We would like to express our gratitude to Mrs. Gorjana Djordjevic, for meticulous proofread‐ ing and assistance with the English text.

## **Author details**

Goran Stanojević1,2 and Zoran Krivokapić3,4


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**Section 4**

**Adjuvant Therapy**

**Section 4**

**Adjuvant Therapy**

**Chapter 12**

**Current State-of-the-Science Adjuvant and Neoadjuvant**

Colorectal cancer represents the third most prevalent cancer in the United States, and the third most common cause of cancer-related mortality [1]. Due to the widespread introduction of screening of asymptomatic patients age 50 and above, the incidence of colorectal cancer has been declining [2]. Unfortunately the incidence of colorectal cancer in those under the age of 50 is increasing [3]. In its earliest stages colorectal cancer is highly treatable and curable. Cures in patients with advanced disease are uncommon, but with improved systemic therapies and oncologic surgery, is increasing over time. However, despite modern therapeutic advances, less than 20% of patients with distant metastatic disease will be alive and disease free for five

Management of colorectal cancer highlights the importance of oncologic multidisciplinary care. Surgical adjuvant chemotherapy and chemoradiation therapy have led to improved outcomes for patients with colon cancer and rectal cancer, respectively. This is one of the factors associated with a decrease in colorectal cancer mortality over the last decade. Adherence to treatment guidelines has been shown to be associated with improved patient outcomes [5].Further refinements in adjuvant therapy will involve molecular risk adaption and im‐ proved selection of patients for chemotherapy and adjuvant chemoradiation therapy, incor‐ poration of molecularly targeted agents into the treatment paradigm, and studies to define more clearly the optimal time and duration of adjuvant therapy following colorectal surgery.

The pathologic stage of colon cancer is currently based on the seventh version of the American Joint Commission of Cancer Staging [6]; a simplified version is reproduced in Table 1.

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Therapy in Surgically Resected Colorectal Cancer**

I.H. Sahin and C.R. Garrett

http://dx.doi.org/10.5772/57481

years following the diagnosis [4].

**2. Staging of colon cancer**

**1. Introduction**

Additional information is available at the end of the chapter

## **Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer**

I.H. Sahin and C.R. Garrett

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57481

## **1. Introduction**

Colorectal cancer represents the third most prevalent cancer in the United States, and the third most common cause of cancer-related mortality [1]. Due to the widespread introduction of screening of asymptomatic patients age 50 and above, the incidence of colorectal cancer has been declining [2]. Unfortunately the incidence of colorectal cancer in those under the age of 50 is increasing [3]. In its earliest stages colorectal cancer is highly treatable and curable. Cures in patients with advanced disease are uncommon, but with improved systemic therapies and oncologic surgery, is increasing over time. However, despite modern therapeutic advances, less than 20% of patients with distant metastatic disease will be alive and disease free for five years following the diagnosis [4].

Management of colorectal cancer highlights the importance of oncologic multidisciplinary care. Surgical adjuvant chemotherapy and chemoradiation therapy have led to improved outcomes for patients with colon cancer and rectal cancer, respectively. This is one of the factors associated with a decrease in colorectal cancer mortality over the last decade. Adherence to treatment guidelines has been shown to be associated with improved patient outcomes [5].Further refinements in adjuvant therapy will involve molecular risk adaption and im‐ proved selection of patients for chemotherapy and adjuvant chemoradiation therapy, incor‐ poration of molecularly targeted agents into the treatment paradigm, and studies to define more clearly the optimal time and duration of adjuvant therapy following colorectal surgery.

## **2. Staging of colon cancer**

The pathologic stage of colon cancer is currently based on the seventh version of the American Joint Commission of Cancer Staging [6]; a simplified version is reproduced in Table 1.

Pathologic stage is currently the most accurate predictor of those at greatest risk of relapse, and those most likely to benefit from additional adjuvant therapy. As greater than 80% of patients with stage I disease are cured with surgery alone additional adjuvant therapy has not been shown to improve the already favorable prognosis. Patients with stage II and III are at high risk of systemic relapse and in stage III patients the benefit of adjuvant chemotherapy has clearly been demonstrated and the data supporting it will be reviewed in section 3. Systemic therapy for patients with resected stage II disease remains highly controversial and will be addressed in section 4.

be less effective, in terms of 5-year disease free survival. Thus, six months of therapy is determined to be the optimal. As will be reviewed the optimal duration of chemotherapy is

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

http://dx.doi.org/10.5772/57481

285

It had been noted that in the metastatic setting, meta-analysis of randomized phase II trials suggested that infusional 5-flurouracil is more active when compared to bolus intravenous 5 flurouracil [11]. 5-flurouracil has a different mechanism of action when given continuously, with a greater inhibition of messenger ribonucleic acid (RNA), when compared to bolus 5 flurouracil, where the action is more directed at targeting DNA synthesis through inhibition of thymidylate synthetase. Reduced folate (leucovorin) increases the binding of 5-flurouracil to thymidylate synthase, thereby increasing the efficacy of 5-flurouracil in inhibiting DNA synthesis (see Figure 1). Although no large, randomized studies comparing bolus 5-flurouracil compared to infusional 5-flurouracil have been performed, the superior toxicity profile of infusional 5-flurouracil (less diarrhea, mucositis, and myelosuppression), and the potential for additive benefit of infusional 5-flurouracil (given its different mechanism of action) have led to infusional 5-flurouracil combined with bolus 5-flurouracil being used more commonly in

Capecitabine is an oral pro-drug which is converted to thymidine phosphorylase into 5 flurouracil. It has been demonstrated that tumor cells have higher levels of thymidine phosphorylase and therefore at least theoretically there could be preferential accumulation of 5-FU in tumor cells. In a large phase III study (the X-ACT) trial was found to be non-inferior to bolus 5-flurouracil/leucovorin (Mayo Clinic regimen) [12]. Therefore capecitabine is currently approved for patients who are deemed to be suitable candidates for monotherapy, and is an alternative to bolus or infusional 5- flurouracil. Other oral fluropyrimidines have been examined for efficacy; UFT is a combination of uracil (a dihydropyrimidine dehydryo‐ genase inhibitor (DPD), the enzyme responsible for metabolizing 5-FU, and tegafur (a 5-FU prodrug). When evaluated in a randomized phase III study of stage II and III patients, and compared to bolus flurouracil modulated with leucovorin (Roswell Park regimen) it was found to be equal in efficacy [13]. UFT was approved for use in much Europe and Asia but has not

CapeOx is currently recommended as one of the chemotherapy regimens in the latest version of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (version 1.2011) for the adjuvant treatment of stage III colon cancer. The NO16968 (XELOXA) trial, a large randomized phase III study of CapeOx versus bolus 5-flurouracil (Roswell Park) was performed in more than 1,800 stage III colon cancer patients. It showed a significantly superior three-year disease free survival with CapeOx when compared to the control arm (71% versus 67%, *P* = 0.0045) [14]. CapeOx was associated with less febrile neutropenia and stomatitis than 5FU/LV, although as expected peripheral neuropathy were more frequent; peripheral neuropathy was observed in a similar proportion of patients

5-flurouracil adjuvant chemotherapy combined with other novel agents.

currently under active investigation.

*Oral Fluropyrimidines*

been approved for use in the United States.

receiving FOLFOX or CapeOx.


**Table 1.** Simplified AJCC Staging Classification and Estimated 5-year Survival

## **3. Treatment of stage III colon cancer**

#### *5-Flurouracil -based Adjuvant Chemotherapy*

The prodrug 5-flurouracil was synthesized and patented in 1957 [7] and had shown modest efficacy in the treatment of patients with metastatic colorectal cancer, increasing the median survival from 6-9 months without therapy to an average of 12-14 months. Initial studies evaluating its efficacy, combined with the immune modulatory agent levamisole, were conducted by the North Central Cancer Treatment Group (NCCTG) in the 1980s. In a large, randomized, prospective trial, involving multiple sites across the United States, patients treated with 5-flurouracil and levamisole for 12 months were noted to have a 40% reduction in the relative risk of recurrence, and a 33% reduction in the relative risk of mortality [8]. Long term follow up data from this study confirms the increased cure rate in association with the use of adjuvant chemotherapy, not merely the representation of a lead-time bias [9]. Thus 5 flurouracil became, and remains, the backbone of surgical adjuvant therapy for resected stage III colon cancer. Levamisole was associated with significant toxicity however, and subsequent clinical trials demonstrated that 5-flurouracil, modulated by leucovorin, was also associated with a survival benefit [10] but with less neurological toxicity.

Adjuvant 5-flurouracil -based chemotherapy for colon cancer has been refined over time. Weekly 5-flurouracil has been administered (Roswell Park regimen) and in a randomized clinical trial, was demonstrated to be superior to the combination of 5-FU, semustine, and vincristine [10]. Studies comparing 5-flurouracil combined with leucovorin versus levamisole demonstrated that 6 months treatment of 5-flurouracil + leucovorin was equivalent to 12 months 5-flurouracil levamisole; 6 months of 5-flurouracil plus levamisole was determined to be less effective, in terms of 5-year disease free survival. Thus, six months of therapy is determined to be the optimal. As will be reviewed the optimal duration of chemotherapy is currently under active investigation.

It had been noted that in the metastatic setting, meta-analysis of randomized phase II trials suggested that infusional 5-flurouracil is more active when compared to bolus intravenous 5 flurouracil [11]. 5-flurouracil has a different mechanism of action when given continuously, with a greater inhibition of messenger ribonucleic acid (RNA), when compared to bolus 5 flurouracil, where the action is more directed at targeting DNA synthesis through inhibition of thymidylate synthetase. Reduced folate (leucovorin) increases the binding of 5-flurouracil to thymidylate synthase, thereby increasing the efficacy of 5-flurouracil in inhibiting DNA synthesis (see Figure 1). Although no large, randomized studies comparing bolus 5-flurouracil compared to infusional 5-flurouracil have been performed, the superior toxicity profile of infusional 5-flurouracil (less diarrhea, mucositis, and myelosuppression), and the potential for additive benefit of infusional 5-flurouracil (given its different mechanism of action) have led to infusional 5-flurouracil combined with bolus 5-flurouracil being used more commonly in 5-flurouracil adjuvant chemotherapy combined with other novel agents.

#### *Oral Fluropyrimidines*

Pathologic stage is currently the most accurate predictor of those at greatest risk of relapse, and those most likely to benefit from additional adjuvant therapy. As greater than 80% of patients with stage I disease are cured with surgery alone additional adjuvant therapy has not been shown to improve the already favorable prognosis. Patients with stage II and III are at high risk of systemic relapse and in stage III patients the benefit of adjuvant chemotherapy has clearly been demonstrated and the data supporting it will be reviewed in section 3. Systemic therapy for patients with resected stage II disease remains highly controversial and will be

The prodrug 5-flurouracil was synthesized and patented in 1957 [7] and had shown modest efficacy in the treatment of patients with metastatic colorectal cancer, increasing the median survival from 6-9 months without therapy to an average of 12-14 months. Initial studies evaluating its efficacy, combined with the immune modulatory agent levamisole, were conducted by the North Central Cancer Treatment Group (NCCTG) in the 1980s. In a large, randomized, prospective trial, involving multiple sites across the United States, patients treated with 5-flurouracil and levamisole for 12 months were noted to have a 40% reduction in the relative risk of recurrence, and a 33% reduction in the relative risk of mortality [8]. Long term follow up data from this study confirms the increased cure rate in association with the use of adjuvant chemotherapy, not merely the representation of a lead-time bias [9]. Thus 5 flurouracil became, and remains, the backbone of surgical adjuvant therapy for resected stage III colon cancer. Levamisole was associated with significant toxicity however, and subsequent clinical trials demonstrated that 5-flurouracil, modulated by leucovorin, was also associated

Adjuvant 5-flurouracil -based chemotherapy for colon cancer has been refined over time. Weekly 5-flurouracil has been administered (Roswell Park regimen) and in a randomized clinical trial, was demonstrated to be superior to the combination of 5-FU, semustine, and vincristine [10]. Studies comparing 5-flurouracil combined with leucovorin versus levamisole demonstrated that 6 months treatment of 5-flurouracil + leucovorin was equivalent to 12 months 5-flurouracil levamisole; 6 months of 5-flurouracil plus levamisole was determined to

**Stage Description 5-year survival**

**I T1,2, N0 85-95% II T3,4 N0 60-80% III Any T, N 1,2, M0 30-60% IV M1 < 20%**

**Table 1.** Simplified AJCC Staging Classification and Estimated 5-year Survival

with a survival benefit [10] but with less neurological toxicity.

**3. Treatment of stage III colon cancer**

*5-Flurouracil -based Adjuvant Chemotherapy*

addressed in section 4.

284 Colorectal Cancer - Surgery, Diagnostics and Treatment

Capecitabine is an oral pro-drug which is converted to thymidine phosphorylase into 5 flurouracil. It has been demonstrated that tumor cells have higher levels of thymidine phosphorylase and therefore at least theoretically there could be preferential accumulation of 5-FU in tumor cells. In a large phase III study (the X-ACT) trial was found to be non-inferior to bolus 5-flurouracil/leucovorin (Mayo Clinic regimen) [12]. Therefore capecitabine is currently approved for patients who are deemed to be suitable candidates for monotherapy, and is an alternative to bolus or infusional 5- flurouracil. Other oral fluropyrimidines have been examined for efficacy; UFT is a combination of uracil (a dihydropyrimidine dehydryo‐ genase inhibitor (DPD), the enzyme responsible for metabolizing 5-FU, and tegafur (a 5-FU prodrug). When evaluated in a randomized phase III study of stage II and III patients, and compared to bolus flurouracil modulated with leucovorin (Roswell Park regimen) it was found to be equal in efficacy [13]. UFT was approved for use in much Europe and Asia but has not been approved for use in the United States.

CapeOx is currently recommended as one of the chemotherapy regimens in the latest version of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (version 1.2011) for the adjuvant treatment of stage III colon cancer. The NO16968 (XELOXA) trial, a large randomized phase III study of CapeOx versus bolus 5-flurouracil (Roswell Park) was performed in more than 1,800 stage III colon cancer patients. It showed a significantly superior three-year disease free survival with CapeOx when compared to the control arm (71% versus 67%, *P* = 0.0045) [14]. CapeOx was associated with less febrile neutropenia and stomatitis than 5FU/LV, although as expected peripheral neuropathy were more frequent; peripheral neuropathy was observed in a similar proportion of patients receiving FOLFOX or CapeOx.

As a consequence of the efficacy of oxaliplatin, demonstrated in the metastatic setting, a large randomized trial compared the efficacy of infusional 5-FU plus oxaliplatin, and infusional 5- FU combined with bolus 5-FU (the Multi-center International Study of Oxaliplatin, 5-FU, and Leucovorin, in the Adjuvant Treatment of Colon Cancer, or MOSAIC Study). Initial data reported a 23% risk reduction of disease recurrence at three years [15]. Updated 6-year diseasefree survival data demonstrated a 6% improvement in disease-free survival, confirming the initial positive results [16]. Since 2003 FOLFOX has been the standard-of-care for patients with resected stage III disease with no contraindications to adjuvant chemotherapy.

harbored a KRAS mutation (see Figure 2). Despite this selection of therapy there was no

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

http://dx.doi.org/10.5772/57481

287

**Figure 1.** Possible Explanation for Lack of Efficacy of Anti-Epidermal Growth Factor Antibodies in KRAS Mutant Color‐

*Efficacy of Anti-Epidermal Growth Factor Monoclonal Antibodies in the Adjuvant Therapy of Colon*

Colorectal cancer is the first tumor for which anti-angiogenesis therapies have proven to be effective. The addition of irinotecan plus 5-FU plus the fully humanized anti-vascular endo‐ thelial antibody bevacizumab was associated with a 5 month prolongation in overall survival when compared to chemotherapy alone in patients with metastatic disease. This suggested a potential role for this novel targeted agent in the adjuvant therapy of stage III colon cancer. However two studies, the C08 [27] and the AVANT trial [28], both failed to demonstrate a disease free survival benefit to the addition of bevacizumab to standard chemotherapy.

Although irinotecan did not add to the efficacy of adjuvant chemotherapy there is a suggestion that certain patients with molecular subtypes of colon cancer may benefit from it, possibly patients with microsatellite instable disease [29] Recent randomized phase III clinical trials suggests superior efficacy of the three agents (5-FU, oxaliplatin, and irinotecan, or FOLFOXIRI) when compared to two agents FOLFIRI [30-33]. The efficacy of FOLFOXIRI is under consid‐ eration for testing in a prospective randomized clinical trial compared to FOLFOX chemo‐

*Future Cytotoxic Approaches to Adjuvant Colon Therapy*

ectal Cancer

*Cancer*

therapy.

improvement in the disease-free survival in the cetuximab treated arm [26].

Due to the young age of participants in the MOSIAC trial the efficacy of FOLFOX chemother‐ apy has been questioned in elderly patients, given its increased toxicity, primarily peripheral neuropathy. Pooled analysis of four randomized trials, involving 3,742 patients (of whom 614 were greater or equal to 70 years old) demonstrated that the benefit of FOLFOX chemotherapy did not differ by age, nor did dose intensity [17]. Thus in patients over the age of 70 who are deemed appropriate candidates may still benefit from the addition of oxaliplatin, although very few patients over 80 were included in these studies, thus the data for octogenarians and nonagenarians is limited.

Oxaliplatin was also evaluated in combination with bolus 5-FU (FLOX); in the National Surgical Adjuvant Breast **Project (NSABP)** randomized 2,407 patients with stage II or III colon cancer to either the Roswell Park regiment (bolus 5-FU modulated with leucovorin) or the Roswell Park regimen combined with fortnightly oxaliplatin. There was a superior 5-year disease-free survival with FLOX but not a difference in 5-year overall survival [18].

#### *Adjuvant Irinotecan*

Other combination cytotoxic regimens have been subjected to randomized phase III clinical trial evaluation in the stage III setting. Given the trend to evaluate agents with efficacy in the metastatic setting, and assume at least the potential for benefit in the adjuvant setting, irinotecan has been studied in combination with 5-FU. Prior metastatic studies confirmed the superiority of combination bolus 5-FU plus irinotecan when compared to bolus 5-Flurouracil monotherapy alone [19], as well as when combined with infusional 5-FU (FOLFIRI) (Douillard JY, et al. 2000). Thus irinotecan was evaluated in the surgical adjuvant setting for high risk patients, both combined with bolus 5-FU (IFL) [21] or as FOLFIRI compared to infusional and bolus 5-flurouracil (LV5-FU2), the **PETACC-3 study** [22]; neither of these studies demonstrated a benefit to the addition of irinotecan. Therefore at this time irinotecan is not indicated in the adjuvant treatment of colon cancer.

#### *Efficacy of Anti-Epidermal Growth Factor Monoclonal Antibodies in the Adjuvant Therapy of Colon Cancer*

Given the efficacy of the anti-epidermal growth factor antibodies cetuximab [23] and panitu‐ mumab [24] in the metastatic setting, it seemed reasonable to explore the efficacy of these antibodies in the adjuvant setting. A large prospective randomized study evaluated the efficacy of FOLFOX with or without cetuximab chemotherapy. During the course of the trial studies demonstrated that the benefit to cetuximab therapy was limited to those patients with KRAS wild type tumors [25]; thus protocol entry to limited to those patients whose tumors harbored a KRAS mutation (see Figure 2). Despite this selection of therapy there was no improvement in the disease-free survival in the cetuximab treated arm [26].

As a consequence of the efficacy of oxaliplatin, demonstrated in the metastatic setting, a large randomized trial compared the efficacy of infusional 5-FU plus oxaliplatin, and infusional 5- FU combined with bolus 5-FU (the Multi-center International Study of Oxaliplatin, 5-FU, and Leucovorin, in the Adjuvant Treatment of Colon Cancer, or MOSAIC Study). Initial data reported a 23% risk reduction of disease recurrence at three years [15]. Updated 6-year diseasefree survival data demonstrated a 6% improvement in disease-free survival, confirming the initial positive results [16]. Since 2003 FOLFOX has been the standard-of-care for patients with

Due to the young age of participants in the MOSIAC trial the efficacy of FOLFOX chemother‐ apy has been questioned in elderly patients, given its increased toxicity, primarily peripheral neuropathy. Pooled analysis of four randomized trials, involving 3,742 patients (of whom 614 were greater or equal to 70 years old) demonstrated that the benefit of FOLFOX chemotherapy did not differ by age, nor did dose intensity [17]. Thus in patients over the age of 70 who are deemed appropriate candidates may still benefit from the addition of oxaliplatin, although very few patients over 80 were included in these studies, thus the data for octogenarians and

Oxaliplatin was also evaluated in combination with bolus 5-FU (FLOX); in the National Surgical Adjuvant Breast **Project (NSABP)** randomized 2,407 patients with stage II or III colon cancer to either the Roswell Park regiment (bolus 5-FU modulated with leucovorin) or the Roswell Park regimen combined with fortnightly oxaliplatin. There was a superior 5-year

Other combination cytotoxic regimens have been subjected to randomized phase III clinical trial evaluation in the stage III setting. Given the trend to evaluate agents with efficacy in the metastatic setting, and assume at least the potential for benefit in the adjuvant setting, irinotecan has been studied in combination with 5-FU. Prior metastatic studies confirmed the superiority of combination bolus 5-FU plus irinotecan when compared to bolus 5-Flurouracil monotherapy alone [19], as well as when combined with infusional 5-FU (FOLFIRI) (Douillard JY, et al. 2000). Thus irinotecan was evaluated in the surgical adjuvant setting for high risk patients, both combined with bolus 5-FU (IFL) [21] or as FOLFIRI compared to infusional and bolus 5-flurouracil (LV5-FU2), the **PETACC-3 study** [22]; neither of these studies demonstrated a benefit to the addition of irinotecan. Therefore at this time irinotecan is not indicated in the

*Efficacy of Anti-Epidermal Growth Factor Monoclonal Antibodies in the Adjuvant Therapy of Colon*

Given the efficacy of the anti-epidermal growth factor antibodies cetuximab [23] and panitu‐ mumab [24] in the metastatic setting, it seemed reasonable to explore the efficacy of these antibodies in the adjuvant setting. A large prospective randomized study evaluated the efficacy of FOLFOX with or without cetuximab chemotherapy. During the course of the trial studies demonstrated that the benefit to cetuximab therapy was limited to those patients with KRAS wild type tumors [25]; thus protocol entry to limited to those patients whose tumors

disease-free survival with FLOX but not a difference in 5-year overall survival [18].

resected stage III disease with no contraindications to adjuvant chemotherapy.

nonagenarians is limited.

286 Colorectal Cancer - Surgery, Diagnostics and Treatment

*Adjuvant Irinotecan*

*Cancer*

adjuvant treatment of colon cancer.

**Figure 1.** Possible Explanation for Lack of Efficacy of Anti-Epidermal Growth Factor Antibodies in KRAS Mutant Color‐ ectal Cancer

#### *Efficacy of Anti-Epidermal Growth Factor Monoclonal Antibodies in the Adjuvant Therapy of Colon Cancer*

Colorectal cancer is the first tumor for which anti-angiogenesis therapies have proven to be effective. The addition of irinotecan plus 5-FU plus the fully humanized anti-vascular endo‐ thelial antibody bevacizumab was associated with a 5 month prolongation in overall survival when compared to chemotherapy alone in patients with metastatic disease. This suggested a potential role for this novel targeted agent in the adjuvant therapy of stage III colon cancer. However two studies, the C08 [27] and the AVANT trial [28], both failed to demonstrate a disease free survival benefit to the addition of bevacizumab to standard chemotherapy.

#### *Future Cytotoxic Approaches to Adjuvant Colon Therapy*

Although irinotecan did not add to the efficacy of adjuvant chemotherapy there is a suggestion that certain patients with molecular subtypes of colon cancer may benefit from it, possibly patients with microsatellite instable disease [29] Recent randomized phase III clinical trials suggests superior efficacy of the three agents (5-FU, oxaliplatin, and irinotecan, or FOLFOXIRI) when compared to two agents FOLFIRI [30-33]. The efficacy of FOLFOXIRI is under consid‐ eration for testing in a prospective randomized clinical trial compared to FOLFOX chemo‐ therapy.

#### *Duration of Adjuvant Therapy in Colon Cancer*

As discussed previously, the standard duration of adjuvant chemotherapy was initially 12 months when adjuvant therapy was first approved for colon cancer in 1990. As noted previ‐ ously subsequent studies determined that 6 months adjuvant duration was determined to be equally effective. A prospective randomized trial comparing 3 months of LV5-FU2 when compared to 6 months 5-flurouracil modulated with leucovorin (Mayo regimen) did not demonstrate a statistically significant difference in overall survival (P>0.05Given as the trial was not powered as a non-inferiority study, there are four ongoing studies comparing 3 versus 6 months adjuvant chemotherapy (see table 2). Although there are some differences in the study design, close to 18,000 patients will be entered on these four studies during this decade. In order to pool the data from these studies, the International Drug Evaluation of Adjuvant Chemotherapy (IDEA) was formed to coordinate the data analysis of the pooled results. It is hoped that by the end of the decade the question of whether or not the shorter course (3 months) is equally effective will be satisfactorily answered.

patient's specific risk factors for local recurrence. At this time the use of radiation as adjuvant for resected stage III colon cancer is mainly limited to those patients with microscopic residual

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

http://dx.doi.org/10.5772/57481

289

Due to the significantly better prognosis, with the majority of patients being cured with surgery alone, it is more difficult to demonstrate a significant survival benefit with the use of adjuvant chemotherapy. The initial adjuvant NCCTG adjuvant study of 5-flurouracil and levamisole was unable to demonstrate a survival benefit for the chemotherapy arm; this may in part be due to the higher number of non-cancer-related deaths in the 5-flurouracil treated group [8]. A large randomized, prospective trial of 3,239 patients with resected stage II disease demon‐ strated a 3.6% 5-year improvement in survival following 6 months adjuvant 5-fluorouracil and leucovorin (Mayo regimen) when compared to observation alone [35]. All agree that if a benefit exists it is relatively small and that the routine use of chemotherapy is not indicated. Of note, in the MOSIAC trial, there was no difference in outcome between stage II patients treated with FOLFOX when compared to infusional and bolus 5-flurouracil chemotherapy. Different pathologic characteristics may indicate those patients at slightly higher risk of relapse [see table 3]. Tumor microsatellite instability analysis has been associated with a more favorable prognosis, as well as a lack of benefit from adjuvant 5-flurouracil chemotherapy in resected stage II and stage III tumors; in stage II tumors those patients with mismatch repair tumors had an inferior outcome with the use of 5-fluoruracil adjuvant chemotherapy when compared to observation [39]. Tumor molecular genotyping is being utilized in order to predict those stage II tumors most likely to relapse. To date, these genomic tests have not been sufficiently

predictive of those most likely to relapse and are of limited clinical utility [40-41].

**Table 3.** Pathologic Features Associated with a Relatively Adverse Prognosis in Stage II Disease

**6. Adjuvant and neoadjuvant approaches in rectal cancer**

Rectal adenocarcinomas present a unique challenge given its anatomic location in the pelvis and the fact that part of the rectum is intraperitoneal and part is extraperitoneal. The vast majority of rectal malignancies are adenocarcinomas; less common pathologies are gastroin‐ testinal stromal tumor (GIST), carcinoid, squamous, adenosquamous tumors and melanoma. For the purposes of this chapter we will limit our discussed to rectal adenocarcinomas.

**Pathologic Feature Reference Less than 12 Lymph Nodes Analyzed 36, 37 Poorly differentiated 38 Clinical Perforation 38**

disease (positive pathologic margin).

**5. Adjuvant treatment of stage II colon cancer**


**Table 2.** Planned Randomized Phase III Studies Evaluating the Duration of Adjuvant Chemotherapy

## **4. Adjuvant radiation therapy for colon cancer**

No prospective data to date has suggested a survival benefit with the addition of radiation therapy as adjuvant following surgery. Retrospective data suggests that patients with high risk features for recurrence may receive benefit from radiation, including those who had T4 disease (involving another organ), a positive margin (microscopic residual disease, not true adjuvant), and clinical perforation had a better disease-free survival with the addition of adjuvant chemoradiation [34]. One large prospective randomized study evaluating the efficacy of radiation in colon cancers (non-transverse colon) was inconclusive due to the failure to meet accrual. The study was underpowered but was not able to demonstrate a benefit of the addition of radiation to chemotherapy [35]. Treatment decisions have to be made based upon the patient's specific risk factors for local recurrence. At this time the use of radiation as adjuvant for resected stage III colon cancer is mainly limited to those patients with microscopic residual disease (positive pathologic margin).

## **5. Adjuvant treatment of stage II colon cancer**

*Duration of Adjuvant Therapy in Colon Cancer*

288 Colorectal Cancer - Surgery, Diagnostics and Treatment

is equally effective will be satisfactorily answered.

**Evaluated**

**TOSCA II, III 6/20/2007 3,450**

**Clinical Trial Stage**

**CALGB/SWOG C80702**

\*Short Course Oncology Therapy

As discussed previously, the standard duration of adjuvant chemotherapy was initially 12 months when adjuvant therapy was first approved for colon cancer in 1990. As noted previ‐ ously subsequent studies determined that 6 months adjuvant duration was determined to be equally effective. A prospective randomized trial comparing 3 months of LV5-FU2 when compared to 6 months 5-flurouracil modulated with leucovorin (Mayo regimen) did not demonstrate a statistically significant difference in overall survival (P>0.05Given as the trial was not powered as a non-inferiority study, there are four ongoing studies comparing 3 versus 6 months adjuvant chemotherapy (see table 2). Although there are some differences in the study design, close to 18,000 patients will be entered on these four studies during this decade. In order to pool the data from these studies, the International Drug Evaluation of Adjuvant Chemotherapy (IDEA) was formed to coordinate the data analysis of the pooled results. It is hoped that by the end of the decade the question of whether or not the shorter course (3 months)

**Start Date Target Accrual Treatment Plan**

**III 7/1/2010 2,500 FOLFOX 6 vs. 3 ± celecoxib/placebo**

**FOLFOX 3 months**

**IIIc)**

**FOLFOX 6 vs. 3 months (plus optional bevacizumab randomization for stage**

**SCOT\* III 3/27/2008 9,500 CapeOx/FOLFOX 6 months vs. CapeOx/**

No prospective data to date has suggested a survival benefit with the addition of radiation therapy as adjuvant following surgery. Retrospective data suggests that patients with high risk features for recurrence may receive benefit from radiation, including those who had T4 disease (involving another organ), a positive margin (microscopic residual disease, not true adjuvant), and clinical perforation had a better disease-free survival with the addition of adjuvant chemoradiation [34]. One large prospective randomized study evaluating the efficacy of radiation in colon cancers (non-transverse colon) was inconclusive due to the failure to meet accrual. The study was underpowered but was not able to demonstrate a benefit of the addition of radiation to chemotherapy [35]. Treatment decisions have to be made based upon the

**GERCOR III 5/2/2009 2,500 FOLFOX 6 vs. 3 months**

**Table 2.** Planned Randomized Phase III Studies Evaluating the Duration of Adjuvant Chemotherapy

**4. Adjuvant radiation therapy for colon cancer**

Due to the significantly better prognosis, with the majority of patients being cured with surgery alone, it is more difficult to demonstrate a significant survival benefit with the use of adjuvant chemotherapy. The initial adjuvant NCCTG adjuvant study of 5-flurouracil and levamisole was unable to demonstrate a survival benefit for the chemotherapy arm; this may in part be due to the higher number of non-cancer-related deaths in the 5-flurouracil treated group [8]. A large randomized, prospective trial of 3,239 patients with resected stage II disease demon‐ strated a 3.6% 5-year improvement in survival following 6 months adjuvant 5-fluorouracil and leucovorin (Mayo regimen) when compared to observation alone [35]. All agree that if a benefit exists it is relatively small and that the routine use of chemotherapy is not indicated. Of note, in the MOSIAC trial, there was no difference in outcome between stage II patients treated with FOLFOX when compared to infusional and bolus 5-flurouracil chemotherapy. Different pathologic characteristics may indicate those patients at slightly higher risk of relapse [see table 3]. Tumor microsatellite instability analysis has been associated with a more favorable prognosis, as well as a lack of benefit from adjuvant 5-flurouracil chemotherapy in resected stage II and stage III tumors; in stage II tumors those patients with mismatch repair tumors had an inferior outcome with the use of 5-fluoruracil adjuvant chemotherapy when compared to observation [39]. Tumor molecular genotyping is being utilized in order to predict those stage II tumors most likely to relapse. To date, these genomic tests have not been sufficiently predictive of those most likely to relapse and are of limited clinical utility [40-41].


**Table 3.** Pathologic Features Associated with a Relatively Adverse Prognosis in Stage II Disease

## **6. Adjuvant and neoadjuvant approaches in rectal cancer**

Rectal adenocarcinomas present a unique challenge given its anatomic location in the pelvis and the fact that part of the rectum is intraperitoneal and part is extraperitoneal. The vast majority of rectal malignancies are adenocarcinomas; less common pathologies are gastroin‐ testinal stromal tumor (GIST), carcinoid, squamous, adenosquamous tumors and melanoma. For the purposes of this chapter we will limit our discussed to rectal adenocarcinomas. Compared the large bowel the close proximity of rectum to other local organs such as uro‐ genital system requires different surgical techniques and significantly increases the likelihood of local relapse after surgery when compared to colon cancer [42]. For this reason, in addition to total mesorectal excision combination therapeutic options have arisen to decrease local recurrence. Subsequently, these multimodality therapy approaches have become standard-ofcare in locally advanced rectal cancer. In this book chapter, we aimed to summarize scientific progression in the field of treatment of locally advanced rectal cancer.

in two arms. The combined modality arm was found to have 34% reduced overall recurrence compared to the radiation alone. (*P* < 0.003) [47]. Decreased recurrence incidence was observed in both local (25% versus 13% *P* < 0.02) and distant relapse (43% versus 29.5% *P* < 0.003). After this study National Surgical Adjuvant Breast Program (NSABP) examined the impact of the adjuvant chemotherapy alone versus chemoradiotherapy on overall survival and disease free survival in protocol R-02. In this study, all female patients received 5-flurouracil and leuco‐ vorin whereas male patients either received MOF regimen including 5-flurouracil, semustine, vincristine or 5-flurouracil combined with leucovorin. Radiotherapy was given in 25 fractions at a daily 18 Gray dose. Although there was a significant decrease in cumulative local relapse incidence after 5-year follow-up (13% versus 8%, *P* = 0.02), they observed no overall or disease-

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

http://dx.doi.org/10.5772/57481

291

Absence of clinical evidence to use radiotherapy in adjuvant settings urged the researchers to test the efficacy of radiotherapy in preoperative settings. Swedish investigators conducted a phase III clinical trial to understand the possible role of neoadjuvant radiotherapy (i.e. preoperative radiation therapy) [48]. They enrolled 1,168 patients and randomly assigned to receive either conventional surgery alone or surgery with preceded neoadjuvant radiotherapy designed as a total dose of 25 Gy in five fractions. After five years follow up, recurrence rate was found 11% in neoadjuvant radiotherapy group, whereas it was observed as high as 27% in patients with surgery alone (*P* < 0.001). Additionally, the authors reported significantly better five year-survival in radiotherapy arm (58% compared to 48%, *P* = 0.004). Since con‐ ventional surgery was performed in this study, the additive role of the radiation in TME was still not clear. In 2007, this question was addressed by Dutch Colorectal Cancer Group. They conducted a randomized clinical trial enrolled the patients into TME alone and 5 fractions radiotherapy with total 25 Gray dose plus total mesorectal excision [49]. After a median 6.1 years follow- up, no significant overall survival difference was demonstrated. Moreover, there was no significant difference in distal recurrence incidence. On the other hand, they found a

Currently, two different preoperative radiotherapy protocols are commonly preferred in locally advanced rectal cancer treatment including conventional (50.4 Gray administered in 28 fractions) and short-term treatment (25 Gray in 5 fractions). Although both models have been shown to decrease local recurrence, there are debates on prolonged side effect in short-term radiotherapy modality [50]. While short-term neoadjuvant radiation treatment is commonly used in European countries, conventional radiation is standard-of-care of locally advance

Better outcomes observed in chemoradiation in adjuvant settings raised the question of possible neoadjuvant chemoradiation for treatment of patients with locally advanced rectal cancer. In 2004, German Rectal Cancer Study Group (GRCSG) examined the role preoperative chemoradiation in rectal cancer patients with T3 or T4 stages or node positivity [51]. They randomized 823 patients in two groups; the neoadjuvant arm received a total 50.4 Gray dose

free survival differences in between these two groups.

significant decrease in local recurrence rate (5.6 % vs 10.9%, *P* < 0.001).

*Neoadjuvant Chemoradiation Therapy (Combined Modality Therapy)*

*Neoadjuvant Radiotherapy*

rectal cancer in USA.

#### *Development of Adjuvant Therapy*

The standard care of rectal cancer remains surgery with a total mesorectal excision. However locally advanced disease were relapsing significantly higher than early stage disease after surgery-only approach [43]. Rectal cancer transmurally invades the rectal wall directly and can spread through the lymphatic system to regional lymph nodes. These characteristics of locally advanced disease put the patients at higher risk of local and distant recurrence which is associated worse overall survival. Given the high rate of the recurrent disease, combination treatment approaches have evolved in locally advance rectal cancer over the last two decades. First, adjuvant radiotherapy and then combined modality therapy (chemotherapy concur‐ rently with radiation therapy) was integrated in standard care to enhance survival outcomes of locally advanced rectal cancer.

An early prospectively randomized clinical trial was conducted to assess the question of the adjuvant benefit roles of radiation, chemotherapy, or combined modality therapy (chemoradiation) in the treatment of locally advance rectal cancer by the Gastrointestinal Tumor Study Group (GTSG) in 1985 [44]. In this study, patients after having curative surgery (202 in total), were enrolled and randomized into four different groups includ‐ ing; patients received no adjuvant treatment, patients treated with adjuvant radiotherapy either at dose of 40 or 48 Gray, patients received adjuvant chemotherapy with semustine and 5-fluorouracil, and a final group treated with combination of chemotherapy and radiotherapy. All patients were followed up to for 80 months. Although there was no significant difference for OS in four groups, authors found significantly better diseasefree survival in combination therapy arm compared to resection-alone [44]. In same study, recurrence rate was highest in resection-alone with 55%, while the lowest relapse was observed in combination therapy group (33%). The follow-up results of this study con‐ firmed a significantly improved overall survival reported in combination treatment group compared to surgery alone group [45]. By the end of the 10 year follow up, 10-year survival rates were 26% vs. 45% in control group vs. combination treatment group and was showing the superiority of combination treatment group. Independently, The National Surgical Adjuvant and Breast and Bowel Project (NSABP) released the result of R-01 that compar‐ ing adjuvant radiation or chemotherapy to surgery alone and provided superior overall and disease-free survival in chemo group respect to the surgery alone (*P* = 0.03, *P* = 0.006 respectively) [46]. No significant survival benefit observed in radiation alone group.

The North Central Cancer Treatment Group (NCCTG) reported a trial comparing the adjuvant radiation versus the combined chemoradiation. In this study, total 209 patients randomized in two arms. The combined modality arm was found to have 34% reduced overall recurrence compared to the radiation alone. (*P* < 0.003) [47]. Decreased recurrence incidence was observed in both local (25% versus 13% *P* < 0.02) and distant relapse (43% versus 29.5% *P* < 0.003). After this study National Surgical Adjuvant Breast Program (NSABP) examined the impact of the adjuvant chemotherapy alone versus chemoradiotherapy on overall survival and disease free survival in protocol R-02. In this study, all female patients received 5-flurouracil and leuco‐ vorin whereas male patients either received MOF regimen including 5-flurouracil, semustine, vincristine or 5-flurouracil combined with leucovorin. Radiotherapy was given in 25 fractions at a daily 18 Gray dose. Although there was a significant decrease in cumulative local relapse incidence after 5-year follow-up (13% versus 8%, *P* = 0.02), they observed no overall or diseasefree survival differences in between these two groups.

#### *Neoadjuvant Radiotherapy*

Compared the large bowel the close proximity of rectum to other local organs such as uro‐ genital system requires different surgical techniques and significantly increases the likelihood of local relapse after surgery when compared to colon cancer [42]. For this reason, in addition to total mesorectal excision combination therapeutic options have arisen to decrease local recurrence. Subsequently, these multimodality therapy approaches have become standard-ofcare in locally advanced rectal cancer. In this book chapter, we aimed to summarize scientific

The standard care of rectal cancer remains surgery with a total mesorectal excision. However locally advanced disease were relapsing significantly higher than early stage disease after surgery-only approach [43]. Rectal cancer transmurally invades the rectal wall directly and can spread through the lymphatic system to regional lymph nodes. These characteristics of locally advanced disease put the patients at higher risk of local and distant recurrence which is associated worse overall survival. Given the high rate of the recurrent disease, combination treatment approaches have evolved in locally advance rectal cancer over the last two decades. First, adjuvant radiotherapy and then combined modality therapy (chemotherapy concur‐ rently with radiation therapy) was integrated in standard care to enhance survival outcomes

An early prospectively randomized clinical trial was conducted to assess the question of the adjuvant benefit roles of radiation, chemotherapy, or combined modality therapy (chemoradiation) in the treatment of locally advance rectal cancer by the Gastrointestinal Tumor Study Group (GTSG) in 1985 [44]. In this study, patients after having curative surgery (202 in total), were enrolled and randomized into four different groups includ‐ ing; patients received no adjuvant treatment, patients treated with adjuvant radiotherapy either at dose of 40 or 48 Gray, patients received adjuvant chemotherapy with semustine and 5-fluorouracil, and a final group treated with combination of chemotherapy and radiotherapy. All patients were followed up to for 80 months. Although there was no significant difference for OS in four groups, authors found significantly better diseasefree survival in combination therapy arm compared to resection-alone [44]. In same study, recurrence rate was highest in resection-alone with 55%, while the lowest relapse was observed in combination therapy group (33%). The follow-up results of this study con‐ firmed a significantly improved overall survival reported in combination treatment group compared to surgery alone group [45]. By the end of the 10 year follow up, 10-year survival rates were 26% vs. 45% in control group vs. combination treatment group and was showing the superiority of combination treatment group. Independently, The National Surgical Adjuvant and Breast and Bowel Project (NSABP) released the result of R-01 that compar‐ ing adjuvant radiation or chemotherapy to surgery alone and provided superior overall and disease-free survival in chemo group respect to the surgery alone (*P* = 0.03, *P* = 0.006 respectively) [46]. No significant survival benefit observed in radiation alone group.

The North Central Cancer Treatment Group (NCCTG) reported a trial comparing the adjuvant radiation versus the combined chemoradiation. In this study, total 209 patients randomized

progression in the field of treatment of locally advanced rectal cancer.

*Development of Adjuvant Therapy*

290 Colorectal Cancer - Surgery, Diagnostics and Treatment

of locally advanced rectal cancer.

Absence of clinical evidence to use radiotherapy in adjuvant settings urged the researchers to test the efficacy of radiotherapy in preoperative settings. Swedish investigators conducted a phase III clinical trial to understand the possible role of neoadjuvant radiotherapy (i.e. preoperative radiation therapy) [48]. They enrolled 1,168 patients and randomly assigned to receive either conventional surgery alone or surgery with preceded neoadjuvant radiotherapy designed as a total dose of 25 Gy in five fractions. After five years follow up, recurrence rate was found 11% in neoadjuvant radiotherapy group, whereas it was observed as high as 27% in patients with surgery alone (*P* < 0.001). Additionally, the authors reported significantly better five year-survival in radiotherapy arm (58% compared to 48%, *P* = 0.004). Since con‐ ventional surgery was performed in this study, the additive role of the radiation in TME was still not clear. In 2007, this question was addressed by Dutch Colorectal Cancer Group. They conducted a randomized clinical trial enrolled the patients into TME alone and 5 fractions radiotherapy with total 25 Gray dose plus total mesorectal excision [49]. After a median 6.1 years follow- up, no significant overall survival difference was demonstrated. Moreover, there was no significant difference in distal recurrence incidence. On the other hand, they found a significant decrease in local recurrence rate (5.6 % vs 10.9%, *P* < 0.001).

Currently, two different preoperative radiotherapy protocols are commonly preferred in locally advanced rectal cancer treatment including conventional (50.4 Gray administered in 28 fractions) and short-term treatment (25 Gray in 5 fractions). Although both models have been shown to decrease local recurrence, there are debates on prolonged side effect in short-term radiotherapy modality [50]. While short-term neoadjuvant radiation treatment is commonly used in European countries, conventional radiation is standard-of-care of locally advance rectal cancer in USA.

#### *Neoadjuvant Chemoradiation Therapy (Combined Modality Therapy)*

Better outcomes observed in chemoradiation in adjuvant settings raised the question of possible neoadjuvant chemoradiation for treatment of patients with locally advanced rectal cancer. In 2004, German Rectal Cancer Study Group (GRCSG) examined the role preoperative chemoradiation in rectal cancer patients with T3 or T4 stages or node positivity [51]. They randomized 823 patients in two groups; the neoadjuvant arm received a total 50.4 Gray dose radiation in 28 fractions and 5-flurouracil 120-hour continuous infusion during the first and fifth weeks of radiation at a dose of 1,000 mg per square meter of body surface then followed by surgery after completing the chemoradiation. Patients also received four cycles of 5 flurouracil (500 mg per square meter body surface) which was designed as five time weekly during the four weeks. The adjuvant group also received the same treatment except additional a boost of 5.4 Gray radiation after total mesorectal excision. No significant difference was reported for five year-survival in between neoadjuvant and adjuvant group (74% vs 76% respectively, *P* = 0.80). Interestingly, five years cumulative incidence of local recurrence was significantly lower in neoadjuvant group than the adjuvant. (6% versus 13% respectively, *P* = 0.006). Moreover they observed less acute and long term toxicity in neoadjuvant arm of the study compared the adjuvant arm (*P* = 0.001 versus *P* = 0.01).

prolonged treatment related toxicities and improved sphincter preservation observed in

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

5-flurouracil has become the recommended first-line chemotherapy in locally advanced rectal cancer patients based on the GTSG and NCCTG data [44,47].The most commonly preferred administration mode of 5-flurouracil is continuous intravenous infusion( 225-300mg/m2

To compare the bolus administration with continuous intravenous infusion, the NCCTG randomized 660 patients in two arms. Both arms received concurrent radiotherapy. First group received bolus 5-flurouracil on three consecutive days as s rapid infusion of 500 mg/m2

survival was 63% in continuous infusion group while it was 53% in the bolus arm (*P* = 0.01). Significant difference for 4-year overall survival was also observed in the same study. Fouryear overall survival was 70% as compared to 60% in continuous infusion and bolus group respectively (*P* = 0.005). Interestingly, no benefit was observed for local relapse in continuous infusion group (*P* = 0.110). While leukopenia was more common in bolus group, diarrhea

Since superior outcomes observed in continuous intravenous administration of 5-flurouracil in chemoradiation regimens, an equivalent fluropyrimidine, capecitabine was studied for locally advanced rectal cancer treatment. Oral administration of capecitabine which has very similar pharmacokinetics to continuous intravenous 5-flurouracil provided more convenient treatment for patients if they are able to tolerate oral administration. In a phase I clinical study, the recommended dose of the capecitabine was determined as 1800 mg/m2 daily given orally in two divided doses combined with 50.4 Gray preoperative radiation [56]. A prospectively randomized study of 1,987 patients was enrolled into two groups; a) patients who received capecitabine orally, b) patients who were administered bolus 5-flurouracil modulated with leucovorin [58]. In the results of this study, non-inferior disease-free survival was observed in capecitabine group. The capecitabine improved relapse-free survival (*P* = 0.04). Moreover, fewer adverse effects were seen with capecitabine treatment compared to bolus 5-flurouracil

The NSABP R-04 trial compared the use of capecitabine to continuous infusion 5-flurouracil with or without oxaliplatin during combined modality therapy in locally advance rectal cancer. 5-fluorouracil was given as a 225 mg/m2 daily protracted venous infusion during radiation and

only. There was no significant different regarding pathologic complete response, surgical downstaging or sphincter-saving surgery. Local recurrence and overall survival have yet to

More recently, in a randomized phase III study, German researchers compared the efficacy of capecitabine with 5-flurouracil as neoadjuvant radiosensitizing agent [60]. In this study, 392

orally in two divided doses daily on the days of radiation

daily).

293

while

/day). Four-year relapse free

http://dx.doi.org/10.5772/57481

preoperative treatment also favor the neoadjuvant chemoradiation modality [54].

*Current Drugs for Neoadjuvant Therapy of Rectal Cancer*

the other group received as protracted infusion (225 mg/m2

incidence was found higher in continuous infusion group.

plus leucovorin arm (*P* < 0.001) [58].

capecitabine was given at 1650 mg/m2

be reported [59].

*5-Fluorouracil*

*Capecitabine*

In another study, European Organization for Research and Treatment of Cancer (EORTC) randomized 1,011 patients with locally advanced rectal cancer into four different groups: a) preoperative radiotherapy designed as 45 Gy in five weeks, b) preoperative radiotherapy plus two course of 5-flurouracil and leucovorin (350 mg/m2 /day and 20 mg/m2 /day), c) preoperative radiotherapy plus postoperative four course of 5-flurouracil and leucovorin, and d) preoper‐ ative radiotherapy and two course of bolus 5-flurouracil and leucovorin, plus postoperative four course of postoperative 5-flurouracil and leucovorin. In early preliminary results of the study, authors reported a significant benefit towards preoperative chemoradiotherapy groups for tumor size, lymph node involvement, pathological complete response (*P* < 0.0001, *P* = 0.046, *P* < 0.001). [52]. Later in follow up results, no significant difference was observed in OS between neoadjuvant chemoradiotherapy and neoadjuvant radiotherapy (P=0.085). On the other hand, local recurrence was significantly lower in preoperative chemoradiation groups (*P* = 0.002) [53]. Chemotherapy protocol which was given in this study was an uncommon protocol possibly is a contributing factor for absence of survival difference in between chemoradiation and radiation alone group in preoperative settings.

To better understand the additive role of neoadjuvant chemoradiation for patients with locally advanced rectal cancer, NSABP R-03 trial was conducted. Two hundreds and sixty-seven patients enrolled in two arms; patients who received neoadjuvant or adjuvant chemoradiation. Neoadjuvant group received a bolus of 5-flurouracil with leucovorin for six weeks followed by radiation given as a total 45 Gray dose in 25 fractions with an additional 5.4 Gray boost. Then, patients were resected and postoperatively received 24 more weeks of weekly 5-FU and LV. Patients in adjuvant arm also received same courses of treatment in the same order except initial surgical resection. The most striking finding of this study was superior 5-year diseasefree survival observed in neoadjuvant arm (64.7% vs 53.4%, P=0.011). Although there was not a significant difference in OS (P = 0.65), There was trend for observed five-year overall survival as 74.7% vs 65.6% in the neoadjuvant and adjuvant arms respectively [54]. Overall, all these clinical trials support the use neoadjuvuvant chemotheradiation as standart-care-of locally advance colorectal cancer. Although there is no clear result proving as an evidence for the superior OS compared to adjuvant chemoradiation, decreased local recurrence incidence with neoadjuvant treatment promises better local disease control. Moreover decreased acute and prolonged treatment related toxicities and improved sphincter preservation observed in preoperative treatment also favor the neoadjuvant chemoradiation modality [54].

*Current Drugs for Neoadjuvant Therapy of Rectal Cancer*

#### *5-Fluorouracil*

radiation in 28 fractions and 5-flurouracil 120-hour continuous infusion during the first and fifth weeks of radiation at a dose of 1,000 mg per square meter of body surface then followed by surgery after completing the chemoradiation. Patients also received four cycles of 5 flurouracil (500 mg per square meter body surface) which was designed as five time weekly during the four weeks. The adjuvant group also received the same treatment except additional a boost of 5.4 Gray radiation after total mesorectal excision. No significant difference was reported for five year-survival in between neoadjuvant and adjuvant group (74% vs 76% respectively, *P* = 0.80). Interestingly, five years cumulative incidence of local recurrence was significantly lower in neoadjuvant group than the adjuvant. (6% versus 13% respectively, *P* = 0.006). Moreover they observed less acute and long term toxicity in neoadjuvant arm of the

In another study, European Organization for Research and Treatment of Cancer (EORTC) randomized 1,011 patients with locally advanced rectal cancer into four different groups: a) preoperative radiotherapy designed as 45 Gy in five weeks, b) preoperative radiotherapy plus

radiotherapy plus postoperative four course of 5-flurouracil and leucovorin, and d) preoper‐ ative radiotherapy and two course of bolus 5-flurouracil and leucovorin, plus postoperative four course of postoperative 5-flurouracil and leucovorin. In early preliminary results of the study, authors reported a significant benefit towards preoperative chemoradiotherapy groups for tumor size, lymph node involvement, pathological complete response (*P* < 0.0001, *P* = 0.046, *P* < 0.001). [52]. Later in follow up results, no significant difference was observed in OS between neoadjuvant chemoradiotherapy and neoadjuvant radiotherapy (P=0.085). On the other hand, local recurrence was significantly lower in preoperative chemoradiation groups (*P* = 0.002) [53]. Chemotherapy protocol which was given in this study was an uncommon protocol possibly is a contributing factor for absence of survival difference in between chemoradiation

To better understand the additive role of neoadjuvant chemoradiation for patients with locally advanced rectal cancer, NSABP R-03 trial was conducted. Two hundreds and sixty-seven patients enrolled in two arms; patients who received neoadjuvant or adjuvant chemoradiation. Neoadjuvant group received a bolus of 5-flurouracil with leucovorin for six weeks followed by radiation given as a total 45 Gray dose in 25 fractions with an additional 5.4 Gray boost. Then, patients were resected and postoperatively received 24 more weeks of weekly 5-FU and LV. Patients in adjuvant arm also received same courses of treatment in the same order except initial surgical resection. The most striking finding of this study was superior 5-year diseasefree survival observed in neoadjuvant arm (64.7% vs 53.4%, P=0.011). Although there was not a significant difference in OS (P = 0.65), There was trend for observed five-year overall survival as 74.7% vs 65.6% in the neoadjuvant and adjuvant arms respectively [54]. Overall, all these clinical trials support the use neoadjuvuvant chemotheradiation as standart-care-of locally advance colorectal cancer. Although there is no clear result proving as an evidence for the superior OS compared to adjuvant chemoradiation, decreased local recurrence incidence with neoadjuvant treatment promises better local disease control. Moreover decreased acute and

/day and 20 mg/m2

/day), c) preoperative

study compared the adjuvant arm (*P* = 0.001 versus *P* = 0.01).

two course of 5-flurouracil and leucovorin (350 mg/m2

292 Colorectal Cancer - Surgery, Diagnostics and Treatment

and radiation alone group in preoperative settings.

5-flurouracil has become the recommended first-line chemotherapy in locally advanced rectal cancer patients based on the GTSG and NCCTG data [44,47].The most commonly preferred administration mode of 5-flurouracil is continuous intravenous infusion( 225-300mg/m2 daily). To compare the bolus administration with continuous intravenous infusion, the NCCTG randomized 660 patients in two arms. Both arms received concurrent radiotherapy. First group received bolus 5-flurouracil on three consecutive days as s rapid infusion of 500 mg/m2 while the other group received as protracted infusion (225 mg/m2 /day). Four-year relapse free survival was 63% in continuous infusion group while it was 53% in the bolus arm (*P* = 0.01). Significant difference for 4-year overall survival was also observed in the same study. Fouryear overall survival was 70% as compared to 60% in continuous infusion and bolus group respectively (*P* = 0.005). Interestingly, no benefit was observed for local relapse in continuous infusion group (*P* = 0.110). While leukopenia was more common in bolus group, diarrhea incidence was found higher in continuous infusion group.

#### *Capecitabine*

Since superior outcomes observed in continuous intravenous administration of 5-flurouracil in chemoradiation regimens, an equivalent fluropyrimidine, capecitabine was studied for locally advanced rectal cancer treatment. Oral administration of capecitabine which has very similar pharmacokinetics to continuous intravenous 5-flurouracil provided more convenient treatment for patients if they are able to tolerate oral administration. In a phase I clinical study, the recommended dose of the capecitabine was determined as 1800 mg/m2 daily given orally in two divided doses combined with 50.4 Gray preoperative radiation [56]. A prospectively randomized study of 1,987 patients was enrolled into two groups; a) patients who received capecitabine orally, b) patients who were administered bolus 5-flurouracil modulated with leucovorin [58]. In the results of this study, non-inferior disease-free survival was observed in capecitabine group. The capecitabine improved relapse-free survival (*P* = 0.04). Moreover, fewer adverse effects were seen with capecitabine treatment compared to bolus 5-flurouracil plus leucovorin arm (*P* < 0.001) [58].

The NSABP R-04 trial compared the use of capecitabine to continuous infusion 5-flurouracil with or without oxaliplatin during combined modality therapy in locally advance rectal cancer. 5-fluorouracil was given as a 225 mg/m2 daily protracted venous infusion during radiation and capecitabine was given at 1650 mg/m2 orally in two divided doses daily on the days of radiation only. There was no significant different regarding pathologic complete response, surgical downstaging or sphincter-saving surgery. Local recurrence and overall survival have yet to be reported [59].

More recently, in a randomized phase III study, German researchers compared the efficacy of capecitabine with 5-flurouracil as neoadjuvant radiosensitizing agent [60]. In this study, 392 patients were randomized into two groups. Patients in capecitabine arm were enrolled to receive two cycles of capecitabine (2,500 mg/m2 days 1-14, repeated day 22), then followed by chemoradiotherapy (50 4 Gray plus capecitabine 1650 mg/m2 days 1-38 and additionally three cycles of capecitabine). Two cycles of bolus 5-flurouracil (500 mg/m2 days 1-5, repeated day 29), followed by chemoradiotherapy (50 4 Gray plus infusional 5-flurouracil 225 mg/m2 daily), finally two cycles of bolus 5-FU were administered patients in 5-flurouracil arm. Results were promising for non-inferiority with significantly better 5-year OS in capecitabine group (76% as compared to 67%, *P* = 0.05). Similarly disease-free survival was also higher in capecitabine group (75% versus 67%, *P* = 0.07).

*Targeted Therapies*

radiotherapy 650 mg/m2

to receive initial intravenous dose of 400 mg/m2

embolism, and one pulmonary infection with sepsis.

initiation of radiation followed by 250 mg/m2

survival (*P* = 1.0, *P* = 0.363 respectively)

significant hematologic toxicity.

Monoclonal antibodies targeting the critical survival signaling pathways such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are currently under the investigation to determine their role in neoadjuvant chemoradiaton treatment in rectal cancers. The potential role of cetuximab and bevacizumab in the treatment

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

In a phase I/II clinical study the safety and potential benefit of cetuximab in neoadjuvant chemoradiation investigated in locally advanced rectal cancer patients. Forty patients enrolled

[65]. Observed pathologic complete response was only in two patients (5%), while diarrhea was seen in 65% of the patients. Grade 3 diarrhea was detected in 15% of cases. In one patient three grade 4 toxic effect was reported by authors; one myocardial infarction, one pulmonary

In the EXPERT-C trial, combination of cetuximab and capecitabine plus oxaliplatin was studied in neoadjuvant settings. One hundred sixty-five patients enrolled in two arms to receive four cycles of capecitabine/oxaliplatin and then capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab [66]. In this study the most striking finding was significantly improved OS in cetuximab plus group (*P* = 0.034). Additionally, a better radiologic response was determined in cetuximab group. On the other hand there was no difference either in pathologic complete response rate or progression-free

Another fully humanized monoclonal antibody, that binds circulating anti-vascular epithelial growth factor, bevacizumab, has also been investigated in combination neoadjuvant treatment of rectal cancer. In a phase I/II study, bevacizumab combined with preoperative 5-FU and radiotherapy in 32 locally advanced rectal cancer patients [67]. Patients were administered four cycles of bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 5-FU (225 mg/m2

hours) during cycles 2 to 4; radiotherapy in 28 fractions with a total dose of 50.4 Gy over 5.5 weeks. Surgery was performed 7 to 10 weeks after completion of all therapies. No grade4 toxicity was detected and the most frequent toxicity was diarrhea. Pathologic complete response was achieved in 5 out of 32 patients. In another phase II study, bevacizumab was explored in a combination treatment of capecitabine and radiotherapy [68]. Twenty-five rectal cancer patients received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m2 orally twice daily during the radiation). Surgical resection was performed a median of 7.3 weeks later initial treatment. An encouraging pathologic complete response rate was reported in 8 of 25 patients (32%). Six of 24 patients showed less than 10% viable tumor cells in final pathological specimens. No patient was reported with grade 3 gastrointestinal toxicity or

cetuximab which was given 1 week before the

http://dx.doi.org/10.5772/57481

295

/24

/week for 5 weeks and capecitabine during the

orally twice daily and 825 mg/m2 twice daily, as a second dose level

of locally advanced rectal cancer has been tested in phase I and phase II clinical trials.

#### *Oxaliplatin*

Given the promising results of oxaliplatin treatment of colon cancer in adjuvant setting [15] and metastatic disease [61] its possible additive effect to the neoadjuvant treatment of rectal cancer has been investigated. In a phase II clinical trial, oxaliplatin (at 50 mg/m2 on days 1, 8, 22, and 29) plus capecitabine (1,650 mg/m2 on days 1 to 14 and 22 to 35) with radiotherapy (50.4 Gray in 28 fraction) was tested both for activity and safety [62]. Pathologic complete response was achieved in 17% patients whereas 53/103 patients showed more than 50% tumor regres‐ sion. Although results were not superior to standard 5-FU treatment phase III trials were warranted. The randomized phase III Studio Terapia Adiuvante Retto ( STAR)-01 trial has tested to outcomes of addition of oxaliplatin (60 mg/m2) to chemoradiation (225 mg/m2 /day plus 50.4 Gray in 28 daily fractions) comparing with standard chemoradiation [62]. Addition of oxaliplation did not increase pathologic complete response rate (16% versus 16% ) but rather increased grade 3 to 4 adverse events in oxaliplatin arms (*P* < 0.001).

Recently published German CAO/ARO/AIO-04 randomised phase III trial also investigated the role of oxaliplatin in neoadjuvant chemoradiation [63]. In the study control group was treated with standard 5-flurouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil (1000 mg/m2 days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2 days 1-5 and 29). Oxaliplatin arm received preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil (250 mg/m2 days 1-14 and 22-35) and oxaliplatin (50 mg/m2 days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2 days 1 and 15), leucovorin (400 mg/m2 days 1 and 15), and again infusional 5-flurouracil. Authors reported better pathologic complete response outcomes in oxaliplatin treatment arm compared to standard group (17% vs 13% respectively, *P* = 0.038). Controversially, ACCORD 12/0405- PRODIGE 2 trial reported no benefit with additional oxaliplatin [64]. In this study control patients were assigned to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m2 twice daily (5 days per week). The experimental arm of the study received 50 Gray in 25 fractions radiation with capecitabine 800 mg/m2 twice daily (5 days per week) and oxaliplatin 50 mg/m2 (once weekly). Although there was trend toward oxaliplatin plus group for pCR it was not significant (19.2% s 13.9% P=0.09). Preoperative grade 3 and 4 toxicities were observed significantly higher in oxalipatin plus arm *(P* < 0.001). Since there is no consensus in clinical trials for benefit with additional oxaliplatin it is not currently standard-of-care of locally advanced rectal cancer.

#### *Targeted Therapies*

patients were randomized into two groups. Patients in capecitabine arm were enrolled to

finally two cycles of bolus 5-FU were administered patients in 5-flurouracil arm. Results were promising for non-inferiority with significantly better 5-year OS in capecitabine group (76% as compared to 67%, *P* = 0.05). Similarly disease-free survival was also higher in capecitabine

Given the promising results of oxaliplatin treatment of colon cancer in adjuvant setting [15] and metastatic disease [61] its possible additive effect to the neoadjuvant treatment of rectal cancer has been investigated. In a phase II clinical trial, oxaliplatin (at 50 mg/m2 on days 1, 8,

Gray in 28 fraction) was tested both for activity and safety [62]. Pathologic complete response was achieved in 17% patients whereas 53/103 patients showed more than 50% tumor regres‐ sion. Although results were not superior to standard 5-FU treatment phase III trials were warranted. The randomized phase III Studio Terapia Adiuvante Retto ( STAR)-01 trial has tested to outcomes of addition of oxaliplatin (60 mg/m2) to chemoradiation (225 mg/m2

plus 50.4 Gray in 28 daily fractions) comparing with standard chemoradiation [62]. Addition of oxaliplation did not increase pathologic complete response rate (16% versus 16% ) but rather

Recently published German CAO/ARO/AIO-04 randomised phase III trial also investigated the role of oxaliplatin in neoadjuvant chemoradiation [63]. In the study control group was treated with standard 5-flurouracil-based combined modality treatment, consisting of

Oxaliplatin arm received preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil

15), leucovorin (400 mg/m2 days 1 and 15), and again infusional 5-flurouracil. Authors reported better pathologic complete response outcomes in oxaliplatin treatment arm compared to standard group (17% vs 13% respectively, *P* = 0.038). Controversially, ACCORD 12/0405- PRODIGE 2 trial reported no benefit with additional oxaliplatin [64]. In this study control patients were assigned to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions

oxaliplatin plus group for pCR it was not significant (19.2% s 13.9% P=0.09). Preoperative grade 3 and 4 toxicities were observed significantly higher in oxalipatin plus arm *(P* < 0.001). Since there is no consensus in clinical trials for benefit with additional oxaliplatin it is not currently

preoperative radiotherapy of 50.4 Gray plus infusional 5-flurouracil (1000 mg/m2

surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2

of the study received 50 Gray in 25 fractions radiation with capecitabine 800 mg/m2

29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2

days 1-14 and 22-35) and oxaliplatin (50 mg/m2

29), followed by chemoradiotherapy (50 4 Gray plus infusional 5-flurouracil 225 mg/m2

days 1-14, repeated day 22), then followed by

on days 1 to 14 and 22 to 35) with radiotherapy (50.4

days 1-38 and additionally three

days 1-5, repeated day

daily),

/day

days 1-5 and

days 1 and

twice daily

days 1-5 and 29).

days 1, 8, 22, and 29), followed by

twice daily (5 days per week). The experimental arm

(once weekly). Although there was trend toward

receive two cycles of capecitabine (2,500 mg/m2

294 Colorectal Cancer - Surgery, Diagnostics and Treatment

group (75% versus 67%, *P* = 0.07).

22, and 29) plus capecitabine (1,650 mg/m2

with concurrent capecitabine 800 mg/m2

(5 days per week) and oxaliplatin 50 mg/m2

standard-of-care of locally advanced rectal cancer.

*Oxaliplatin*

(250 mg/m2

chemoradiotherapy (50 4 Gray plus capecitabine 1650 mg/m2

cycles of capecitabine). Two cycles of bolus 5-flurouracil (500 mg/m2

increased grade 3 to 4 adverse events in oxaliplatin arms (*P* < 0.001).

Monoclonal antibodies targeting the critical survival signaling pathways such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are currently under the investigation to determine their role in neoadjuvant chemoradiaton treatment in rectal cancers. The potential role of cetuximab and bevacizumab in the treatment of locally advanced rectal cancer has been tested in phase I and phase II clinical trials.

In a phase I/II clinical study the safety and potential benefit of cetuximab in neoadjuvant chemoradiation investigated in locally advanced rectal cancer patients. Forty patients enrolled to receive initial intravenous dose of 400 mg/m2 cetuximab which was given 1 week before the initiation of radiation followed by 250 mg/m2 /week for 5 weeks and capecitabine during the radiotherapy 650 mg/m2 orally twice daily and 825 mg/m2 twice daily, as a second dose level [65]. Observed pathologic complete response was only in two patients (5%), while diarrhea was seen in 65% of the patients. Grade 3 diarrhea was detected in 15% of cases. In one patient three grade 4 toxic effect was reported by authors; one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis.

In the EXPERT-C trial, combination of cetuximab and capecitabine plus oxaliplatin was studied in neoadjuvant settings. One hundred sixty-five patients enrolled in two arms to receive four cycles of capecitabine/oxaliplatin and then capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab [66]. In this study the most striking finding was significantly improved OS in cetuximab plus group (*P* = 0.034). Additionally, a better radiologic response was determined in cetuximab group. On the other hand there was no difference either in pathologic complete response rate or progression-free survival (*P* = 1.0, *P* = 0.363 respectively)

Another fully humanized monoclonal antibody, that binds circulating anti-vascular epithelial growth factor, bevacizumab, has also been investigated in combination neoadjuvant treatment of rectal cancer. In a phase I/II study, bevacizumab combined with preoperative 5-FU and radiotherapy in 32 locally advanced rectal cancer patients [67]. Patients were administered four cycles of bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 5-FU (225 mg/m2 /24 hours) during cycles 2 to 4; radiotherapy in 28 fractions with a total dose of 50.4 Gy over 5.5 weeks. Surgery was performed 7 to 10 weeks after completion of all therapies. No grade4 toxicity was detected and the most frequent toxicity was diarrhea. Pathologic complete response was achieved in 5 out of 32 patients. In another phase II study, bevacizumab was explored in a combination treatment of capecitabine and radiotherapy [68]. Twenty-five rectal cancer patients received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m2 orally twice daily during the radiation). Surgical resection was performed a median of 7.3 weeks later initial treatment. An encouraging pathologic complete response rate was reported in 8 of 25 patients (32%). Six of 24 patients showed less than 10% viable tumor cells in final pathological specimens. No patient was reported with grade 3 gastrointestinal toxicity or significant hematologic toxicity.

In a recent study, bevacizumab was tested in a combined treatment including the oxaliplatin, 5-FU, and radiotherapy in 26 patients [69]. Patients were initially treated with 1 month of induction bevacizumab and FOLFOX6, then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m2 /week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). This trial was terminated early because of high incidence of significant grade 3 toxicity. Authors reported 19 (75%) of 25 patients experienced grade 3 toxicities. Five (20%) out of 25 patients had pathologic response. The effect of bevacu‐ zimab was also studied with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor in a combination treatment of 5-flurouracil and external beam radiation in 21 patients [70]. Seven (47%) of 15 patients who completed the therapy and had surgery achieved pathologic complete response. Reported toxicities were including lympho‐ penia 6 (40%), diarrhea 4 (24%), rash 2 (12%), cardiac ischemia 1(6%), transaminitis (6%) and mucositis (6%).

[2] Printz C. American Cancer Society reports progress in reducing cancer deaths. Can‐

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[3] Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiology Biomarkers &

[4] Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resec‐ tion and improved chemotherapy. Journal of Clinical Oncology. 2009;27(22):3677-83.

[5] Chagpar R, Xing Y, Chiang YJ, Feig BW, Chang GJ, You YN, et al. Adherence to Stage-Specific Treatment Guidelines for Patients With Colon Cancer. Journal of Clini‐

[6] Compton CC, Byrd DR, Garcia-Aguilar J, Kurtzman S, Olawaiye A, Washington MK.

[8] Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Le‐ vamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New

[9] Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, et al. Flu‐ orouracil plus levamisole as effective adjuvant therapy after resection of stage III co‐

[10] Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel

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[12] Twelves C, Wong A, Nowacki MP, Abt M, Burris III H, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. New England Journal of Medicine.

[13] Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. Journal of Clinical Oncology.

[14] Haller D, Tabernero J, Maroun J, De Braud F, Price T, Van Cutsem E, et al. 5LBA First efficacy findings from a randomized phase III trial of capecitabine+ oxaliplatin vs.

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Obtained promising pathologic response and observed safety results by the addition of monoclonal antibodies in neoadjuvant chemoradiation encourages to further explore the role of these drugs in treatment of locally advanced rectal cancer. On the other hand these targeting agents are yet to be standard-care-of rectal cancer in neoadjuvant settings.

## **7. Conclusions**

The clinical advances over the last two decades have led to demonstrable improvements in the outcomes of patients with colorectal cancer and are a testament to the success of multidisci‐ plinary cancer care. Continued development of novel therapeutics in the metastatic setting will undoubtedly lead to changes in our surgical adjuvant treatments. Refinement in predictive and prognostic studies will allow us greater ability to tailor the appropriate therapy for patients, and allow for greater patient's participation in the shared decision process.

## **Author details**

I.H. Sahin and C.R. Garrett

University of Texas MD Anderson Cancer Center Houston, Texas, USA

## **References**

[1] Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA: a cancer journal for clinicians. 2012 Jul-Aug; 62(4):220-41. PubMed PMID: 22700443.


In a recent study, bevacizumab was tested in a combined treatment including the oxaliplatin, 5-FU, and radiotherapy in 26 patients [69]. Patients were initially treated with 1 month of induction bevacizumab and FOLFOX6, then received 50.4 Gy of radiation and concurrent

continuous infusion 5-FU (200 mg/m(2)/day). This trial was terminated early because of high incidence of significant grade 3 toxicity. Authors reported 19 (75%) of 25 patients experienced grade 3 toxicities. Five (20%) out of 25 patients had pathologic response. The effect of bevacu‐ zimab was also studied with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor in a combination treatment of 5-flurouracil and external beam radiation in 21 patients [70]. Seven (47%) of 15 patients who completed the therapy and had surgery achieved pathologic complete response. Reported toxicities were including lympho‐ penia 6 (40%), diarrhea 4 (24%), rash 2 (12%), cardiac ischemia 1(6%), transaminitis (6%) and

Obtained promising pathologic response and observed safety results by the addition of monoclonal antibodies in neoadjuvant chemoradiation encourages to further explore the role of these drugs in treatment of locally advanced rectal cancer. On the other hand these targeting

The clinical advances over the last two decades have led to demonstrable improvements in the outcomes of patients with colorectal cancer and are a testament to the success of multidisci‐ plinary cancer care. Continued development of novel therapeutics in the metastatic setting will undoubtedly lead to changes in our surgical adjuvant treatments. Refinement in predictive and prognostic studies will allow us greater ability to tailor the appropriate therapy for

[1] Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA: a cancer journal for clinicians. 2012 Jul-Aug;

patients, and allow for greater patient's participation in the shared decision process.

University of Texas MD Anderson Cancer Center Houston, Texas, USA

62(4):220-41. PubMed PMID: 22700443.

/week for 6 weeks), and

bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m2

296 Colorectal Cancer - Surgery, Diagnostics and Treatment

agents are yet to be standard-care-of rectal cancer in neoadjuvant settings.

mucositis (6%).

**7. Conclusions**

**Author details**

**References**

I.H. Sahin and C.R. Garrett


bolus 5-FU/LV for stage III colon cancer (NO16968/XELOXA study). EJC Supple‐ ments. 2009;7(3):4-.

control in metastatic colorectal cancer patients treated with cetuximab. Journal of

Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer

http://dx.doi.org/10.5772/57481

299

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302 Colorectal Cancer - Surgery, Diagnostics and Treatment


**Chapter 13**

**Adjuvant Treatment in Colorectal Cancer**

Worldwide, more than 1 million people develop colorectal cancer (CRC) annually [1]. CRC is a major health problem in the Western world and the second most common cause of cancer mortality [2]. To improve performance, the role of chemotherapy for CRC has increased dramatically over the last decade. Of course surgery remains the cornerstone of treatment, the vast majority of CRC patients now receive chemotherapy with multiple agents that are currently approved for the treatment in the appropriate setting. However, it is a complex process to select the optimal chemotherapy for each patient and practice evidence gap is still a problem. We found large differences in patterns of institution, region and country. The results suggest that the lack of evidence for CRC chemotherapy prac‐ tice still exists around the world. [3] Recently, standardization of cancer treatment, including chemotherapy, has become of particular importance for the quality of cancer therapy. It is important to know whether the overhaul performed normalization of CRC chemothera‐ py. Measures and quality indicators are needed and several studies on indicators of quality of cancer care have been reported. However, measures to assess the standardization of cancer therapy are not well established. In this study, we evaluated the usefulness of the oncology market research to assess the evidence gap in practice CRC chemotherapy. We also discuss the role of the method to measure the effect of normalization of CRC chemo‐

Although surgery remains the cornerstone of treatment, the vast majority of CRC pa‐ tients now receive chemotherapy to reduce the risk of metastatic spread by eradicating microscopic tumor foci that are distant from the primary tumor and undetectable in

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Krassimir Ivanov, Nikola Kolev, Ivan Shterev,

Additional information is available at the end of the chapter

Tanya Kirilova

**1. Introduction**

therapy. [4, 5]

http://dx.doi.org/10.5772/56914

Anton Tonev, Valentin Ignatov, Vasil Bojkov and

## **Adjuvant Treatment in Colorectal Cancer**

Krassimir Ivanov, Nikola Kolev, Ivan Shterev, Anton Tonev, Valentin Ignatov, Vasil Bojkov and Tanya Kirilova

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56914

### **1. Introduction**

Worldwide, more than 1 million people develop colorectal cancer (CRC) annually [1]. CRC is a major health problem in the Western world and the second most common cause of cancer mortality [2]. To improve performance, the role of chemotherapy for CRC has increased dramatically over the last decade. Of course surgery remains the cornerstone of treatment, the vast majority of CRC patients now receive chemotherapy with multiple agents that are currently approved for the treatment in the appropriate setting. However, it is a complex process to select the optimal chemotherapy for each patient and practice evidence gap is still a problem. We found large differences in patterns of institution, region and country. The results suggest that the lack of evidence for CRC chemotherapy prac‐ tice still exists around the world. [3] Recently, standardization of cancer treatment, including chemotherapy, has become of particular importance for the quality of cancer therapy. It is important to know whether the overhaul performed normalization of CRC chemothera‐ py. Measures and quality indicators are needed and several studies on indicators of quality of cancer care have been reported. However, measures to assess the standardization of cancer therapy are not well established. In this study, we evaluated the usefulness of the oncology market research to assess the evidence gap in practice CRC chemotherapy. We also discuss the role of the method to measure the effect of normalization of CRC chemo‐ therapy. [4, 5]

Although surgery remains the cornerstone of treatment, the vast majority of CRC pa‐ tients now receive chemotherapy to reduce the risk of metastatic spread by eradicating microscopic tumor foci that are distant from the primary tumor and undetectable in

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

perioperative assessment of tumor extension. [5] Five-year survival of patients are mainly determined by the histological stage of the tumor at the time of resection. The most important prognostic factor for survival in patients without visceral metastases is the stage of the tumor determined by the depth of penetration of the tumor in the bowel wall and the number of lymph nodes [4] (lymph nodes >12 examined). Result of the meta - analy‐ sis of over 10 studies showed that each - two-month delay of adjuvant chemotherapy resulted in a 14% decrease in overall survival, suggesting that adjuvant chemotherapy should be administered as soon as possible [5].

**2. Treatment guidelines for CRC**

treated as clinical issues with many references.

study.

Some guidelines for the treatment of CRC have been developed to promote the standardization of CRC treatment. Only two drugs, panitumumab and cetuximab first line were still causing discord. Bevacizumab or capecitabine combined with oxaliplatin is used for the treatment of advanced and recurrent CRC, while the FOLFOX regimen is used in patients with a high risk of recurrence in the adjuvant chemotherapy. In this major revision, current controversies are

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 307

Adjuvant 5-FU chemotherapy is the standard treatment used in patients with stage III (Dukes C) and high-risk stage II (Dukes B) tumors. Capecitabine and bolus 5FU regimes have proven efficacy and are associated with a low risk of severe toxicity. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of random‐ ized trials in 2246 patients with stage 2 or 3 of the CRC to receive LV5FU2 or FOLFOX-4 chemotherapy. The operating system after 6 years of follow-up for all patients was 78.5% for FOLFOX-4 against 76% for LV5FU2. Subgroup analysis showed stage-specific 6-year OS rate of 72.9% against 68.7% in patients with stage 3 of the CRC and 86.9% compared with 86.8% in patients with stage 2 CRC for FOLFOX-4 and LV5FU2, respectively. The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5FU adjuvant chemothera‐ py, but used a different calendar 5FU and oxaliplatin doses delivered also less than in the MOSAIC study (nine against twelve). The first results showed a similar improvement in disease-free survival (DFS) than that observed in the MOSAIC trial. A recently presented the final results confirm improved DFS, but showed shorter survival time after recur‐ rence in the oxaliplatin arm and an improvement in overall survival has not been seen. A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while patients over 70 years, no benefit was observed consistently. The analysis of the ACCENT data‐ base, including 10, 449 patients less than 70 years and 2170 patients over 70 years from six randomized trials have demonstrated a significant interaction between age and treatment effect. No differences in results were noted between experimental (combination) chemother‐ apy and chemotherapy in patients with fluoropyrimidine control over 70 years. Adding oxaliplatin to 5FU increases the overall incidence of grade 3 toxicity and is associated with the occurrence of peripheral sensory neuropathy. Over 90% of patients experience tempora‐ ry symptoms typically induced cold, with a minority of patients with persistent symp‐ toms affecting activities of daily living (grade 2 and 3 toxicity). In the MOSAIC study, grade 3 peripheral sensory neuropathy was noted in 12.5% of patients treated with oxaliplatin for the treatment. After 48 months of follow-up, rates of toxicity were grade 11.9% 1, % [22] 8 degree and 0.7% grade 3, respectively. Similar data were presented for the NSABP C-07

Decisions regarding the use of adjuvant chemotherapy combinations are more complex. The incidence of approximately 3% of significant long-term peripheral neuropathy and MS MT Seymour Braun could interfere with the activities of the daily life of the patient influences decision-making in relation to the small additional benefit accrued to receive the

The introduction of new cytotoxic agents such as oral fluoropyrimidines, oxaliplatin and irinotecan in chemotherapy (CT) regimens have improved the response rate, disease-free survival (DFS) and overall survival (OS) in patients with metastatic colorectal cancer. [6, 7] This has encouraged the trials in the adjuvant treatment of non-metastatic disease, especially in patients with stage III tumors. Table 1 shows the most common regimens used for the CT adjuvant. Surgery alone is usually curative for colon cancer stage II, but about 20% to 30% of these patients develop recurrence and die of metastatic disease. [8] This under‐ pins the need for prognostic factors such as microsatellite instability (MSI), which are potentially predictive of tumor response to cytotoxic agents. [7] Prognostic factors are particularly useful in the context of stage II colorectal cancer, where the benefits of cytotoxic adjuvant therapy are more controversial than in stage III disease. The identification of accurate and validated predictive and prognostic markers help clinicians in choosing appropriate use of adjuvant chemotherapy in patients with stage II CRC.

MSI is a change in the length of microsatellite DNA due to the insertion or deletion of repeating units – from 1to 5 nucleotides caused by defects in mismatch repair genes or methylation of their promoters. [9] Tumors with MSI are more often proximal, poorly differentiated, mucinous, and show a significant lymphocytic infiltration. [9] Colon cancers with high-frequency MSI have clinical and pathological features that distinguish them from microsatellite stable tumors and MSI is a marker of favorable outcome and a predictor for the benefit decreased from fluorouracil - based adjuvant chemotherapy in patients with stage II or colon cancer stage III with microsatellite stable tumors or tumors with lowfrequency microsatellite instability. [10] Silence or mutation of mismatch repair (MMR) genes can lead to protein deficiency MMR and MSI 10. This is observed in patients with Lynch syndrome, and it is a rare cause of hereditary colon cancer 2 to 4% of the 11 cases. Somatic mutation is reported in 19% of CRC [12], while silencing of MMR genes can be observed in up to 52% of sporadic colon cancers [13].

In sporadic CRC, three tumor phenotypes were defined: microsatellite stable (MSS), lowfrequency MSI (MSI-L) and high frequency MSI (MSI-H). It has been reported that MSI-H are more frequently found in stage II disease than in stage III disease 14. This may partly explain the benefit decreased from 5 - fluorouracil adjuvant chemotherapy (5FU) in patients with stage II. Tente identify patients who might benefit from adjuvant chemotherapy led to the devel‐ opment of multigene tests as several Oncotype DX etc. Unfortunately, there is no evidence that any of them can predict the potential benefit of adjuvant chemotherapy. [13]

## **2. Treatment guidelines for CRC**

perioperative assessment of tumor extension. [5] Five-year survival of patients are mainly determined by the histological stage of the tumor at the time of resection. The most important prognostic factor for survival in patients without visceral metastases is the stage of the tumor determined by the depth of penetration of the tumor in the bowel wall and the number of lymph nodes [4] (lymph nodes >12 examined). Result of the meta - analy‐ sis of over 10 studies showed that each - two-month delay of adjuvant chemotherapy resulted in a 14% decrease in overall survival, suggesting that adjuvant chemotherapy

The introduction of new cytotoxic agents such as oral fluoropyrimidines, oxaliplatin and irinotecan in chemotherapy (CT) regimens have improved the response rate, disease-free survival (DFS) and overall survival (OS) in patients with metastatic colorectal cancer. [6, 7] This has encouraged the trials in the adjuvant treatment of non-metastatic disease, especially in patients with stage III tumors. Table 1 shows the most common regimens used for the CT adjuvant. Surgery alone is usually curative for colon cancer stage II, but about 20% to 30% of these patients develop recurrence and die of metastatic disease. [8] This under‐ pins the need for prognostic factors such as microsatellite instability (MSI), which are potentially predictive of tumor response to cytotoxic agents. [7] Prognostic factors are particularly useful in the context of stage II colorectal cancer, where the benefits of cytotoxic adjuvant therapy are more controversial than in stage III disease. The identification of accurate and validated predictive and prognostic markers help clinicians in choosing

MSI is a change in the length of microsatellite DNA due to the insertion or deletion of repeating units – from 1to 5 nucleotides caused by defects in mismatch repair genes or methylation of their promoters. [9] Tumors with MSI are more often proximal, poorly differentiated, mucinous, and show a significant lymphocytic infiltration. [9] Colon cancers with high-frequency MSI have clinical and pathological features that distinguish them from microsatellite stable tumors and MSI is a marker of favorable outcome and a predictor for the benefit decreased from fluorouracil - based adjuvant chemotherapy in patients with stage II or colon cancer stage III with microsatellite stable tumors or tumors with lowfrequency microsatellite instability. [10] Silence or mutation of mismatch repair (MMR) genes can lead to protein deficiency MMR and MSI 10. This is observed in patients with Lynch syndrome, and it is a rare cause of hereditary colon cancer 2 to 4% of the 11 cases. Somatic mutation is reported in 19% of CRC [12], while silencing of MMR genes can be

In sporadic CRC, three tumor phenotypes were defined: microsatellite stable (MSS), lowfrequency MSI (MSI-L) and high frequency MSI (MSI-H). It has been reported that MSI-H are more frequently found in stage II disease than in stage III disease 14. This may partly explain the benefit decreased from 5 - fluorouracil adjuvant chemotherapy (5FU) in patients with stage II. Tente identify patients who might benefit from adjuvant chemotherapy led to the devel‐ opment of multigene tests as several Oncotype DX etc. Unfortunately, there is no evidence that

any of them can predict the potential benefit of adjuvant chemotherapy. [13]

appropriate use of adjuvant chemotherapy in patients with stage II CRC.

observed in up to 52% of sporadic colon cancers [13].

should be administered as soon as possible [5].

306 Colorectal Cancer - Surgery, Diagnostics and Treatment

Some guidelines for the treatment of CRC have been developed to promote the standardization of CRC treatment. Only two drugs, panitumumab and cetuximab first line were still causing discord. Bevacizumab or capecitabine combined with oxaliplatin is used for the treatment of advanced and recurrent CRC, while the FOLFOX regimen is used in patients with a high risk of recurrence in the adjuvant chemotherapy. In this major revision, current controversies are treated as clinical issues with many references.

Adjuvant 5-FU chemotherapy is the standard treatment used in patients with stage III (Dukes C) and high-risk stage II (Dukes B) tumors. Capecitabine and bolus 5FU regimes have proven efficacy and are associated with a low risk of severe toxicity. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of random‐ ized trials in 2246 patients with stage 2 or 3 of the CRC to receive LV5FU2 or FOLFOX-4 chemotherapy. The operating system after 6 years of follow-up for all patients was 78.5% for FOLFOX-4 against 76% for LV5FU2. Subgroup analysis showed stage-specific 6-year OS rate of 72.9% against 68.7% in patients with stage 3 of the CRC and 86.9% compared with 86.8% in patients with stage 2 CRC for FOLFOX-4 and LV5FU2, respectively. The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5FU adjuvant chemothera‐ py, but used a different calendar 5FU and oxaliplatin doses delivered also less than in the MOSAIC study (nine against twelve). The first results showed a similar improvement in disease-free survival (DFS) than that observed in the MOSAIC trial. A recently presented the final results confirm improved DFS, but showed shorter survival time after recur‐ rence in the oxaliplatin arm and an improvement in overall survival has not been seen. A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while patients over 70 years, no benefit was observed consistently. The analysis of the ACCENT data‐ base, including 10, 449 patients less than 70 years and 2170 patients over 70 years from six randomized trials have demonstrated a significant interaction between age and treatment effect. No differences in results were noted between experimental (combination) chemother‐ apy and chemotherapy in patients with fluoropyrimidine control over 70 years. Adding oxaliplatin to 5FU increases the overall incidence of grade 3 toxicity and is associated with the occurrence of peripheral sensory neuropathy. Over 90% of patients experience tempora‐ ry symptoms typically induced cold, with a minority of patients with persistent symp‐ toms affecting activities of daily living (grade 2 and 3 toxicity). In the MOSAIC study, grade 3 peripheral sensory neuropathy was noted in 12.5% of patients treated with oxaliplatin for the treatment. After 48 months of follow-up, rates of toxicity were grade 11.9% 1, % [22] 8 degree and 0.7% grade 3, respectively. Similar data were presented for the NSABP C-07 study.

Decisions regarding the use of adjuvant chemotherapy combinations are more complex. The incidence of approximately 3% of significant long-term peripheral neuropathy and MS MT Seymour Braun could interfere with the activities of the daily life of the patient influences decision-making in relation to the small additional benefit accrued to receive the oxaliplatin. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluat‐ ing shorter periods of oxaliplatin-based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the noninferiority of short periods of treatment, as well as consideration of the evaluation criteria of quality of life. The relative benefit of chemotherapy is also a key factor in the choice of treatment for patients in the adjuvant setting. Patients with stage 3 are a heterogeneous group and decisions based on age, the relative risk of recurrence (N1 N2 against disease), and the additional benefit that can be achieved by adding oxaliplatin need to be carefully considered. Given the new data in patients over 70 years, it seems likely that chemothera‐ py oxaliplatin are used less frequently in this group. Patients with disease stage 2 have an excellent prognosis with or without chemotherapy 5FU-based and high-risk patients functions are selected for processing. Both C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5-FU in patients with stage 2 disease, but a trend towards improved DFS was noted. However, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of operation) and the risk of neurotoxicity. [23]

regimen (5FU bolus followed by LV 15 minutes) with double - monthly infusion LV5FU2 (LV for 2 hours, followed by bolus 5-FU, followed by a continuous infusion of 5-FU over 2 days) in 905 patients with stage II (43%) or III (57%) colon cancer showed that the regime was less toxic LV5FU2, especially regarding hematological and gastrointestinal events (P <0.001) [19]. No significant difference in DFS and OS was observed in one of two regi mens median follow-up 6 years. Two other studies have shown that the two ways of 5FU bolus administration combined with LV with or without levamisole and a continuous infusion of 5-FU are equivalent. Saini and colleagues conducted a multicenter randomized trial comparing the efficacy and toxicity of 12 weeks of 5FU delivered by continuous intrave‐ nous infusion against the standard bolus 5-FU and LV for 6 months as adjuvant treat‐ ment in colorectal cancer. The two schemes are equivalent, but the plan 12 weeks was less toxic [20]. The analysis of data from several trials in which patients were randomly resection of the tumor or tumor resection followed by adjuvant 5-FU/LV showed that the benefit of adjuvant chemotherapy was observed in patients with stage III [21, 22], which suggests that because of nodal status of these patients are at higher risk. Both studies showed that the addition of oxaliplatin to 5-FU/LV as adjuvant therapy in stage II and elderly patients showed no significant DFS or OS [23, 24] benefits even in patients with characteristics high risk - T4 tumors, intestinal obstruction, venous invasion, etc. This suggests that, despite the failure of our definition of high-risk patients with stage II, 5-FU/LV regimen may be preferable. QUASAR investigators reported their analysis of 3238 patients, the majority of them were in stage II colon cancer. Patients were randomized to receive 5-FU/LV or observation. The relative risk of death from all causes in the 5-FU/LV arm versus observa‐ tion was 0.82 (95% CI, 0.70 to 0.95, p = 0.008). The relative risk of recurrence was 0.78 (95% CI, 0.67-0, 91, p = 0.001) [7]. The investigators did not separate patients into individuals high or low risk. Risk factors are obstruction or bowel perforation, elevated preoperative CEA, poorly differentiated tumors, removal of CDC patients and MSI-S. The impact of adjuvant chemotherapy and the potential benefit of this new could not be clearly demon‐

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 309

Two oral prodrugs of 5FU - capecetabine and uracil / tegafur (UFT), has demonstrated efficacy in metastatic disease, which is comparable with bolus 5-FU/LV regimens [25, 26]. After oral administration, capecitabine is rapidly absorbed with plasma concentrations peaking after 1.5 hours [27]. Pharmacokinetics is largely dose - dependent. The pharmacol‐ ogy of capecitabine is not significantly influenced by gender, race, performance status, body surface area, albumin or hepatic dysfunction [28]. The half-life of capecitabine is between 0.49 and 0.89 hours, whereas the half-life of the metabolite (5-FU) extends from 0.67 to 1.15 hours [29]. Regarding renal excretion primarily (more than 70% of metabolites), capecita‐ bine is against - in patients with severe renal impairment (creatinine clearance less than 30

strated in this study of patients with stage II.

**4. Oral fluoropyrimidines**

mL / min).

#### **3. 5FU**

In 1990, Moertel and colleagues first reported the value of adjuvant chemotherapy in patients with stage III colon cancer (Dukes C, Tx N + M0). [15] This study showed an increase in overall survival and progression-free survival in patients receiving 5FU/ Levamisole - based chemotherapy for 1 year against levamisole alone or without chemother‐ apy. With a median follow - up of 6.5 years, patients treated with 5-FU / levamisole showed a 40% reduction in recidivism and an estimated reduction of 33% of overall mortality [16]. 5-FU is a pyrimidine analogue, which inhibits thymidylate synthase (TS) (involved in the de novo synthesis of thymidine) and is involved in incorporation into RNA and DNA with the inhibition of DNA synthesis and function [17]. With 5FU bolus injection maximum concentration is reached in the plasma and bone marrow 100-1000 times higher than with continuous infusion. More than 85% of the administered drug is inactivated by dihydropyr‐ imidine dehydrogenase (DPD), expressed mainly in the liver. Some mutation in DPD in about 2% in the general population can lead to serious life-threatening toxicity [17]. Leucovorin (LV) or folinic acid enhance the antitumor activity of 5FU. Today, there is a lack of LV in the United States, despite the absence of specific data confirming this statement. The QUASAR study investigators demonstrated that patients treated with 175 mg of LV similar survival and 3 - year recurrence rate of LV 25 mg when administered as a bolus 5-FU as adjuvant therapy for CRC 7. Similar results have been reported in the parameters in metastatic CRC patients - there was no difference in survival or response rate in patients receiving 5FU bolus high - dose or low-dose LV [18]. Therefore, when LV is not available without LV treatment is reasonable. Comparison of monthly bolus FU / LV

regimen (5FU bolus followed by LV 15 minutes) with double - monthly infusion LV5FU2 (LV for 2 hours, followed by bolus 5-FU, followed by a continuous infusion of 5-FU over 2 days) in 905 patients with stage II (43%) or III (57%) colon cancer showed that the regime was less toxic LV5FU2, especially regarding hematological and gastrointestinal events (P <0.001) [19]. No significant difference in DFS and OS was observed in one of two regi mens median follow-up 6 years. Two other studies have shown that the two ways of 5FU bolus administration combined with LV with or without levamisole and a continuous infusion of 5-FU are equivalent. Saini and colleagues conducted a multicenter randomized trial comparing the efficacy and toxicity of 12 weeks of 5FU delivered by continuous intrave‐ nous infusion against the standard bolus 5-FU and LV for 6 months as adjuvant treat‐ ment in colorectal cancer. The two schemes are equivalent, but the plan 12 weeks was less toxic [20]. The analysis of data from several trials in which patients were randomly resection of the tumor or tumor resection followed by adjuvant 5-FU/LV showed that the benefit of adjuvant chemotherapy was observed in patients with stage III [21, 22], which suggests that because of nodal status of these patients are at higher risk. Both studies showed that the addition of oxaliplatin to 5-FU/LV as adjuvant therapy in stage II and elderly patients showed no significant DFS or OS [23, 24] benefits even in patients with characteristics high risk - T4 tumors, intestinal obstruction, venous invasion, etc. This suggests that, despite the failure of our definition of high-risk patients with stage II, 5-FU/LV regimen may be preferable. QUASAR investigators reported their analysis of 3238 patients, the majority of them were in stage II colon cancer. Patients were randomized to receive 5-FU/LV or observation. The relative risk of death from all causes in the 5-FU/LV arm versus observa‐ tion was 0.82 (95% CI, 0.70 to 0.95, p = 0.008). The relative risk of recurrence was 0.78 (95% CI, 0.67-0, 91, p = 0.001) [7]. The investigators did not separate patients into individuals high or low risk. Risk factors are obstruction or bowel perforation, elevated preoperative CEA, poorly differentiated tumors, removal of CDC patients and MSI-S. The impact of adjuvant chemotherapy and the potential benefit of this new could not be clearly demon‐ strated in this study of patients with stage II.

## **4. Oral fluoropyrimidines**

oxaliplatin. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluat‐ ing shorter periods of oxaliplatin-based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the noninferiority of short periods of treatment, as well as consideration of the evaluation criteria of quality of life. The relative benefit of chemotherapy is also a key factor in the choice of treatment for patients in the adjuvant setting. Patients with stage 3 are a heterogeneous group and decisions based on age, the relative risk of recurrence (N1 N2 against disease), and the additional benefit that can be achieved by adding oxaliplatin need to be carefully considered. Given the new data in patients over 70 years, it seems likely that chemothera‐ py oxaliplatin are used less frequently in this group. Patients with disease stage 2 have an excellent prognosis with or without chemotherapy 5FU-based and high-risk patients functions are selected for processing. Both C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5-FU in patients with stage 2 disease, but a trend towards improved DFS was noted. However, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of

In 1990, Moertel and colleagues first reported the value of adjuvant chemotherapy in patients with stage III colon cancer (Dukes C, Tx N + M0). [15] This study showed an increase in overall survival and progression-free survival in patients receiving 5FU/ Levamisole - based chemotherapy for 1 year against levamisole alone or without chemother‐ apy. With a median follow - up of 6.5 years, patients treated with 5-FU / levamisole showed a 40% reduction in recidivism and an estimated reduction of 33% of overall mortality [16]. 5-FU is a pyrimidine analogue, which inhibits thymidylate synthase (TS) (involved in the de novo synthesis of thymidine) and is involved in incorporation into RNA and DNA with the inhibition of DNA synthesis and function [17]. With 5FU bolus injection maximum concentration is reached in the plasma and bone marrow 100-1000 times higher than with continuous infusion. More than 85% of the administered drug is inactivated by dihydropyr‐ imidine dehydrogenase (DPD), expressed mainly in the liver. Some mutation in DPD in about 2% in the general population can lead to serious life-threatening toxicity [17]. Leucovorin (LV) or folinic acid enhance the antitumor activity of 5FU. Today, there is a lack of LV in the United States, despite the absence of specific data confirming this statement. The QUASAR study investigators demonstrated that patients treated with 175 mg of LV similar survival and 3 - year recurrence rate of LV 25 mg when administered as a bolus 5-FU as adjuvant therapy for CRC 7. Similar results have been reported in the parameters in metastatic CRC patients - there was no difference in survival or response rate in patients receiving 5FU bolus high - dose or low-dose LV [18]. Therefore, when LV is not available without LV treatment is reasonable. Comparison of monthly bolus FU / LV

operation) and the risk of neurotoxicity. [23]

308 Colorectal Cancer - Surgery, Diagnostics and Treatment

**3. 5FU**

Two oral prodrugs of 5FU - capecetabine and uracil / tegafur (UFT), has demonstrated efficacy in metastatic disease, which is comparable with bolus 5-FU/LV regimens [25, 26]. After oral administration, capecitabine is rapidly absorbed with plasma concentrations peaking after 1.5 hours [27]. Pharmacokinetics is largely dose - dependent. The pharmacol‐ ogy of capecitabine is not significantly influenced by gender, race, performance status, body surface area, albumin or hepatic dysfunction [28]. The half-life of capecitabine is between 0.49 and 0.89 hours, whereas the half-life of the metabolite (5-FU) extends from 0.67 to 1.15 hours [29]. Regarding renal excretion primarily (more than 70% of metabolites), capecita‐ bine is against - in patients with severe renal impairment (creatinine clearance less than 30 mL / min).


LV. After a median follow-up of 6.9 years, both treatments showed similar efficacy in terms of DFS and OS [30]. The HR for DFS of capecitabine compared 5-FU/LV was 0.88 (95% CI, 0.77 to 1.01), the upper limit of the 95% is well below the predefined non-inferiority margin of 1.20 (p <0.0001) [30]. The 5-year DFS rate for capecitabine and 5-FU/LV were 60.8% and 56.7%, respectively. These monitoring data confirm that, as adjunctive therapy for patients with colon cancer resected stage III oral capecitabine is at least equivalent to iv bolus treatment of 5- FU/LV in terms of 5 - year DFS, the primary endpoint of X-ACT study. Infusional 5-FU regimens are now often favored because they offer similar efficacy or improved slightly bolus 5-FU/LV regimes and are generally better tolerated [31]. However, the plasma concentration profile of capecitabine is administered twice daily for 14 days, closer to that of a continuous infusion of 5-FU bolus injections as daily or weekly 5FU.La capecitabine Profile improved safety compared to bolus 5-FU/LV in terms of significantly lower rates of diarrhea, stomatitis,

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 311

UFT and oral LV was evaluated in the adjuvant setting in the NSABP C-06 trial. More than 1000 patients with colon cancer were randomized to receive either oral or intravenous UFT with LV 5FU with LV. 47% of patients had colon cancer stage II, and 53% had colon cancer stage III. Median follow-up was 62.3 months time. There was no significant difference in disease-free survival - or overall showing that the UFT is an acceptable alternative to parenteral 5-FU/LV [32]. No difference in toxicity profiles of the two regimens has been reported.

The hypothesis that the antitumor activity of the combination agent, including oxalipla‐ tin, irinotecan, bevacizumab, cetuximab in metastatic cure rates would result in increased adjuvant proved to be often wrong. Oxaliplatin is a platinum compound and third generation of the safe administration of evidence of clinical activity has been reported 33. Platinum compounds exert their effect through the development of covalent adducts with cellular DNA, which is not portable - specific cycle [34]. Platinum derivative oxaliplatin is described as having a "tri-exponential" reason for removing the half - life being successive‐ ly 0.28 hours, 16.3 hours and 273 hours [35]. The fact that the third half-life of oxaliplatin hundreds of hours, the accumulation of the drug in the tissues can reasonably be expect‐ ed. In this regard, one study examined the long - term retention of platinum 8-75 months after treatment with cisplatin and oxaliplatin [36]. Narrow therapeutic index of oxalipla‐ tin and adverse reactions are mainly reported in the hematopoietic system, peripheral nerves, and gastrointestinal tract [35]. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of randomized 2246 patients with stage II or III CRC will LV5FU2 or FOLFOX-4 (which is LV5FU2 chemotherapy plus oxaliplatin on day 1]. The 5-year DFS rate of Phase II and III patients were 73.3% and 67.4% in the FOL‐ FOX-4 groups and LV5FU2, respectively (RR 0.80, 95% CI, 0.68-0, 93, p = 0.003) [37]. Subgroup analysis showed stage - specific 6 years OS rate of 72.9% against 68.7% in patients with stage III CRC (HR 0.80, 95% CI, 0.65-0, 97, P = 0.023) and 85.0% against 83.3% in patients with stage II CRC (P = 0.65] in the FOLFOX-4 and LV5FU2, respectively [38]. As

neutropenia, nausea, alopecia, febrile neutropenia [30].

**5. Adjuvant therapy combination**

**Table 1.** Types of therapeutical agents and their mechanism of action

The X-ACT (Xeloda (capecitabine) in adjuvant therapy of colon cancer) Phase III trial in patients (N = 1.987) compared capecitabine (2500 mg / m 2 / day, 14 to 21 days) for bolus 5-FU/ LV. After a median follow-up of 6.9 years, both treatments showed similar efficacy in terms of DFS and OS [30]. The HR for DFS of capecitabine compared 5-FU/LV was 0.88 (95% CI, 0.77 to 1.01), the upper limit of the 95% is well below the predefined non-inferiority margin of 1.20 (p <0.0001) [30]. The 5-year DFS rate for capecitabine and 5-FU/LV were 60.8% and 56.7%, respectively. These monitoring data confirm that, as adjunctive therapy for patients with colon cancer resected stage III oral capecitabine is at least equivalent to iv bolus treatment of 5- FU/LV in terms of 5 - year DFS, the primary endpoint of X-ACT study. Infusional 5-FU regimens are now often favored because they offer similar efficacy or improved slightly bolus 5-FU/LV regimes and are generally better tolerated [31]. However, the plasma concentration profile of capecitabine is administered twice daily for 14 days, closer to that of a continuous infusion of 5-FU bolus injections as daily or weekly 5FU.La capecitabine Profile improved safety compared to bolus 5-FU/LV in terms of significantly lower rates of diarrhea, stomatitis, neutropenia, nausea, alopecia, febrile neutropenia [30].

UFT and oral LV was evaluated in the adjuvant setting in the NSABP C-06 trial. More than 1000 patients with colon cancer were randomized to receive either oral or intravenous UFT with LV 5FU with LV. 47% of patients had colon cancer stage II, and 53% had colon cancer stage III. Median follow-up was 62.3 months time. There was no significant difference in disease-free survival - or overall showing that the UFT is an acceptable alternative to parenteral 5-FU/LV [32]. No difference in toxicity profiles of the two regimens has been reported.

## **5. Adjuvant therapy combination**

**Therapy Mechanism of Action Indications Potential Common Toxicities**

Multiple uses in combination with other agents, both in the adjuvant (postop) and palliative setting

Multiple uses in combination with other agents, both in the adjuvant (postop) and metastatic setting

setting

setting

Used alone or in

combination with 5FU, LV (FOLFIRI) in the metastatic

Used in combination with either FOLFOX or FOLFIRI in the metastatic setting

Used with irinotecan or as a single agent in the metastatic setting

Used as a single agent in the metastatic setting

The X-ACT (Xeloda (capecitabine) in adjuvant therapy of colon cancer) Phase III trial in patients (N = 1.987) compared capecitabine (2500 mg / m 2 / day, 14 to 21 days) for bolus 5-FU/

Used in combination with 5FU, leucovorin (LV) (FOLFOX) in the adjuvant (postop) and metastatic

Gastrointestinal (nausea,

Gastrointestinal (nausea,

Palmar-plantar syndrome (hand-foot syndrome)

Peripheral neuropathy Gastrointestinal (nausea,

Myelosuppression Hypersensitivity

late diarrhea) Fatigue

Alopecia

Hypertension

Acneform rash Hypersensitivity Hypomagnesemia

Acneform rash Hypomagnesemia

Fatigue

Fatigue

Myelosuppression

Cholinergic (acute diarrhea) Gastrointestinal (nausea,

Arterial thrombotic events Impaired wound healing Gastrointestinal perforation

diarrhea) Myelosuppression

Fatigue

diarrhea) Myelosuppression

Fatigue

diarrhea) Fatigue

5- Fluorouracil (5FU) Blocks the enzyme

310 Colorectal Cancer - Surgery, Diagnostics and Treatment

synthesis

Capecitabine Blocks thymidylate synthase

Oxaliplatin Inhibits DNA replication and

Irinotecan Inhibits topoisomerase I, an

Bevacizumab Monoclonal antibody which

Cetuximab Monoclonal antibody to

Panitumumab Monoclonal antibody to

site

thymidylate synthase (TS), which is essential for DNA

(orally administered prodrug

transcription by forming inter- and intra-strand DNA adducts/cross-links

enzyme that facilitates the uncoiling and recoiling of DNA during replication

binds to VEGF ligand

EGFR (chimeric) that blocks the ligand-binding site

EGFR (fully humanized) that blocks the ligand-binding

VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.

**Table 1.** Types of therapeutical agents and their mechanism of action

converted to 5FU)

The hypothesis that the antitumor activity of the combination agent, including oxalipla‐ tin, irinotecan, bevacizumab, cetuximab in metastatic cure rates would result in increased adjuvant proved to be often wrong. Oxaliplatin is a platinum compound and third generation of the safe administration of evidence of clinical activity has been reported 33. Platinum compounds exert their effect through the development of covalent adducts with cellular DNA, which is not portable - specific cycle [34]. Platinum derivative oxaliplatin is described as having a "tri-exponential" reason for removing the half - life being successive‐ ly 0.28 hours, 16.3 hours and 273 hours [35]. The fact that the third half-life of oxaliplatin hundreds of hours, the accumulation of the drug in the tissues can reasonably be expect‐ ed. In this regard, one study examined the long - term retention of platinum 8-75 months after treatment with cisplatin and oxaliplatin [36]. Narrow therapeutic index of oxalipla‐ tin and adverse reactions are mainly reported in the hematopoietic system, peripheral nerves, and gastrointestinal tract [35]. The addition of oxaliplatin to 5FU improves patient outcomes in the adjuvant setting. Mosaic of randomized 2246 patients with stage II or III CRC will LV5FU2 or FOLFOX-4 (which is LV5FU2 chemotherapy plus oxaliplatin on day 1]. The 5-year DFS rate of Phase II and III patients were 73.3% and 67.4% in the FOL‐ FOX-4 groups and LV5FU2, respectively (RR 0.80, 95% CI, 0.68-0, 93, p = 0.003) [37]. Subgroup analysis showed stage - specific 6 years OS rate of 72.9% against 68.7% in patients with stage III CRC (HR 0.80, 95% CI, 0.65-0, 97, P = 0.023) and 85.0% against 83.3% in patients with stage II CRC (P = 0.65] in the FOLFOX-4 and LV5FU2, respectively [38]. As

expected, the toxicity of the regimen FOLFOX-4 was higher than that observed in the LV5FU2 arm. All - cause mortality in the first 60 days was the same in both arms.The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5-FU adjuvant chemotherapy, but using a different calendar 5FU and also provide fewer doses of oxaliplatin in the MOSAIC study (nine against twelve). FLOX regimen in this trial was studied - oxaliplatin was given on weeks 1, 3, and 5 more per week 5-FU/LV bolus of 1-6 weeks, repeated at 8 week cycle, depending on the standard weekly 5-FU/LV treatment. Over 2000 patients were randomized to receive 5-FU/LV and FLOX treatment. Stage II patients were 29% and stage III patients was 71%. The median duration of follow up was 34 months. The hazard ratio of FLOX against 5-FU/LV was 0.79 (95% CI, 0.67 to 0.93], with a risk reduction of 21% in favor of FLOX [39]. As expected, treatment toxicity FLOX was higher than that observed in the 5-FU/LV arm. 15 deaths were recorded in the treatment with FLOX and 14 deaths 5-FU/LV. Update this study showed that the benefit of FLOX in DFS was observed in 7 - year median follow - but there was no significant difference in overall survival when the two arms were compared 24 (HR, 0.88, 95% CI, 0.74 to 1.05, P = 0.1428). A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while in patients over 70 years, no benefit was observed consistently. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluating shorter periods of oxaliplatin - based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the non-inferiority of short periods treatment.Both NSABP C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5- FU in patients with stage II disease, but a trend towards improved DFS was noted.Howev‐ er, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of operation) and the risk of neurotox‐ icity. Analysis of a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus 5-FU/LV as adjuvant treatment for colon cancer stage III showed that XELOX was an improvement of 3 years compared to 5-FU/LV DFS rate [40, 41]. Patients receiving XELOX had less adverse reactions such as diarrhea, alopecia, and more neurosensory toxicity, vomiting and hand-foot syndrome than patients receiving FU / LV. All these studies suggest that FOLFOX, XELOX FLOX and can be used interchangeably in contexts adjuvant. Irinotecan is a semisynthetic analogue of camptothecin, originally isolated from the China / Tibet ornamental tree Camptotheca acuminata.It is a chemotherapy agent that causes destruction of cells in S phase-specific topoisomerase I poison in the cell [42]. CALGB 89803 trial by Saltz and colleagues randomized 1264 patients to receive standard weekly bolus 5- FU / LV bolus regimen or weekly irinotecan and 5-FU bolus / LV. The primary endpoints of the study were overall survival and disease-free survival. Surprisingly, they found no difference in either DFS (0.84] or OS (P = 0.74] between the two treatment arms with lethal and non-lethal toxicity increased by the addition of irinotecan to standard 5FU / LV pattern 43.This trial showed the need for randomized controlled trials adjuvant because advances in the treatment of metastatic disease does not necessarily translate into advances in adjuvant therapy. Phase III trial was conducted by large investigators PETACC-3. They

investigated whether the addition of irinotecan to LV5FU2 would improve disease-free survival in patients with colon cancer. After surgery, patients with stage II and III colon cancer were randomized to receive surgery LV5FU2 (LV 200 mg / m 2 infused over 2 hours, followed by 5-FU as a 400 mg / m 2 bolus and then one of 600 mg / m 2 by continuous infusion over 22 hours on days 1 and 2 every 2 weeks for 12 cycles) with or without irinotecan (180 mg / m 2 infused over 30 to 90 minutes, day 1, every 2 weeks) [44]. After a median follow-up of 66.3 months, the rate at 5 years was 56.7% with DFS irinotecan/ LV5FU2 and 54.3% for LV5FU2 alone (p = 0.106). They observed that the addition of irinotecan to LV5FU2 was associated with an increased incidence of adverse reactions and neutropenia. They concluded that irinotecan added to LV5FU2 as adjuvant therapy does not confer a statistically significant improvement in overall survival or DFS in patients with colon cancer stage III versus LV5FU2 alone. For the moment, there are no data support‐ ing the use of irinotecan-containing regimens in adjuvant stage II and III patients. Analy‐ sis PETACC-3 trial could not confirm the expected benefit of adding irinotecan in MSI-H patients. Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF) which is used to inhibit the function of VEGF in vascular endothelial cells and thereby inhibit tumor angiogenesis-dependent solid tumors for growth and metastasis [45]. Bevacizumab has demonstrated clinical activity to in‐ crease in the standard CT metastatic settings.This led to the consideration of this agent in the adjuvant chemotherapy in the NSABP C-08 trial. More than 2500 patients, most of whom had stage III were randomized to receive FOLFOX6 modified 6 months, alone or with bevacizumab [46]. In the bevacizumab arm, bevacizumab was administered for more than 6 months, for a total of 1 year of bevacizumab.The primary endpoint of the study was 3 years DFS. The relative risk of FOLFOX plus bevacizumab versus FOLFOX alone was 0.89 (95% CI, 0.76 to 1.04, p = 0.15). This study did not demonstrate the benefits of the use of bevacizumab in the adjuvant treatment of stage II and III CRC and for this reason the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer. Cetuximab is a monoclonal antibody capable of inhibiting the degradation and transmembrane receptor EGFR epidermal growth factor 47.Inhibition of EGFR is of major importance because EGFR control many important activities of tumor cells, includ‐ ing tumor growth and neo - angiogenesis, inhibition of the apoptotic response to chemother‐ apy and radiotherapy. In a Phase III, randomized, Alberts and colleagues evaluated the potential benefit of cetuximab added to the sixth amended plan FOLFOX.Ils randomized over 2500 patients to receive 12 cycles of FOLFOX every two weeks with or without cetuximab. The mutational status of the KRAS gene was decided at the central level. The median follow-up of 28 months. Three-year disease-free survival for FOLFOX alone was 74.6% against 71.5% with the addition of cetuximab (HR, 1.21, 95% CI, 0.98 to 1.49, P = 0 08) in patients with wild-type KRAS, and 67.1% against 65.0% (HR 1.12, 95% CI, 0.86 to 1.46, p = 0.38) in patients with mutated KRAS 48.The trial did not demonstrate any benefit when adding cetuximab to FOLFOX regimen. More patients with grade 3 or higher adverse events (72.5% versus 52.3%, odds ratio (OR) 2.4, 95% CI, 2.1 to 2.8, p <.001) and failure to carry Good 12 cycles (33% versus 23%, OR 1.6, 95% CI, 1.4 to 1.9, p <0, 001) were significant‐

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 313

investigated whether the addition of irinotecan to LV5FU2 would improve disease-free survival in patients with colon cancer. After surgery, patients with stage II and III colon cancer were randomized to receive surgery LV5FU2 (LV 200 mg / m 2 infused over 2 hours, followed by 5-FU as a 400 mg / m 2 bolus and then one of 600 mg / m 2 by continuous infusion over 22 hours on days 1 and 2 every 2 weeks for 12 cycles) with or without irinotecan (180 mg / m 2 infused over 30 to 90 minutes, day 1, every 2 weeks) [44]. After a median follow-up of 66.3 months, the rate at 5 years was 56.7% with DFS irinotecan/ LV5FU2 and 54.3% for LV5FU2 alone (p = 0.106). They observed that the addition of irinotecan to LV5FU2 was associated with an increased incidence of adverse reactions and neutropenia. They concluded that irinotecan added to LV5FU2 as adjuvant therapy does not confer a statistically significant improvement in overall survival or DFS in patients with colon cancer stage III versus LV5FU2 alone. For the moment, there are no data support‐ ing the use of irinotecan-containing regimens in adjuvant stage II and III patients. Analy‐ sis PETACC-3 trial could not confirm the expected benefit of adding irinotecan in MSI-H patients. Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF) which is used to inhibit the function of VEGF in vascular endothelial cells and thereby inhibit tumor angiogenesis-dependent solid tumors for growth and metastasis [45]. Bevacizumab has demonstrated clinical activity to in‐ crease in the standard CT metastatic settings.This led to the consideration of this agent in the adjuvant chemotherapy in the NSABP C-08 trial. More than 2500 patients, most of whom had stage III were randomized to receive FOLFOX6 modified 6 months, alone or with bevacizumab [46]. In the bevacizumab arm, bevacizumab was administered for more than 6 months, for a total of 1 year of bevacizumab.The primary endpoint of the study was 3 years DFS. The relative risk of FOLFOX plus bevacizumab versus FOLFOX alone was 0.89 (95% CI, 0.76 to 1.04, p = 0.15). This study did not demonstrate the benefits of the use of bevacizumab in the adjuvant treatment of stage II and III CRC and for this reason the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer. Cetuximab is a monoclonal antibody capable of inhibiting the degradation and transmembrane receptor EGFR epidermal growth factor 47.Inhibition of EGFR is of major importance because EGFR control many important activities of tumor cells, includ‐ ing tumor growth and neo - angiogenesis, inhibition of the apoptotic response to chemother‐ apy and radiotherapy. In a Phase III, randomized, Alberts and colleagues evaluated the potential benefit of cetuximab added to the sixth amended plan FOLFOX.Ils randomized over 2500 patients to receive 12 cycles of FOLFOX every two weeks with or without cetuximab. The mutational status of the KRAS gene was decided at the central level. The median follow-up of 28 months. Three-year disease-free survival for FOLFOX alone was 74.6% against 71.5% with the addition of cetuximab (HR, 1.21, 95% CI, 0.98 to 1.49, P = 0 08) in patients with wild-type KRAS, and 67.1% against 65.0% (HR 1.12, 95% CI, 0.86 to 1.46, p = 0.38) in patients with mutated KRAS 48.The trial did not demonstrate any benefit when adding cetuximab to FOLFOX regimen. More patients with grade 3 or higher adverse events (72.5% versus 52.3%, odds ratio (OR) 2.4, 95% CI, 2.1 to 2.8, p <.001) and failure to carry Good 12 cycles (33% versus 23%, OR 1.6, 95% CI, 1.4 to 1.9, p <0, 001) were significant‐

expected, the toxicity of the regimen FOLFOX-4 was higher than that observed in the LV5FU2 arm. All - cause mortality in the first 60 days was the same in both arms.The NSABP C-07 trial had a similar design, the addition of oxaliplatin to 5-FU adjuvant chemotherapy, but using a different calendar 5FU and also provide fewer doses of oxaliplatin in the MOSAIC study (nine against twelve). FLOX regimen in this trial was studied - oxaliplatin was given on weeks 1, 3, and 5 more per week 5-FU/LV bolus of 1-6 weeks, repeated at 8 week cycle, depending on the standard weekly 5-FU/LV treatment. Over 2000 patients were randomized to receive 5-FU/LV and FLOX treatment. Stage II patients were 29% and stage III patients was 71%. The median duration of follow up was 34 months. The hazard ratio of FLOX against 5-FU/LV was 0.79 (95% CI, 0.67 to 0.93], with a risk reduction of 21% in favor of FLOX [39]. As expected, treatment toxicity FLOX was higher than that observed in the 5-FU/LV arm. 15 deaths were recorded in the treatment with FLOX and 14 deaths 5-FU/LV. Update this study showed that the benefit of FLOX in DFS was observed in 7 - year median follow - but there was no significant difference in overall survival when the two arms were compared 24 (HR, 0.88, 95% CI, 0.74 to 1.05, P = 0.1428). A significant interaction between age and survival of certain parameters were observed. Patients less than 70 years appeared to benefit from the addition of oxaliplatin while in patients over 70 years, no benefit was observed consistently. MOSAIC and NSABP the C-07 trials delivered a total dose of oxaliplatin different, but both studies noted similar improvements in DFS. International trials evaluating shorter periods of oxaliplatin - based chemotherapy in the adjuvant setting (12 versus 24 weeks of chemotherapy oxaliplatin/5FU ISRCTN 59757862) in order to assess the non-inferiority of short periods treatment.Both NSABP C-07 and MOSAIC are powered to assess the benefit of adding oxaliplatin to 5- FU in patients with stage II disease, but a trend towards improved DFS was noted.Howev‐ er, no OS benefit is probably very low in absolute terms (<2%) and difficult to justify given the excellent overall performance (> 80% at 5 years of operation) and the risk of neurotox‐ icity. Analysis of a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus 5-FU/LV as adjuvant treatment for colon cancer stage III showed that XELOX was an improvement of 3 years compared to 5-FU/LV DFS rate [40, 41]. Patients receiving XELOX had less adverse reactions such as diarrhea, alopecia, and more neurosensory toxicity, vomiting and hand-foot syndrome than patients receiving FU / LV. All these studies suggest that FOLFOX, XELOX FLOX and can be used interchangeably in contexts adjuvant. Irinotecan is a semisynthetic analogue of camptothecin, originally isolated from the China / Tibet ornamental tree Camptotheca acuminata.It is a chemotherapy agent that causes destruction of cells in S phase-specific topoisomerase I poison in the cell [42]. CALGB 89803 trial by Saltz and colleagues randomized 1264 patients to receive standard weekly bolus 5- FU / LV bolus regimen or weekly irinotecan and 5-FU bolus / LV. The primary endpoints of the study were overall survival and disease-free survival. Surprisingly, they found no difference in either DFS (0.84] or OS (P = 0.74] between the two treatment arms with lethal and non-lethal toxicity increased by the addition of irinotecan to standard 5FU / LV pattern 43.This trial showed the need for randomized controlled trials adjuvant because advances in the treatment of metastatic disease does not necessarily translate into advances in adjuvant therapy. Phase III trial was conducted by large investigators PETACC-3. They

312 Colorectal Cancer - Surgery, Diagnostics and Treatment

ly higher with cetuximab.Increased toxicity was observed in patients aged 70 years or older. Therefore, the role of cetuximab in the adjuvant treatment is insignificant for the moment.

**3.** overall survival (OS), which is the length of time patients are alive after diagnosis or

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 315

Postoperative, or "adjuvant" systemic therapy has become standard for stage III colon cancer. Adjuvant therapy should also be strongly considered in stage II patients. It is generally recommended for any medically fit patient with stage II cancer with unfavorable factors, including colonic perforation, poorly differentiated histology, colonic obstruction, lympho vascular invasion, or inadequately sampled lymph nodes [61]. The optimal choice of adjuvant chemotherapy has recently changed from a 6-month course of 5FU-based chemotherapy alone to a 6-month course of infusional 5FU plus LV and oxaliplatin (FOLFOX) based on a large trial of adjuvant systemic therapy for resected stage II or III colon cancer [62].This trial demon‐ strated an increase in disease-free survival at 3 years from 72.9 to 78.2% (*p* = 0.002) with addition of oxaliplatin to FU/LV. Five-year disease-free survival remained significant (HR: 0.80; *p* = 0.003) and at 6 years there was an overall survival benefit for stage III patients (68.3% versus 72.9%) [64].Toxicities were comparable between the two groups, with the exception that oxaliplatin is associated with a much higher rate of paresthesia: 12.4% versus 0.2% grade 3 (serious) toxicity. This neurotoxicity persisted at a grade 3 level in 1.1% of treated patients at

Many advances have occurred recently in the treatment of metastatic CRC. Active agents, in addition to the original 5FU, that have been approved by the Food & Drug Administration (FDA) for mCRC include irinotecan, capecitabine, oxaliplatin, bevacizumab, cetuximab, and panitumumab. The goals of systemic therapy of mCRC include palliation of symptoms, prolongation of life, and in selected cases of liver-only metastases, tumor regression to facilitate surgical resection of these metastases. The median survival of a patient with mCRC has improved during the last decade from less than 1 year, with only 5FU-based therapy, to ~2

5FU, often modified by LV, has been clinically used for half a century as a standard agent for mCRC [64]. This was the only available agent until 1996, when irinotecan was approved. Over the last decade, chemotherapies such as oxaliplatin and capecitabine and targeted agents such as bevacizumab, cetuximab, and panitumumab have been approved. 5FU blocks the enzyme thymidylate synthase (TS), which is essential for DNA synthesis. Leucovorin (LV), also known as folinic acid, enhances the antineoplastic effects of 5FU. Both LV (FOL = folinic acid) and 5FU (F = fluorouracil) can be combined with irinotecan (IRI) or oxaliplatin (OX) with the treatment acronyms FOLFIRI or FOLFOX, respectively. These alternative treatments consist of admin‐ istration of a bolus of 5FU, LV, and either oxaliplatin or irinotecan. The patient is then sent home with a 2-day infusion of low-dose 5FU, administered by a small, lightweight, portable pump, usually worn on a belt or shoulder strap, infused through a centrally placed catheter. The patient or health care provider can simply disconnect the catheter after the 2-day infusion. Capecitabine is an oral fluoropyrimidine with a similar mechanism of action and similar

initiation of treatment for metastatic disease.

**8. Postoperative management**

one-year of follow-up.

efficacy as 5FU.

years, with multiagent systemic therapy.

## **6. Chemotherapy in elderly**

Colon cancer usually occurs in the elderly with a median age at diagnosis> 70 years in the USA. Given the increasing life expectancy, patients aged >75 years will be an important component of oncology practice in the future. Despite this fact, very few patients >75 years participate in clinical trials. There is disagreement in the administration of standard adjuvant therapy between young and elderly patients, despite a significant survival benefit for most patients [49]. The pooled analyzes of safety and efficacy of adjuvant chemotherapy in the elderly showed comparable rates of toxicity and similar survival benefits compared to younger patients [50].The majority of data for adjuvant therapy in elderly patients is not the incorpo‐ ration of new therapeutic agents such as oxaliplatin. Subsequent population-based studies have suggested that older people (eg the elderly category <75 years versus> 75 years [51] were less likely to have received adjuvant therapy, but experienced similar survival rates compared younger patients [52]. Finally, although the majority of recommendations to reduce colorectal cancer screening for persons aged <75 years, the study results indicate that [53] patients aged >75 years account for almost 20% of cases of colon cancer lymph nodes.In this large populationbased study, investigators found that age was associated with significantly lower rates of adjuvant chemotherapy administration, whereas the survival benefits of such treatment are comparable to those of younger patients with stage III in [53] colon cancer.Although chrono‐ logical age alone should not be an exclusion criterion, more work is needed to establish an optimal strategy and effective way to understand who would benefit most from adjuvant therapy after surgical resection.

#### **7. Efectivness**

Patients with metastatic CRC being treated with chemotherapy are followed closely to monitor efficacy. There are standardized efficacy measures, such as the RECIST (response evaluation criteria in solid tumors) criteria, used as endpoints for large clinical trials. A partial response is defined as a 30% decrease in the longest dimension of each measurable tumor deposit, using unidimentional, or RECIST criteria [54-56]. A complete response is complete disappearance of all clinically detectable disease. The response rate (RR) is the percentage of patients who meet either a partial or complete response. Measures used to determine the duration of treatment benefit include:


**3.** overall survival (OS), which is the length of time patients are alive after diagnosis or initiation of treatment for metastatic disease.

### **8. Postoperative management**

ly higher with cetuximab.Increased toxicity was observed in patients aged 70 years or older. Therefore, the role of cetuximab in the adjuvant treatment is insignificant for the moment.

Colon cancer usually occurs in the elderly with a median age at diagnosis> 70 years in the USA. Given the increasing life expectancy, patients aged >75 years will be an important component of oncology practice in the future. Despite this fact, very few patients >75 years participate in clinical trials. There is disagreement in the administration of standard adjuvant therapy between young and elderly patients, despite a significant survival benefit for most patients [49]. The pooled analyzes of safety and efficacy of adjuvant chemotherapy in the elderly showed comparable rates of toxicity and similar survival benefits compared to younger patients [50].The majority of data for adjuvant therapy in elderly patients is not the incorpo‐ ration of new therapeutic agents such as oxaliplatin. Subsequent population-based studies have suggested that older people (eg the elderly category <75 years versus> 75 years [51] were less likely to have received adjuvant therapy, but experienced similar survival rates compared younger patients [52]. Finally, although the majority of recommendations to reduce colorectal cancer screening for persons aged <75 years, the study results indicate that [53] patients aged >75 years account for almost 20% of cases of colon cancer lymph nodes.In this large populationbased study, investigators found that age was associated with significantly lower rates of adjuvant chemotherapy administration, whereas the survival benefits of such treatment are comparable to those of younger patients with stage III in [53] colon cancer.Although chrono‐ logical age alone should not be an exclusion criterion, more work is needed to establish an optimal strategy and effective way to understand who would benefit most from adjuvant

Patients with metastatic CRC being treated with chemotherapy are followed closely to monitor efficacy. There are standardized efficacy measures, such as the RECIST (response evaluation criteria in solid tumors) criteria, used as endpoints for large clinical trials. A partial response is defined as a 30% decrease in the longest dimension of each measurable tumor deposit, using unidimentional, or RECIST criteria [54-56]. A complete response is complete disappearance of all clinically detectable disease. The response rate (RR) is the percentage of patients who meet either a partial or complete response. Measures used to determine the duration of treatment

**1.** progression-free survival (PFS), which is the time from the start of treatment to the date

**2.** disease-free survival (DFS), which is the length of time patients are free of disease after

**6. Chemotherapy in elderly**

314 Colorectal Cancer - Surgery, Diagnostics and Treatment

therapy after surgical resection.

**7. Efectivness**

benefit include:

the disease, worsens;

completion of curative treatment; and

Postoperative, or "adjuvant" systemic therapy has become standard for stage III colon cancer. Adjuvant therapy should also be strongly considered in stage II patients. It is generally recommended for any medically fit patient with stage II cancer with unfavorable factors, including colonic perforation, poorly differentiated histology, colonic obstruction, lympho vascular invasion, or inadequately sampled lymph nodes [61]. The optimal choice of adjuvant chemotherapy has recently changed from a 6-month course of 5FU-based chemotherapy alone to a 6-month course of infusional 5FU plus LV and oxaliplatin (FOLFOX) based on a large trial of adjuvant systemic therapy for resected stage II or III colon cancer [62].This trial demon‐ strated an increase in disease-free survival at 3 years from 72.9 to 78.2% (*p* = 0.002) with addition of oxaliplatin to FU/LV. Five-year disease-free survival remained significant (HR: 0.80; *p* = 0.003) and at 6 years there was an overall survival benefit for stage III patients (68.3% versus 72.9%) [64].Toxicities were comparable between the two groups, with the exception that oxaliplatin is associated with a much higher rate of paresthesia: 12.4% versus 0.2% grade 3 (serious) toxicity. This neurotoxicity persisted at a grade 3 level in 1.1% of treated patients at one-year of follow-up.

Many advances have occurred recently in the treatment of metastatic CRC. Active agents, in addition to the original 5FU, that have been approved by the Food & Drug Administration (FDA) for mCRC include irinotecan, capecitabine, oxaliplatin, bevacizumab, cetuximab, and panitumumab. The goals of systemic therapy of mCRC include palliation of symptoms, prolongation of life, and in selected cases of liver-only metastases, tumor regression to facilitate surgical resection of these metastases. The median survival of a patient with mCRC has improved during the last decade from less than 1 year, with only 5FU-based therapy, to ~2 years, with multiagent systemic therapy.

5FU, often modified by LV, has been clinically used for half a century as a standard agent for mCRC [64]. This was the only available agent until 1996, when irinotecan was approved. Over the last decade, chemotherapies such as oxaliplatin and capecitabine and targeted agents such as bevacizumab, cetuximab, and panitumumab have been approved. 5FU blocks the enzyme thymidylate synthase (TS), which is essential for DNA synthesis. Leucovorin (LV), also known as folinic acid, enhances the antineoplastic effects of 5FU. Both LV (FOL = folinic acid) and 5FU (F = fluorouracil) can be combined with irinotecan (IRI) or oxaliplatin (OX) with the treatment acronyms FOLFIRI or FOLFOX, respectively. These alternative treatments consist of admin‐ istration of a bolus of 5FU, LV, and either oxaliplatin or irinotecan. The patient is then sent home with a 2-day infusion of low-dose 5FU, administered by a small, lightweight, portable pump, usually worn on a belt or shoulder strap, infused through a centrally placed catheter. The patient or health care provider can simply disconnect the catheter after the 2-day infusion. Capecitabine is an oral fluoropyrimidine with a similar mechanism of action and similar efficacy as 5FU.

Irinotecan is a derivative of camptothecin, found in *Camptotheca acuminata*, a plant native to China. It potently inhibits topoisomerase I, an enzyme that facilitates the uncoiling and recoiling of DNA during replication by cleaving one strand and subsequently reattaching that strand. Oxaliplatin is a platinum chemotherapy that inhibits DNA replication and transcrip‐ tion by forming inter- and intrastrand DNA adducts/cross-links.

Although the FDA approved cetuximab for use in epidermal growth factor receptor (EGFR) expressing mCRC, there is no evidence that the presence or absence of EGFR expression influences RR, and routine testing for this is unnecessary. K-ras mutations have been shown to predict response to cetuximab. The K-ras gene encodes a GTPase protein that is involved in cell signal transduction pathways [72]. Wild-type (nonmutated) K-ras is found in normal cells. Approximately 40% of colorectal tumor cells have a mutated K-ras gene resulting in constitu‐ tively active protein and abnormal cell growth, proliferation, and differentiation. Evidence suggests there is no benefit in using cetuximab monotherapy in previously treated and untreated mCRC patients who have mutated K-ras tumors. Previously treated metastatic colorectal patients with mutated K-ras tumors did not benefit from cetuximab monotherapy, in contrast to patients with wild-type K-ras who had significantly improved overall survival and PFS [74]. FOLIFIRI and cetuximab as first-line therapy in mCRC was found to reduce the risk of disease progression; however, the benefit was limited to patients with K-ras wild-type

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 317

In 2006, the FDA approved panitumumab, a monoclonal antibody to EGFR, which unlike cetuximab, is fully humanized (not chimeric). It is indicated for patients with mCRC who have progressed on or are following 5FU, oxaliplatin, and irinotecan-containing regimens. In a large randomized trial of panitumumab versus best supportive care for mCRC, a response rate of 10% was found [74]. Like cetuximab, panitumumab causes an acneform skin rash. As a fully human monoclonal antibody, panitumumab has a lower risk of serious infusion reactions than the 3% rate observed with cetuximab. Similar to cetuximab, panitumumab monotherapy is more efficacious in patients with wild- rather than mutant-type K-ras tumors. In a randomized clinical trial of previously treated mCRC patients, median PFS and OS was significantly improved in the wild-type K-ras group compared with the mutant group [75]. 17% of patients with wild-type K-ras responded to treatment versus 0% of patients with mutant K-ras. The relative activity of cetuximab versus panitumumab, as well as the relative activity of panitu‐

Given the higher local recurrence rates and poorer overall survival of patients with rectal cancer, multimodality management is important. In the early 1990s, the standard of care following surgical resection for full thickness (T3–4) or lymph node positive rectal cancer was postoperative chemoradiotherapy as it was found to improve both local control and OS compared with surgery alone [77, 78]. Recently, preoperative chemoradiotherapy has become the treatment of choice for full thickness rectal cancers prior to total mesorectal excision based on a randomized clinical trial conducted by Sauer et al. Although this trial showed no difference in OS, improved local recurrence rates (6% versus 13%) were found for patients receiving preoperative 5FU-based chemoradiotherapy as compared with postoperative chemoradiotherapy [79]. Preoperative 5FU chemoradiotherapy as compared with preoperative radiation alone also has been shown to improve local recurrence rates

mumab when given with chemotherapy, is currently unknown.

tumors (HR 0.68, CI 0.50–0.94) [73].

**9. Rectal cancer**

(2.7% versus 14.6%) [80].

In patients with mCRC, optimal chemotherapy consists of initial administration of a fluoro‐ pyrimidine and oxaliplatin or irinotecan (e.g., FOLFOX or FOLFIRI). Tournigand et al [65] and Colucci et al [66] performed randomized trials where patients received either FOLFIRI followed by FOLFOX, or vice versa. In the Tournigand et al study, FOLIRI was found to have a response rate (RR) of 56% and a 8.5-month median progression free survival (mPFS), whereas FOLFOX had a RR of 54% and a mPFS of 8 months. Colucci et al found that FOLFIRI had a RR of 31% and FOLFOX had a RR of 34%. Both regimens had a mPFS of 7 months. Both investi‐ gators concluded that both regimens had similar efficacy when used as first-line therapy. Therefore, either FOLFOX or FOLFIRI can be considered standard options for first-line treatment of mCRC. These regimens are typically given with bevacizumab.

Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) ligand to inhibit angiogenesis. Its antineoplastic effect is ascribed to regression of microvascular density, inhibition of neovascularization, and "normalization" of grossly abnormal tumor vasculature that permits more effective chemotherapy delivery to the tumor. The FDA recently approved bevacizumab in combination with 5FU-based chemotherapy for mCRC based on findings that addition of bevacizumab to irinotecan, 5FU, and LV for mCRC improved PFS from 6.2 months to 10.6 months, improved the response rate from 35 to 45 [67] and improved overall survival from 15.6 to 20.3 months. Saltz et al found that the addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS from 8.0 to 9.3 months without an improvement in response rate [68]. The finding of improved PFS without improved RR is common in trials of targeted therapy because the metastatic lesions can cavitate or has necrosis rather than regress. Recently, XELOX chemotherapy with or without bevacu‐ zimab was found to be noninferior to FOLFOX with or without bevacuzimab [69]. XELOX chemotherapy includes a combination of oral 5FU known as capecitabine or xeloda (XEL) plus oxaliplatin (OX). XELOX can be used as an alternative in patients who cannot tolerate FOLFOX side effects.

In 2004, the FDA approved cetuximab, the chimeric (human/mouse) monoclonal antibody targeting epidermal growth factor receptor (EGFR), for treatment of mCRC with irinotecan, and as a single agent for patients intolerant of irinotecan-based therapy. Early randomized trials showed benefit of cetuximab in previously treated mCRC patients. When cetuximab was combined with irinotecan in patients refractory to irinotecan-based chemotherapy, the response rate was 22.9% versus 10.8% for irinotecan alone [70]. Among patients who failed previous lines of treatment, monotherapy with cetuximab was found to improve overall survival, PFS, and quality of life compared with best support care alone [71]. Cetuximab causes an acneform rash on the face and upper body in more than 80% of patients. The rash is associated with improved survival.

Although the FDA approved cetuximab for use in epidermal growth factor receptor (EGFR) expressing mCRC, there is no evidence that the presence or absence of EGFR expression influences RR, and routine testing for this is unnecessary. K-ras mutations have been shown to predict response to cetuximab. The K-ras gene encodes a GTPase protein that is involved in cell signal transduction pathways [72]. Wild-type (nonmutated) K-ras is found in normal cells. Approximately 40% of colorectal tumor cells have a mutated K-ras gene resulting in constitu‐ tively active protein and abnormal cell growth, proliferation, and differentiation. Evidence suggests there is no benefit in using cetuximab monotherapy in previously treated and untreated mCRC patients who have mutated K-ras tumors. Previously treated metastatic colorectal patients with mutated K-ras tumors did not benefit from cetuximab monotherapy, in contrast to patients with wild-type K-ras who had significantly improved overall survival and PFS [74]. FOLIFIRI and cetuximab as first-line therapy in mCRC was found to reduce the risk of disease progression; however, the benefit was limited to patients with K-ras wild-type tumors (HR 0.68, CI 0.50–0.94) [73].

In 2006, the FDA approved panitumumab, a monoclonal antibody to EGFR, which unlike cetuximab, is fully humanized (not chimeric). It is indicated for patients with mCRC who have progressed on or are following 5FU, oxaliplatin, and irinotecan-containing regimens. In a large randomized trial of panitumumab versus best supportive care for mCRC, a response rate of 10% was found [74]. Like cetuximab, panitumumab causes an acneform skin rash. As a fully human monoclonal antibody, panitumumab has a lower risk of serious infusion reactions than the 3% rate observed with cetuximab. Similar to cetuximab, panitumumab monotherapy is more efficacious in patients with wild- rather than mutant-type K-ras tumors. In a randomized clinical trial of previously treated mCRC patients, median PFS and OS was significantly improved in the wild-type K-ras group compared with the mutant group [75]. 17% of patients with wild-type K-ras responded to treatment versus 0% of patients with mutant K-ras. The relative activity of cetuximab versus panitumumab, as well as the relative activity of panitu‐ mumab when given with chemotherapy, is currently unknown.

## **9. Rectal cancer**

Irinotecan is a derivative of camptothecin, found in *Camptotheca acuminata*, a plant native to China. It potently inhibits topoisomerase I, an enzyme that facilitates the uncoiling and recoiling of DNA during replication by cleaving one strand and subsequently reattaching that strand. Oxaliplatin is a platinum chemotherapy that inhibits DNA replication and transcrip‐

In patients with mCRC, optimal chemotherapy consists of initial administration of a fluoro‐ pyrimidine and oxaliplatin or irinotecan (e.g., FOLFOX or FOLFIRI). Tournigand et al [65] and Colucci et al [66] performed randomized trials where patients received either FOLFIRI followed by FOLFOX, or vice versa. In the Tournigand et al study, FOLIRI was found to have a response rate (RR) of 56% and a 8.5-month median progression free survival (mPFS), whereas FOLFOX had a RR of 54% and a mPFS of 8 months. Colucci et al found that FOLFIRI had a RR of 31% and FOLFOX had a RR of 34%. Both regimens had a mPFS of 7 months. Both investi‐ gators concluded that both regimens had similar efficacy when used as first-line therapy. Therefore, either FOLFOX or FOLFIRI can be considered standard options for first-line

Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) ligand to inhibit angiogenesis. Its antineoplastic effect is ascribed to regression of microvascular density, inhibition of neovascularization, and "normalization" of grossly abnormal tumor vasculature that permits more effective chemotherapy delivery to the tumor. The FDA recently approved bevacizumab in combination with 5FU-based chemotherapy for mCRC based on findings that addition of bevacizumab to irinotecan, 5FU, and LV for mCRC improved PFS from 6.2 months to 10.6 months, improved the response rate from 35 to 45 [67] and improved overall survival from 15.6 to 20.3 months. Saltz et al found that the addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS from 8.0 to 9.3 months without an improvement in response rate [68]. The finding of improved PFS without improved RR is common in trials of targeted therapy because the metastatic lesions can cavitate or has necrosis rather than regress. Recently, XELOX chemotherapy with or without bevacu‐ zimab was found to be noninferior to FOLFOX with or without bevacuzimab [69]. XELOX chemotherapy includes a combination of oral 5FU known as capecitabine or xeloda (XEL) plus oxaliplatin (OX). XELOX can be used as an alternative in patients who cannot tolerate FOLFOX

In 2004, the FDA approved cetuximab, the chimeric (human/mouse) monoclonal antibody targeting epidermal growth factor receptor (EGFR), for treatment of mCRC with irinotecan, and as a single agent for patients intolerant of irinotecan-based therapy. Early randomized trials showed benefit of cetuximab in previously treated mCRC patients. When cetuximab was combined with irinotecan in patients refractory to irinotecan-based chemotherapy, the response rate was 22.9% versus 10.8% for irinotecan alone [70]. Among patients who failed previous lines of treatment, monotherapy with cetuximab was found to improve overall survival, PFS, and quality of life compared with best support care alone [71]. Cetuximab causes an acneform rash on the face and upper body in more than 80% of patients. The rash is

tion by forming inter- and intrastrand DNA adducts/cross-links.

316 Colorectal Cancer - Surgery, Diagnostics and Treatment

treatment of mCRC. These regimens are typically given with bevacizumab.

side effects.

associated with improved survival.

Given the higher local recurrence rates and poorer overall survival of patients with rectal cancer, multimodality management is important. In the early 1990s, the standard of care following surgical resection for full thickness (T3–4) or lymph node positive rectal cancer was postoperative chemoradiotherapy as it was found to improve both local control and OS compared with surgery alone [77, 78]. Recently, preoperative chemoradiotherapy has become the treatment of choice for full thickness rectal cancers prior to total mesorectal excision based on a randomized clinical trial conducted by Sauer et al. Although this trial showed no difference in OS, improved local recurrence rates (6% versus 13%) were found for patients receiving preoperative 5FU-based chemoradiotherapy as compared with postoperative chemoradiotherapy [79]. Preoperative 5FU chemoradiotherapy as compared with preoperative radiation alone also has been shown to improve local recurrence rates (2.7% versus 14.6%) [80].

#### **10. Liver metastases**

The standard of care for patients with resectable liver metastases as their only site of cancer spread is changing from previous surgical resection alone to a combination of perioperative chemotherapy and surgery based on a trial conducted by Nordlinger et al [76]. This trial randomized patients with one to four potentially resectable liver metastases to either perio‐ perative chemotherapy (six cycles of FOLFOX chemotherapy both pre- and postresection) or surgery alone. The authors concluded that perioperative chemotherapy reduced the risk of events such as progressive or recurrent disease and death by 25% in eligible and resected patients without increased severe, life-threatening toxicity. The results of this trial are contro‐ versial because when all randomized patients were included in the analysis only a trend and not significance in PFS favoring the chemotherapy arm was found.

radiation and medical oncologists, as well as gastroenterologists, radiologists, pathologists, and primary care physicians. Unfortunately, despite improvements in surgical techniques and systemic therapy CRC still remains the number two cause of cancer mortality in North America. This study evaluated the usefulness of oncology assess the standardization of CRC chemotherapy and the results at the rate of recurrence and survival. The methodology has enabled the understanding of patterns used for CRC chemotherapy around the world. The results showed significant differences in patterns between countries, regions and institutions. In addition, the actual use of CRC chemotherapy may depend on the health policies of the respective governments. Schemes used are in line with the recommendations of the new guidelines, with the exception of hospital characteristics depended specialization. In first-line chemotherapy for stage IV CRC, general hospitals still favored the use of oral fluoropyrimi‐ dines, such as UFT / LV and S-1. However, the differences between general hospitals, cancer centers and university hospitals has decreased after the revision of the guidelines. In adjuvant chemotherapy for stage III CRC, cancer centers and general hospitals used similar patterns, but those that are used in different hospitals. Measures and indicators are greatly needed to evaluate and improve the quality of cancer treatment. Using market research to develop indicators for the standardization of care against cancer is a new methodology. Data not only showed evidence practice gap, but also the growing standardization of CRC affected by chemotherapy treatment guidelines. Methodology indicates a lack of standardization in the care of CRC. Oncology market research also has the potential for cost-effectiveness analyzes, such as sales data for each agent can be evaluated using the analysis system of oncology. Efforts to improve screening utilization by the general population are required to improve mortality and morbidity from CRC. Research advances in medical oncology will result in better understanding of tumor genetics and biology of the host. This will allow systemic therapy to be tailored to specific tumor molecular targets, while sparing toxicity to normal tissue. With these improvements in CRC care, the disease will be treatable with tailored medical treatments

Adjuvant Treatment in Colorectal Cancer http://dx.doi.org/10.5772/56914 319

**•** The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, the subset of patients with high-risk stage II disease who should be considered for adjuvant therapy includes patients with inadequately sampled nodes, T4

**•** The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences.

**•** When treated with adjuvant therapy, high-risk stage II patients should receive similar regimens to those recommended for stage III patients. The enrolment of resected high-risk

that are effective with low toxicity.

**13. Recommendations**

**13.1. Stage II colorectal cancer**

lesions, perforation, or poorly differentiated histology.

### **11. Targeted therapy**

Although new drug development takes years, targeted drug use can occur more quickly with advanced tests and will be a focus of future work. In addition, efforts will focus on identifying biomarkers that predict response to systemic therapy so that tailored therapy can be initiated.

With regards to the future of adjuvant systemic chemotherapy, microsatellite-instability (MSI) testing of tumor DNA may be used to identify which patients will benefit from additional therapy (i.e., predictive biomarker) [81, 82]. Approximately 15% of colon cancers exhibit MSI commonly caused by loss of DNA mismatch-repair pathways. Tumors display short repeated nucleotide sequences called microsatellites secondary to frame-shift muta‐ tions and base-pair substitutions. Recent retrospective evidence demonstrated that adju‐ vant 5FU-based chemotherapy improved OS among patients with microsatellite-stable tumors. However, there was no benefit to those patients with high MSI [83-90]. Ongoing trials are attempting to replicate these findings in a prospective manner. The clinical benefit of cetuximab, a monoclonal antibody against EGFR, varies greatly depending on tumor biology: the greatest benefit is among patients with wild-type (nonmutated) K-ras tu‐ mors. In the metastatic setting, potential predictive biomarkers of interest include K-ras, epiregulin, B-raf, PTEN, and Pi3K. Jonker et al found that mCRC patients with both high epiregulin (ligand for EGFR) gene expression and K-ras wild-type status had greater benefit from cetuximab therapy (HR for overall survival 0.43, *p* = 0.001) [94]. In addition, loss of the tumor-suppressor gene PTEN [95] and having mutated protein kinase B-raf may [96]predict for resistance to EGFR therapy such as cetuximab.

#### **12. Discussion**

Over the past decade, the prevention and treatment of colorectal cancer has rapidly evolved. To implement evidence-based care a multidisciplinary team is required including surgeons, radiation and medical oncologists, as well as gastroenterologists, radiologists, pathologists, and primary care physicians. Unfortunately, despite improvements in surgical techniques and systemic therapy CRC still remains the number two cause of cancer mortality in North America. This study evaluated the usefulness of oncology assess the standardization of CRC chemotherapy and the results at the rate of recurrence and survival. The methodology has enabled the understanding of patterns used for CRC chemotherapy around the world. The results showed significant differences in patterns between countries, regions and institutions. In addition, the actual use of CRC chemotherapy may depend on the health policies of the respective governments. Schemes used are in line with the recommendations of the new guidelines, with the exception of hospital characteristics depended specialization. In first-line chemotherapy for stage IV CRC, general hospitals still favored the use of oral fluoropyrimi‐ dines, such as UFT / LV and S-1. However, the differences between general hospitals, cancer centers and university hospitals has decreased after the revision of the guidelines. In adjuvant chemotherapy for stage III CRC, cancer centers and general hospitals used similar patterns, but those that are used in different hospitals. Measures and indicators are greatly needed to evaluate and improve the quality of cancer treatment. Using market research to develop indicators for the standardization of care against cancer is a new methodology. Data not only showed evidence practice gap, but also the growing standardization of CRC affected by chemotherapy treatment guidelines. Methodology indicates a lack of standardization in the care of CRC. Oncology market research also has the potential for cost-effectiveness analyzes, such as sales data for each agent can be evaluated using the analysis system of oncology. Efforts to improve screening utilization by the general population are required to improve mortality and morbidity from CRC. Research advances in medical oncology will result in better understanding of tumor genetics and biology of the host. This will allow systemic therapy to be tailored to specific tumor molecular targets, while sparing toxicity to normal tissue. With these improvements in CRC care, the disease will be treatable with tailored medical treatments that are effective with low toxicity.

### **13. Recommendations**

**10. Liver metastases**

318 Colorectal Cancer - Surgery, Diagnostics and Treatment

**11. Targeted therapy**

**12. Discussion**

The standard of care for patients with resectable liver metastases as their only site of cancer spread is changing from previous surgical resection alone to a combination of perioperative chemotherapy and surgery based on a trial conducted by Nordlinger et al [76]. This trial randomized patients with one to four potentially resectable liver metastases to either perio‐ perative chemotherapy (six cycles of FOLFOX chemotherapy both pre- and postresection) or surgery alone. The authors concluded that perioperative chemotherapy reduced the risk of events such as progressive or recurrent disease and death by 25% in eligible and resected patients without increased severe, life-threatening toxicity. The results of this trial are contro‐ versial because when all randomized patients were included in the analysis only a trend and

Although new drug development takes years, targeted drug use can occur more quickly with advanced tests and will be a focus of future work. In addition, efforts will focus on identifying biomarkers that predict response to systemic therapy so that tailored therapy can be initiated. With regards to the future of adjuvant systemic chemotherapy, microsatellite-instability (MSI) testing of tumor DNA may be used to identify which patients will benefit from additional therapy (i.e., predictive biomarker) [81, 82]. Approximately 15% of colon cancers exhibit MSI commonly caused by loss of DNA mismatch-repair pathways. Tumors display short repeated nucleotide sequences called microsatellites secondary to frame-shift muta‐ tions and base-pair substitutions. Recent retrospective evidence demonstrated that adju‐ vant 5FU-based chemotherapy improved OS among patients with microsatellite-stable tumors. However, there was no benefit to those patients with high MSI [83-90]. Ongoing trials are attempting to replicate these findings in a prospective manner. The clinical benefit of cetuximab, a monoclonal antibody against EGFR, varies greatly depending on tumor biology: the greatest benefit is among patients with wild-type (nonmutated) K-ras tu‐ mors. In the metastatic setting, potential predictive biomarkers of interest include K-ras, epiregulin, B-raf, PTEN, and Pi3K. Jonker et al found that mCRC patients with both high epiregulin (ligand for EGFR) gene expression and K-ras wild-type status had greater benefit from cetuximab therapy (HR for overall survival 0.43, *p* = 0.001) [94]. In addition, loss of the tumor-suppressor gene PTEN [95] and having mutated protein kinase B-raf may

Over the past decade, the prevention and treatment of colorectal cancer has rapidly evolved. To implement evidence-based care a multidisciplinary team is required including surgeons,

not significance in PFS favoring the chemotherapy arm was found.

[96]predict for resistance to EGFR therapy such as cetuximab.

#### **13.1. Stage II colorectal cancer**


stage II patients in clinical trials is encouraged. Additional trials comparing adjuvant therapy with observation are needed and are ethically acceptable in stage II colon cancer.

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[2] Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, et al. The annual report to the nation on the status of cancer, 1973-1997, with a special section on color‐

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#### **13.2. Stage III colorectal cancer**

It could be recommended that patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy and that this treatment should start within eight weeks of surgery. Treatment should depend on factors such as patient suitability and preference, and patients and clinicians must work together to determine the optimal course of treatment. The recommended treatment option is:


Suitable patients should be offered entry into clinical trials testing new adjuvant treatments for resected stage III colon cancer.

## **Author details**

Krassimir Ivanov1 , Nikola Kolev1 , Ivan Shterev2 , Anton Tonev1 , Valentin Ignatov1 , Vasil Bojkov4 and Tanya Kirilova3

1 Department of General and Operative Surgery, University Hospital "St. Marina", Varna, Bulgaria

2 Department of Medical Oncology, University Hospital "St. Marina", Varna, Bulgaria

3 Department of Gastroenterology, University Hospital "St. Marina", Varna, Bulgaria

4 Department of Surgery, University Hospital "St. Marina", Varna, Bulgaria

## **References**

stage II patients in clinical trials is encouraged. Additional trials comparing adjuvant therapy with observation are needed and are ethically acceptable in stage II colon cancer.

It could be recommended that patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy and that this treatment should start within eight weeks of surgery. Treatment should depend on factors such as patient suitability and preference, and patients and clinicians must work together to determine the optimal course of treatment. The

**•** 5-FU given intravenously in combination with leucovorin (LV) and oxaliplatin in the regimens known as FOLFOX or FLOX. These 5-FU/LV/oxaliplatin regimens have demon‐ strated superior DFS when compared with 5-FU plus LV and are the recommended regimens. Oxaliplatin administration is associated with a 1% risk of persistent grade 3 neuropathy that needs to be considered in conjunction with expected benefits of therapy. **•** Some patients would not be considered appropriate for oxaliplatin regimens. Examples include patients with underlying neurologic conditions or at increased risk of neuropathy, patients at increased risk for infections, and patients likely to poorly tolerate infections as a

**•** Oral capecitabine administered for six months, which has equivalent efficacy to intravenous 5-FU/LV. Capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/ vomiting, and alopecia but significantly more hand-foot syndrome when compared with 5-

**•** 5-FU in combination with LV administered for six months using either the weekly or

Suitable patients should be offered entry into clinical trials testing new adjuvant treatments

1 Department of General and Operative Surgery, University Hospital "St. Marina", Varna,

2 Department of Medical Oncology, University Hospital "St. Marina", Varna, Bulgaria

3 Department of Gastroenterology, University Hospital "St. Marina", Varna, Bulgaria

4 Department of Surgery, University Hospital "St. Marina", Varna, Bulgaria

, Anton Tonev1

, Valentin Ignatov1

,

, Ivan Shterev2

result of chemotherapy. For these patients, the treatment options are:

**13.2. Stage III colorectal cancer**

320 Colorectal Cancer - Surgery, Diagnostics and Treatment

recommended treatment option is:

FU/LV.

monthly schedule.

**Author details**

Krassimir Ivanov1

Vasil Bojkov4

Bulgaria

for resected stage III colon cancer.

, Nikola Kolev1

and Tanya Kirilova3


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**Section 5**

**Genomics**


**Section 5**

## **Genomics**

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**Chapter 14**

**Possible Role of**

http://dx.doi.org/10.5772/57380

**1. Introduction**

**Proto-Oncogenes in Colorectal**

**Cancer — A Population Based Study**

Syed Mudassar, Mosin S Khan, Nighat P. Khan, Mahboob ul- Hussain and Khurshid I. Andrabi

Additional information is available at the end of the chapter

Cancer is not just one disease, but a generic term used to encompass a group of more than two hundred diseases sharing common characteristics. From a clinical point of view, cancer is a large group of diseases, that vary in their age of onset, rate of growth, state of cellular differ‐ entiation, diagnostic detectability, invasiveness, metastatic potential, response to treatment, and prognosis. From a molecular and cell biological point of view, however, cancer may be a relatively small number of diseases caused by similar molecular defects in cell function resulting from common types of alterations to a cell's genes. Ultimately, cancer is a disease of abnormal gene expression. There are a number of mechanisms by which this altered gene expression occurs. These mechanisms may occur via a direct insult to DNA, such as a gene mutation, translocation, amplification, deletion, loss of heterozygosity, or via a mechanism resulting from abnormal gene transcription or translation. The overall result is an imbalance of cell replication and cell death in a tumor cell population that leads to an expansion of tumor tissue. Cancers (carcinomas) are characterized by their unregulated growth and spread of cells to other parts of the body [1,2]. Treatment of an individual diagnosed with cancer is not only dependent upon which type of malignancy (cancer) they have, but also on the extent of its spread, together with its sensitivity to treatment [3].The total care of the patient will involve assessment of their physical, psychological and social needs, so that a complete care package can be developed to support them and their carer(s) throughout the whole of their patient.

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **Chapter 14**
