**Diagnostic Modalities in Colorectal Cancer –Endoscopy, Ct and Pet Scanning, Magnetic Resonance Imaging (Mri), Endoluminal Ultrasound and Intraoperative Ultrasound**

Valentin Ignatov, Nikola Kolev, Anton Tonev, Shteryu Shterev, Elitsa Encheva, Tanya Kirilova, Tsvetelina Teneva and Krassimir Ivanov

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57508

**1. Introduction**

Colorectal cancer (CRC) is the third most diagnosed cancer in men, next to prostate and lung cancer. In women it is the second most diagnosed cancer, next to breast cancer. In a time of limited resources in health care, there has been considerable debate which imaging modality offers the best non-invasive examination of colorectal cancer, offering both detection and characterization. The use of multiple diagnostic modalities is both costly and time-consuming. Clinical evidence amassed over the last several decades indicates that routine colorectal cancer (CRC) screening, compared to no screening, detects CRC at an earlier stage, reduces the incidence of CRC or the progression early CRC through polypectomy, and reduces CRC mortality.

## **2. Endoscopy**

The first complete examination of the colon using a flexible fiber optic endoscope is reported by Wolff and Shinya in 1971 [42]. Nowadays colonoscopy is the gold standard for evaluation of the entire colonic mucosa with therapeutic capability of resecting detected malignancies.

In the last years the colonoscopy is the modality of choice to detect and correct the adenomatous polyps and colorectal cancer. The diagnosis CRC can be confirmed after biopsy in a known

© 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.

malignant pathology and by obtaining more tissue sampling and/or a second opinion from a consulting pathologist in none diagnostic, highly suspected colon lesion. Besides the role as a diagnostic tool in CRC, colonoscopy identifies subsequent lesions at the time of surgery, which is called preoperative endoscopic marking. It is performed through metallic clip placement and endoscopic tattooing.

colon model, interpretation of the 2D image slices at transverse, sagital and coronal directions

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The virtual colonoscopy achieves higher sensitivity and specificity rates compared to conven‐ tional colonoscopy for detecting polyps, which are 8 mm and larger by the same bowel preparation, and for polyps larger than 10 mm they have a comparable performance. CTC can be a potential screening tool to supplement OC for colorectal cancer. CTC is refused to be included in Medicare coverage because of its radiation risk- in about 50 mAs or 2 rads. Reducing the radiation could be achieved by decreasing of the mAs level optimization of kVp value, X-ray flux beam collimation, filtering, etc. The low-mAs strategy will lead to higher noise in the acquired data which results in steak artifacts. The significant amount of X-ray radiation exposure and the data noise cannot be disregarded and allowed to the CTC to be a

An alternative method to minimize the radiation is to use magnetic resonance imaging (MRI), i.e., MR colonography (MRC). However, this MRC has several limitation compared to CTChigh costs, sensitiveness to motion and other artifacts, and has lower spatial resolution. Modern CT can reach sub-millimeter spatial resolution and acquire a volumetric image of the

The main reason is due to the partial colon cleansing and air/CO2 inflation and this will not generate a good interface between the colon wall and the lumen. Others include loss of image information in post-imaging processing, different anatomical characteristics in the bowel mucosa, residual fluid or stool covering the polyps. The solution could be virtual or electronic colon cleansing (ECC) - special type of software programming for virtually cleansing of the colon. It consists of three main components - (1) fecal tagging, (2) image segmentation for classifying the tagged image voxels, and (3) post-segmentation operation for cleansing the colon. ECC works virtually on the residual faecal materials with or without adequate bowel preparation with purgatives (the so called cathartic-free CTC). The ECC must handle with the partial volume (PV) effect and with the non-uniformly altered image intensity distribution. Partial volume (PV) effect is the interface between the colon wall and the fecal materials with heterogeneously enhanced image intensities. The PV effect blurs the interface over several image voxels, causing the loss of details about the interface what results in the misdetection of small polyps. A dual energy scans of a modern CT device or a dual X-ray source scanner is a new challenging imagining modality. Two volumetric images can be acquired simultane‐ ously at two energy levels. It is expected that the polyps would have different image contrasts in the two scans and if the contrasts are insufficient for segmenting the image voxels, oral contrast media may be utilized to increase the density of the polyps. The ECC role in this dual energy strategy is to segment the colonic materials from multi-spectral CT images. After ECCcleansing the colon lumen could be easily inspected for abnormalities and polyps along the

Variation among readers with different experience has been noticed. Computer-aided detection (CAD) can minimize the variation among readers' assessments. CAD system's

is often included in the procedure.

preferred screening modality.

abdomen, detecting polyps which are smaller than 5mm.

long colon during the fly-through navigation.

There are other reasons responsibe for missing small polyps.

The colonoscopic equipment consists of camera and four-way tip controls [43]. The camera can produce images of high-definition quality. The four way tip controls include (1) exami‐ nation of a found patch to confirm an abnormal growth; (2) insufflating air to dilate the lumen for mucosal inspection and relieving air after examination, (3) irrigating a suspected region; (4) suctioning to avoid missing lesions under fluid, and (5) inserting biopsy devices.

The patient must undergo bowel preparation - taking clear liquid diet and ingesting laxative solutions for colon cleansing the day before examination. Sedation is needed to relieve the discomfort during the procedure, but it increases the costs. The complication of sedation are different cardiac disturbances such as hypotension, arrhythmias,oxygen desaturation, and others. The preparation with purgatives may cause abdominal discomfort, nausea, and other symptoms. The colonoscopy continues from 30 minutes to an hour. The risk during colono‐ scopy consists in colonic perforation in 0,1 % of cases. Colonoscopy fails to visualize the entire colon in 10–15% and it may miss up to 10–20% of polyps fewer than 10 mm.

Colonoscopy is golden standard for diagnosing of CRC but there are more symptoms which could be evaluated and appreciated by endoscopic examination, for example- abdominal pain, unexplained gastrointestinal bleeding, diarrhea of unexplained origin, chronic inflammatory bowel disease, etc. It is also the most common interventional modality for polypectomy, hemostasis, balloon dilation, foreign body removal, palliative treatment of neoplasms, etc. Colonoscopy could be the best screening option for all none specific underdiagnosed gastro‐ intestinal symptoms.

Colonoscopy removes all detected polyps, regardless of histology type- adenomatous or hyperplastic. Not all of them must undergo resection. The polyps vary in size and polyps under 5 mm are not detected endoscopic. For detection of polyps smaller than 5 mm the virtual colonospcopy is the alternative to the conventional colonoscopy.

## **3. Virtual colonoscopy**

Virtual Colonoscopy uses computed tomography (CT) imaging virtual- reality technology for the purpose of screening the entire colon which is reconstructed from abdominal CT images.

The technique starts after cleansing of the colon with oral laxatives with inflation of air or CO2 introduced through rectal tube [71]. Then abdominal CT images are taken during a single breath holding with sub mm resolution in axial and transverse directions. The volume model of the colon is constructed from the spiral CT images. Image segmentation is necessary for the reconstruction of an accurate colon model [72]. Computer graphics navigate inside the 3D colon model, the navigation is called fly through model. For validating the detection in the 3D colon model, interpretation of the 2D image slices at transverse, sagital and coronal directions is often included in the procedure.

The virtual colonoscopy achieves higher sensitivity and specificity rates compared to conven‐ tional colonoscopy for detecting polyps, which are 8 mm and larger by the same bowel preparation, and for polyps larger than 10 mm they have a comparable performance. CTC can be a potential screening tool to supplement OC for colorectal cancer. CTC is refused to be included in Medicare coverage because of its radiation risk- in about 50 mAs or 2 rads. Reducing the radiation could be achieved by decreasing of the mAs level optimization of kVp value, X-ray flux beam collimation, filtering, etc. The low-mAs strategy will lead to higher noise in the acquired data which results in steak artifacts. The significant amount of X-ray radiation exposure and the data noise cannot be disregarded and allowed to the CTC to be a preferred screening modality.

An alternative method to minimize the radiation is to use magnetic resonance imaging (MRI), i.e., MR colonography (MRC). However, this MRC has several limitation compared to CTChigh costs, sensitiveness to motion and other artifacts, and has lower spatial resolution. Modern CT can reach sub-millimeter spatial resolution and acquire a volumetric image of the abdomen, detecting polyps which are smaller than 5mm.

There are other reasons responsibe for missing small polyps.

malignant pathology and by obtaining more tissue sampling and/or a second opinion from a consulting pathologist in none diagnostic, highly suspected colon lesion. Besides the role as a diagnostic tool in CRC, colonoscopy identifies subsequent lesions at the time of surgery, which is called preoperative endoscopic marking. It is performed through metallic clip placement

The colonoscopic equipment consists of camera and four-way tip controls [43]. The camera can produce images of high-definition quality. The four way tip controls include (1) exami‐ nation of a found patch to confirm an abnormal growth; (2) insufflating air to dilate the lumen for mucosal inspection and relieving air after examination, (3) irrigating a suspected region;

The patient must undergo bowel preparation - taking clear liquid diet and ingesting laxative solutions for colon cleansing the day before examination. Sedation is needed to relieve the discomfort during the procedure, but it increases the costs. The complication of sedation are different cardiac disturbances such as hypotension, arrhythmias,oxygen desaturation, and others. The preparation with purgatives may cause abdominal discomfort, nausea, and other symptoms. The colonoscopy continues from 30 minutes to an hour. The risk during colono‐ scopy consists in colonic perforation in 0,1 % of cases. Colonoscopy fails to visualize the entire

Colonoscopy is golden standard for diagnosing of CRC but there are more symptoms which could be evaluated and appreciated by endoscopic examination, for example- abdominal pain, unexplained gastrointestinal bleeding, diarrhea of unexplained origin, chronic inflammatory bowel disease, etc. It is also the most common interventional modality for polypectomy, hemostasis, balloon dilation, foreign body removal, palliative treatment of neoplasms, etc. Colonoscopy could be the best screening option for all none specific underdiagnosed gastro‐

Colonoscopy removes all detected polyps, regardless of histology type- adenomatous or hyperplastic. Not all of them must undergo resection. The polyps vary in size and polyps under 5 mm are not detected endoscopic. For detection of polyps smaller than 5 mm the virtual

Virtual Colonoscopy uses computed tomography (CT) imaging virtual- reality technology for the purpose of screening the entire colon which is reconstructed from abdominal CT images. The technique starts after cleansing of the colon with oral laxatives with inflation of air or CO2 introduced through rectal tube [71]. Then abdominal CT images are taken during a single breath holding with sub mm resolution in axial and transverse directions. The volume model of the colon is constructed from the spiral CT images. Image segmentation is necessary for the reconstruction of an accurate colon model [72]. Computer graphics navigate inside the 3D colon model, the navigation is called fly through model. For validating the detection in the 3D

(4) suctioning to avoid missing lesions under fluid, and (5) inserting biopsy devices.

colon in 10–15% and it may miss up to 10–20% of polyps fewer than 10 mm.

colonospcopy is the alternative to the conventional colonoscopy.

and endoscopic tattooing.

30 Colorectal Cancer - Surgery, Diagnostics and Treatment

intestinal symptoms.

**3. Virtual colonoscopy**

The main reason is due to the partial colon cleansing and air/CO2 inflation and this will not generate a good interface between the colon wall and the lumen. Others include loss of image information in post-imaging processing, different anatomical characteristics in the bowel mucosa, residual fluid or stool covering the polyps. The solution could be virtual or electronic colon cleansing (ECC) - special type of software programming for virtually cleansing of the colon. It consists of three main components - (1) fecal tagging, (2) image segmentation for classifying the tagged image voxels, and (3) post-segmentation operation for cleansing the colon. ECC works virtually on the residual faecal materials with or without adequate bowel preparation with purgatives (the so called cathartic-free CTC). The ECC must handle with the partial volume (PV) effect and with the non-uniformly altered image intensity distribution. Partial volume (PV) effect is the interface between the colon wall and the fecal materials with heterogeneously enhanced image intensities. The PV effect blurs the interface over several image voxels, causing the loss of details about the interface what results in the misdetection of small polyps. A dual energy scans of a modern CT device or a dual X-ray source scanner is a new challenging imagining modality. Two volumetric images can be acquired simultane‐ ously at two energy levels. It is expected that the polyps would have different image contrasts in the two scans and if the contrasts are insufficient for segmenting the image voxels, oral contrast media may be utilized to increase the density of the polyps. The ECC role in this dual energy strategy is to segment the colonic materials from multi-spectral CT images. After ECCcleansing the colon lumen could be easily inspected for abnormalities and polyps along the long colon during the fly-through navigation.

Variation among readers with different experience has been noticed. Computer-aided detection (CAD) can minimize the variation among readers' assessments. CAD system's disadvantages are many false positives (FPs), such as partial bowel cleansing, image noise, motion artifacts, colon fold structures, etc. High sensitivity CAD with minimal number of FPs and development of various texture features and virtual biopsy features remains an innovative research goal.

**4. Imaging diagnostics in rectal cancer**

positively the staging of the rectal cancer.

**4.1. Endorectal ultrasound**

PET are used to distinguish fibrosis from tumor [33].

novel techniques assign excellent to rectal tumors.

disease neither MRI nor EUS enable reliable diagnosis.

evaluation varies from 60%-90% [45].

technique is operator dependent.

Staging of rectal cancer is of great importance before the surgical treatment, because staging predicts the management, prognosis, recurrence and/or metastatic disease risk (13). Staging is divided into local and distant staging. Local staging points at wall invasion, resection margin involvement and the nodal status for metastasis and distant staging refers to presence or absence of metastatic disease. Rectal examination using proctoscopy may be considered as an important tool for newly diagnosed rectal cancers. Proctoscopy may determine better visual‐ ization, localization and fixity of the tumor, including taking biopsy, which may affects

Diagnostic Modalities in Colorectal Cancer –Endoscopy, Ct and Pet Scanning, Magnetic Resonance...

http://dx.doi.org/10.5772/57508

33

Nowadays several imaging modalities or combination of these are available for evaluating preoperative staging of colorectal cancer- computed tomography (CT), magnetic resonance imaging (MRI), and/or endorectal ultrasonography (EUS). EUS and MRI of the pelvis are used to appreciate the local dissemination while CT defines systemic dissemination. PET is indi‐ cated when there is clinical, biochemical or radiological suspicion of local recurrence or systemic disease. Functional imaging such as diffusion weighted MRI imaging (DWI) and CT/

The T staging accuracy in more advanced cancer is achieved by using MR imaging modality because MRI can distinguish between mesorectum and mesorectal fascia. The N staging accuracy is also provided by MRI particularly using superparamagnetic iron oxide particles.

The advancing of imaging technologies has made endoscopic ultrasound a modality of choice in gastrointestinal diseases, regarding diagnosis, staging and prognosis stratification. These

Endorectal ultrasound (EUS) is useful in evaluating early rectal cancers (T1 and T2 lesions) and post transanal surgery. EUS can visualize the rectal wall without distinguishing of mesorectal fascia, peritumor inflammation, or faeces collections. The accuracy of the T stage

In comparison to MRI EUS was found to be highly accurate in early lesions ( for T1 and T2 the accuracy can reach to 100%), as well as for nodal metastases. For evaluation of metastatic

Besides the misleading lymph node assessment, EUS has its disadvantages in detecting T3 lesions (advanced, stenotic, bulky lesions) or tumors after neoadjuvant therapy, and the

Hypoechoic appearance, size > 5 mm, round shape, peritumoral location are characteristics suggestive of malignant involvement of lymph nodes [45,46,51-53]. EUS-guided fine-needle

An newer technique is the three-dimensional ERUS (3D-ERUS). It consists of transverse, coronal and sagittal scan and has been found to be more reliable in staging colon cancer to

aspiration can be carried out from the lesion or suspiciously looking lymph nodes.

**Figure 1.** Endoscopic view of corectal tumor – conventional endoscopy

**Figure 2.** Virtual colonoscopy – a view of pediculaneted polypus and a small carcinoma - CT images.

**Figure 3.** Virtual colonoscopy – a view of pediculaneted polypus and a small carcinoma - a 3-D reconstruction after software rendering.

## **4. Imaging diagnostics in rectal cancer**

disadvantages are many false positives (FPs), such as partial bowel cleansing, image noise, motion artifacts, colon fold structures, etc. High sensitivity CAD with minimal number of FPs and development of various texture features and virtual biopsy features remains an innovative

**Figure 1.** Endoscopic view of corectal tumor – conventional endoscopy

**Figure 2.** Virtual colonoscopy – a view of pediculaneted polypus and a small carcinoma - CT images.

**Figure 3.** Virtual colonoscopy – a view of pediculaneted polypus and a small carcinoma - a 3-D reconstruction after

research goal.

32 Colorectal Cancer - Surgery, Diagnostics and Treatment

software rendering.

Staging of rectal cancer is of great importance before the surgical treatment, because staging predicts the management, prognosis, recurrence and/or metastatic disease risk (13). Staging is divided into local and distant staging. Local staging points at wall invasion, resection margin involvement and the nodal status for metastasis and distant staging refers to presence or absence of metastatic disease. Rectal examination using proctoscopy may be considered as an important tool for newly diagnosed rectal cancers. Proctoscopy may determine better visual‐ ization, localization and fixity of the tumor, including taking biopsy, which may affects positively the staging of the rectal cancer.

Nowadays several imaging modalities or combination of these are available for evaluating preoperative staging of colorectal cancer- computed tomography (CT), magnetic resonance imaging (MRI), and/or endorectal ultrasonography (EUS). EUS and MRI of the pelvis are used to appreciate the local dissemination while CT defines systemic dissemination. PET is indi‐ cated when there is clinical, biochemical or radiological suspicion of local recurrence or systemic disease. Functional imaging such as diffusion weighted MRI imaging (DWI) and CT/ PET are used to distinguish fibrosis from tumor [33].

The T staging accuracy in more advanced cancer is achieved by using MR imaging modality because MRI can distinguish between mesorectum and mesorectal fascia. The N staging accuracy is also provided by MRI particularly using superparamagnetic iron oxide particles.

#### **4.1. Endorectal ultrasound**

The advancing of imaging technologies has made endoscopic ultrasound a modality of choice in gastrointestinal diseases, regarding diagnosis, staging and prognosis stratification. These novel techniques assign excellent to rectal tumors.

Endorectal ultrasound (EUS) is useful in evaluating early rectal cancers (T1 and T2 lesions) and post transanal surgery. EUS can visualize the rectal wall without distinguishing of mesorectal fascia, peritumor inflammation, or faeces collections. The accuracy of the T stage evaluation varies from 60%-90% [45].

In comparison to MRI EUS was found to be highly accurate in early lesions ( for T1 and T2 the accuracy can reach to 100%), as well as for nodal metastases. For evaluation of metastatic disease neither MRI nor EUS enable reliable diagnosis.

Besides the misleading lymph node assessment, EUS has its disadvantages in detecting T3 lesions (advanced, stenotic, bulky lesions) or tumors after neoadjuvant therapy, and the technique is operator dependent.

Hypoechoic appearance, size > 5 mm, round shape, peritumoral location are characteristics suggestive of malignant involvement of lymph nodes [45,46,51-53]. EUS-guided fine-needle aspiration can be carried out from the lesion or suspiciously looking lymph nodes.

An newer technique is the three-dimensional ERUS (3D-ERUS). It consists of transverse, coronal and sagittal scan and has been found to be more reliable in staging colon cancer to two-dimensional EUS and CT. The accuracy of 3D-ERUS for assessing the depth of cancer infiltration and for nodal involvement is with 10% more than the other imaging modalities. 3D images have proved a better visualization of the mesorectal margins. With 3D-ERUS the surgeon can perform endoscopic mucosal resections of early tumors. A reliable predictor for response after chemoradiation therapy are the accurate volumetric measurements achieved by 3D-ERUS. Using Doppler signal enhancers tumor perfusion can be determine, coming to better results in neoadjuvant therapy and antiangiogenesis treatment.

nodes are less than 5 mm and are located within 3 cm of the primary tumor [31]. Metastatic

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The sensitivity of ERUS in detecting LN metastasis ranges from 50% to 83%, because small lymph node (less than 5mm) is not observed with ERUS and it has limited field of view. Factors for malignancy in lymph node besides node size, echogenicity, shape, border, include:

Detecting of iliac adenopathy is crucial because it goes after total mesorectal excision. This is possible through flexible not rigid probes. In general, ERUS is better at detecting lymph nodes in the distal and middle thirds of the rectum [21,33]. The reactive swollen lymph nodes, small blood vessels, urethra, and seminal vesicle often are mistaken for malignant lymph nodes and these results in over staging of the disease. On the other hand, the major reason for nodal status under staging is misdetecting of very small involved nodes (less than 2 mm) and nodes outside

Preoperative chemoradiation is a limiting factor affecting accurate staging of rectal cancer. There are associated reactive and inflammatory changes in the rectum wall after radiotherapy. However, radiotherapy affects the wall thickness but does not change the five-layered image.

The 3D reconstruction allows improved T and N staging through direct visualization of subtle

Limitations of ERUS are several. Firstly it is operator's experience dependent; it varies after partial excision or neoadjuvant chemoradiation. It has poor patient acceptability and it has limited depth of penetration; Another disadvantages are those that it cannot be performed in obstructive tumors [16,21]; it is unable to visualize tumors located higher with a rigid probe. It is insufficient in detecting lymph nodes outside the range of the transducer, or visualize mesorectal fascia because of its limited field of view. In addition, accuracy is affected by villous

MRI obtain image identification of the distance of the CRM to the tumor, the relation to pelvic floor and anal sphincter complex, differentiation between mucinous and none mucinous neoplasia. T staging accuracy of MRI is 52% when compared to histology, because of the interface between muscularis propria, perirectal fat and mesorectal fascia. MRI cannot

The depth of invasion through the muscle wall is one important element seen on MRI that can help guide clinical decision making for patients with rectal cancer. Not only does the inci‐ dence of nodal involvement increase with increasing tumor penetration [19,20], but clinical studies have shown that patients with stage Ⅰ (T1-2 N0) rectal cancer do not benefit from neoadjuvant radiotherapy [21] and may be amenable to a less than radical surgical treatment [22]. Patients with clinically staged T3-4 tumors typically require preoperative CRT since it re‐ duces the rates of local recurrence more effectively than either postoperative CRT or preopera‐

distinguish between T1 and T2 lesions, as well as between T2 and T3 cancer.

hypoechogenicity, short axis ≥ 5 mm, long axis length greater than 9 mm.

protrusions of tumors infiltrating into adjacent tissues and organs.

or pedunculated tumors, inflammation, hemorrhage [22,31].

disease was shown to predict local recurrence.

the perirectal tissue [21,33].

**MRI**

**T staging**

3D-ERUS, elastography, and contrast enhancement might bring additional information, increasing diagnostic accuracy of ERUS and amplifying its roles in the complex management in rectal cancer.

**Figure 4.** Endorectal ultrasonography – a view of T-3 carcinoma - 3-D reconstruction after real-time software render‐ ing.

#### *T and LN staging*

In colon cancer patients it is essential to correctly determine the TNM stage. The modalities of choice are CT, MRI and, as mentioned above, the novel technique ERUS.

ERUS shows high sensitivity and specificity in T-staging and is prior to CT and MRI for staging superficial rectal tumors, with accuracy in evaluating rectal wall invasion to 97% [23,24]. For T1, T2, T3 and T4 staging accuracy of ERUS is more than 80%. One common finding is a lower accuracy for T2 tumors, because the impossibility in distinguishing those tumors that have deep invasion into the muscularis propria from those with microscopic invasion into the perirectal fat.

Transanal endoscopic microsurgery (TEM) and endoscopic submucosal dissections are novel important strategies which directs the mode of surgery because of the ability to visualize the submucosa. This can lead to down- or upstaging of the detected rectal cancer. Besides ERUS can detect recurrence at the anastomosis site and to differentiate between postoperative scars and local recurrences. Unfortunately assessment for nodal metastases is less accurate than that for tumor depth and reaches 75%. For rectal cancer in particular, over half of the metastatic nodes are less than 5 mm and are located within 3 cm of the primary tumor [31]. Metastatic disease was shown to predict local recurrence.

The sensitivity of ERUS in detecting LN metastasis ranges from 50% to 83%, because small lymph node (less than 5mm) is not observed with ERUS and it has limited field of view. Factors for malignancy in lymph node besides node size, echogenicity, shape, border, include: hypoechogenicity, short axis ≥ 5 mm, long axis length greater than 9 mm.

Detecting of iliac adenopathy is crucial because it goes after total mesorectal excision. This is possible through flexible not rigid probes. In general, ERUS is better at detecting lymph nodes in the distal and middle thirds of the rectum [21,33]. The reactive swollen lymph nodes, small blood vessels, urethra, and seminal vesicle often are mistaken for malignant lymph nodes and these results in over staging of the disease. On the other hand, the major reason for nodal status under staging is misdetecting of very small involved nodes (less than 2 mm) and nodes outside the perirectal tissue [21,33].

Preoperative chemoradiation is a limiting factor affecting accurate staging of rectal cancer. There are associated reactive and inflammatory changes in the rectum wall after radiotherapy. However, radiotherapy affects the wall thickness but does not change the five-layered image.

The 3D reconstruction allows improved T and N staging through direct visualization of subtle protrusions of tumors infiltrating into adjacent tissues and organs.

Limitations of ERUS are several. Firstly it is operator's experience dependent; it varies after partial excision or neoadjuvant chemoradiation. It has poor patient acceptability and it has limited depth of penetration; Another disadvantages are those that it cannot be performed in obstructive tumors [16,21]; it is unable to visualize tumors located higher with a rigid probe. It is insufficient in detecting lymph nodes outside the range of the transducer, or visualize mesorectal fascia because of its limited field of view. In addition, accuracy is affected by villous or pedunculated tumors, inflammation, hemorrhage [22,31].

#### **MRI**

two-dimensional EUS and CT. The accuracy of 3D-ERUS for assessing the depth of cancer infiltration and for nodal involvement is with 10% more than the other imaging modalities. 3D images have proved a better visualization of the mesorectal margins. With 3D-ERUS the surgeon can perform endoscopic mucosal resections of early tumors. A reliable predictor for response after chemoradiation therapy are the accurate volumetric measurements achieved by 3D-ERUS. Using Doppler signal enhancers tumor perfusion can be determine, coming to

3D-ERUS, elastography, and contrast enhancement might bring additional information, increasing diagnostic accuracy of ERUS and amplifying its roles in the complex management

**Figure 4.** Endorectal ultrasonography – a view of T-3 carcinoma - 3-D reconstruction after real-time software render‐

In colon cancer patients it is essential to correctly determine the TNM stage. The modalities of

ERUS shows high sensitivity and specificity in T-staging and is prior to CT and MRI for staging superficial rectal tumors, with accuracy in evaluating rectal wall invasion to 97% [23,24]. For T1, T2, T3 and T4 staging accuracy of ERUS is more than 80%. One common finding is a lower accuracy for T2 tumors, because the impossibility in distinguishing those tumors that have deep invasion into the muscularis propria from those with microscopic invasion into the

Transanal endoscopic microsurgery (TEM) and endoscopic submucosal dissections are novel important strategies which directs the mode of surgery because of the ability to visualize the submucosa. This can lead to down- or upstaging of the detected rectal cancer. Besides ERUS can detect recurrence at the anastomosis site and to differentiate between postoperative scars and local recurrences. Unfortunately assessment for nodal metastases is less accurate than that for tumor depth and reaches 75%. For rectal cancer in particular, over half of the metastatic

choice are CT, MRI and, as mentioned above, the novel technique ERUS.

better results in neoadjuvant therapy and antiangiogenesis treatment.

in rectal cancer.

34 Colorectal Cancer - Surgery, Diagnostics and Treatment

ing.

*T and LN staging*

perirectal fat.

MRI obtain image identification of the distance of the CRM to the tumor, the relation to pelvic floor and anal sphincter complex, differentiation between mucinous and none mucinous neoplasia. T staging accuracy of MRI is 52% when compared to histology, because of the interface between muscularis propria, perirectal fat and mesorectal fascia. MRI cannot distinguish between T1 and T2 lesions, as well as between T2 and T3 cancer.

#### **T staging**

The depth of invasion through the muscle wall is one important element seen on MRI that can help guide clinical decision making for patients with rectal cancer. Not only does the inci‐ dence of nodal involvement increase with increasing tumor penetration [19,20], but clinical studies have shown that patients with stage Ⅰ (T1-2 N0) rectal cancer do not benefit from neoadjuvant radiotherapy [21] and may be amenable to a less than radical surgical treatment [22]. Patients with clinically staged T3-4 tumors typically require preoperative CRT since it re‐ duces the rates of local recurrence more effectively than either postoperative CRT or preopera‐

by marking the outer surface (i.e. the CRM) with ink, taking serial cuts through the specimen and examining the macroscopic and microscopic relations between the tumor and the inked margin. The CRM gives significant information not only about the quality of the performed operation but also prognosis of the disease. Indeed, in a recent study based on the data from a randomized clinical trial, Nagtegaal *et al* [31] demonstrated in a multivariate model that the CRM is more important than the T stage for the prognosis of rectal cancer. The definition of a positive CRM remains a matter of debate. A review of the literature in 2006 showed that the majority of studies that dealt with CRM status used the ≤ 1 mm definition for positive CRM

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Six distinct types of CRM involvement have been described; direct tumor spread which occurs in 18% to 29% of cases; discontinuous tumor spread in 14% to 67% of cases; lymph node metastases in 12% to 14% of cases; venous invasion in 14% to 57% of cases; lymphatic invasion in 9% of cases; and perineural tumor spread in 7% to 14% of cases [32]. In approximately 30% of patients, there is more than one type of margin involvement. In contrast to direct tumor spread, the involvement of the CRM by lymph node metastases is not associated with local recurrence [32]. MRI is highly accurate and reliable for prediction of the CRM [33,34]. In their most recent study of 98 rectal cancer patients, Brown *et al* [27] reported a 92% agreement between MRI images and histologic findings for prediction of CRM involvement. In another study assessing the tumor relationship to the mesorectal fascia, two observers independently scored the tumor stage and the distance to the mesorectal fascia on MRI and compared these observations with the final histological findings [26]. For twelve tumors with involved mesorectal fascia, and thus, a CRM of 0 mm, the accuracy in predicting the CRM was 100% for both readers. In 29 patients with a wide CRM (10 mm), the accuracy for predicting the negative margin was 97% (27 of 28) for one reader and 93% (26 of 28) for the other [26]. It is relevant to point out that 5 mm of mesorectal tissue surrounding the lateral tumor edge on MRI was shown to equal a CRM of 2 mm in the surgical specimen [26]. In the report by Nagtegaal *et al* [35], a linear regression curve showed that the crucial distance of at least 2 mm could be predicted with 97% confidence when the distance on MRI is at least 6 mm. Therefore, the safe rule to predict CRM involvement on MRI is considered to be an MRI measurement minus 4 mm due to shrinkage of the specimen with fixation [6]. Of note, the CRM becomes more difficult to identify in low, anterior tumors and in patients with a limited amount of perirectal fat [36]*.* In a recent study by Frasson *et al* [37], the 5-year local recurrence rates for patients with a preoperative CRM of < 2 mm on MRI or EUS who did not receive preoperative chemoradiation was 19.4% compared to 5.4% for patients with a non-threatened margin. It is important to realize that a short course of preoperative radiotherapy has limited ability to control positive CRM. An analysis of more than 17 500 pathologic specimens by Nagtegaal *et al* [32] revealed that the chance of local recurrence was higher for patients with a positive CRM after neoad‐ juvant treatment (both radiotherapy and radiochemotherapy) than those with a positive CRM following immediate surgery (Hazard ratio 6.3 *vs* 2.0, respectively). Similar results have been reported following postoperative treatment [38]. In the MRC CR-07 trial, patients with positive radial margins who were selected to receive postoperative chemoradiation had a 21% local recurrence rate [39]. Thus, in cases where the tumors are close (< 2 mm) or through the mesorectal margin on preoperative MRI, a more aggressive treatment regimen is required with

(91.1%; 7373 of 8094 patients) [32].

**Figure 5.** Endorectal ultrasonography – a real time 3-D reconstruction with different options for endorectal evaluation of the tumor process.

tive radiotherapy alone [23-25]. However, some problems remain with T stage determination on MR imaging. Overall, the agreement between MRI and histology for T staging has ranged from 66%-94% [18,26-28]. One of the main problems of T staging on MRI is the distinction between T2 and T3 tumors. In fact, investigators have shown that the negative predictive value for invasion beyond the muscularis propria varied from 93% (expert reading) to 76% (general radiologist reading) [26]. This difficulty is attributed to the presence of desmoplastic reac‐ tions around the tumor. This reaction makes it difficult to distinguish between spiculation in the perirectalfat caused by fibrosis alone from that caused by fibrous tissue that contains tumor cells [26]. In contrast, MRI has been shown to be more accurate in imaging the more advanced tumors (T4)[27,29].According to ametaanalysis,MRIforT4 lesionshas a specificity of 96% [30].

#### **CRM**

The CRM (lateral, radial) is defined as the surgical cut surface of the connective tissues (i.e. lymphovascular, fatty and neural tissue) that circumferentially encase the rectum. It equates to the mesorectal fascia that forms the plane of dissection in rectal cancer surgery. It is assessed by marking the outer surface (i.e. the CRM) with ink, taking serial cuts through the specimen and examining the macroscopic and microscopic relations between the tumor and the inked margin. The CRM gives significant information not only about the quality of the performed operation but also prognosis of the disease. Indeed, in a recent study based on the data from a randomized clinical trial, Nagtegaal *et al* [31] demonstrated in a multivariate model that the CRM is more important than the T stage for the prognosis of rectal cancer. The definition of a positive CRM remains a matter of debate. A review of the literature in 2006 showed that the majority of studies that dealt with CRM status used the ≤ 1 mm definition for positive CRM (91.1%; 7373 of 8094 patients) [32].

Six distinct types of CRM involvement have been described; direct tumor spread which occurs in 18% to 29% of cases; discontinuous tumor spread in 14% to 67% of cases; lymph node metastases in 12% to 14% of cases; venous invasion in 14% to 57% of cases; lymphatic invasion in 9% of cases; and perineural tumor spread in 7% to 14% of cases [32]. In approximately 30% of patients, there is more than one type of margin involvement. In contrast to direct tumor spread, the involvement of the CRM by lymph node metastases is not associated with local recurrence [32]. MRI is highly accurate and reliable for prediction of the CRM [33,34]. In their most recent study of 98 rectal cancer patients, Brown *et al* [27] reported a 92% agreement between MRI images and histologic findings for prediction of CRM involvement. In another study assessing the tumor relationship to the mesorectal fascia, two observers independently scored the tumor stage and the distance to the mesorectal fascia on MRI and compared these observations with the final histological findings [26]. For twelve tumors with involved mesorectal fascia, and thus, a CRM of 0 mm, the accuracy in predicting the CRM was 100% for both readers. In 29 patients with a wide CRM (10 mm), the accuracy for predicting the negative margin was 97% (27 of 28) for one reader and 93% (26 of 28) for the other [26]. It is relevant to point out that 5 mm of mesorectal tissue surrounding the lateral tumor edge on MRI was shown to equal a CRM of 2 mm in the surgical specimen [26]. In the report by Nagtegaal *et al* [35], a linear regression curve showed that the crucial distance of at least 2 mm could be predicted with 97% confidence when the distance on MRI is at least 6 mm. Therefore, the safe rule to predict CRM involvement on MRI is considered to be an MRI measurement minus 4 mm due to shrinkage of the specimen with fixation [6]. Of note, the CRM becomes more difficult to identify in low, anterior tumors and in patients with a limited amount of perirectal fat [36]*.* In a recent study by Frasson *et al* [37], the 5-year local recurrence rates for patients with a preoperative CRM of < 2 mm on MRI or EUS who did not receive preoperative chemoradiation was 19.4% compared to 5.4% for patients with a non-threatened margin. It is important to realize that a short course of preoperative radiotherapy has limited ability to control positive CRM. An analysis of more than 17 500 pathologic specimens by Nagtegaal *et al* [32] revealed that the chance of local recurrence was higher for patients with a positive CRM after neoad‐ juvant treatment (both radiotherapy and radiochemotherapy) than those with a positive CRM following immediate surgery (Hazard ratio 6.3 *vs* 2.0, respectively). Similar results have been reported following postoperative treatment [38]. In the MRC CR-07 trial, patients with positive radial margins who were selected to receive postoperative chemoradiation had a 21% local recurrence rate [39]. Thus, in cases where the tumors are close (< 2 mm) or through the mesorectal margin on preoperative MRI, a more aggressive treatment regimen is required with

tive radiotherapy alone [23-25]. However, some problems remain with T stage determination on MR imaging. Overall, the agreement between MRI and histology for T staging has ranged from 66%-94% [18,26-28]. One of the main problems of T staging on MRI is the distinction between T2 and T3 tumors. In fact, investigators have shown that the negative predictive value for invasion beyond the muscularis propria varied from 93% (expert reading) to 76% (general radiologist reading) [26]. This difficulty is attributed to the presence of desmoplastic reac‐ tions around the tumor. This reaction makes it difficult to distinguish between spiculation in the perirectalfat caused by fibrosis alone from that caused by fibrous tissue that contains tumor cells [26]. In contrast, MRI has been shown to be more accurate in imaging the more advanced tumors (T4)[27,29].According to ametaanalysis,MRIforT4 lesionshas a specificity of 96% [30].

**Figure 5.** Endorectal ultrasonography – a real time 3-D reconstruction with different options for endorectal evaluation

The CRM (lateral, radial) is defined as the surgical cut surface of the connective tissues (i.e. lymphovascular, fatty and neural tissue) that circumferentially encase the rectum. It equates to the mesorectal fascia that forms the plane of dissection in rectal cancer surgery. It is assessed

**CRM**

of the tumor process.

36 Colorectal Cancer - Surgery, Diagnostics and Treatment

neoadjuvant CRT or an upfront regimen of chemotherapy before chemoradiation prior to operation. In contrast, patients with a free margin > 2 mm from mesorectal fascia may undergo surgery [total mesorectal excision (TME)] alone, avoiding preoperative chemoradiation. Interestingly, MRI-based therapy for CRM positive tumors was able to reduce the frequency of neoadjuvant therapy for rectal carcinoma by 35% without the risk of worsening the oncological results [40]. However, omitting preoperative chemoradiation for all CRM-negative tumors on MRI needs to be further investigated in prospective clinical trials before it is adopted as standard therapy.

failure and survival. Every center that treats patients with rectal cancer should develop a multidisciplinary team featuring a description of the MRI findings and their implementation in the treatment strategy with the aim of increasing resectability, reducing the local recurrence

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and treatment morbidity, and improving the quality of life.

**Figure 6.** MRI – a view of T-3 carcinoma - 3-D reconstruction after real-time software rendering.

**colorectal cancer**

**CT, MRI and intraoperative ultrasound for evaluation of the systematic progression in**

The morbidity rate for patients with cancer depends on the early detection of liver metastases. The presence of liver metastases makes of the primary tumour non-resectable for oncologic reasons, except for tumour palliative treatment (for example resection for obstruction of the gastrointestinal tract). For a few malignancies, as in colorectal carcinoma, resection of liver metastases has been shown to improve the survival of the patients. The hepatic metastases are divided into synchronous (i.e. occurring at the time of diagnosis of the primary tumour) and metachronous (occurring after diagnosis of the primary tumour). The surgical resection of the metastases depends on the division, number, size, regional distribution and all clinical parameters of the patient, which makes resectable only 30% of all colorectal patients with metastases. The 5-year survival rate of these patients is more than 30% in comparison to a survival of less than 5% of patients with liver metastases not amenable to liver surgery [1–4]. The goal of imaging modalities is to assess the presence or absence of liver metastases in surgical candidates. Different studies indicate ferumoxide-enhanced magnetic resonance (MR) imaging as more sensitive and specific than contrast-enhanced computed tomography (CT) in detection of hepatic metastases. The different MR pulse sequences and MR contrast media

agents makes MRI the modality of choice for non-invasive lesion characterization.

Preoperative assessment of metastatic liver involvement should be performed for all surgery candidates. This preoperative staging is conceivable by contrast-enhanced CT and/or MRI in

**Preoperative assessment of surgical candidates**

#### **N staging**

The presence of involved lymph nodes is an indicator for the likelihood of systemic disease and local recurrence [41]. Therefore node-positive disease is generally an indication for preoperative chemoradiation. However, radiological evaluation of lymph node metastatic involvement remains a challenge. Results of anatomic studies show that over half of the metastatic nodes from rectal cancer are within 3 cm of the primary tumor and are smaller than 5 mm in size [42]. With a standard TME, the perirectal nodes are removed with the primary tumor, but the internal iliac and obturator nodes are left in place. Moriya *et al* [43] reported that as many as 28% of lymph node-positive distal rectal cancers have involvement of lateral nodes and in 6% of cases, these were the only nodes involved. This means that in 6% of patients, the disease was incorrectly staged postoperatively as node-negative at TME. For pre-operative lymph node imaging, MRI at present is only moderately accurate, although this could change with advances in new MR techniques. Currently, the reported accuracy rate of MRI for nodal staging ranges from 71% to 91% [42]. On MRI, lymph nodes typically have lower signal intensity than the perirectal fat but higher signal intensity than arteries and veins. In patients with mucinous carcinoma, metastatic lymph nodes are visualized as hyperintense nodules alone or as hyperintense areas within hypointense nodules. A node is considered enlarged if the major axis length is more than 5 mm (mesorectal), 7 mm (internal iliac), 10 mm (external iliac), or 9 mm (common iliac) [44]. However, the morphological features or signal intensity of the nodes on MRI may more accurately determine metastatic involvement rather than measurement of size. Brown *et al* [45] demonstrated that an irregular border or mixed signal intensity of lymph nodes on MRI improved the specificity of predicting nodal status from 68% (based on size alone) to 97%. One of the more promising advances of MRI may be the use of new lymphographic agents that help assess tumor spread to lymph nodes. In a recent study, gadofosveset-enhanced MRI improved the specificity of nodal staging from 82% achieved with standard MRI to 97% [46]. Fusion of diffusion-weighted MR with T2-weighted images improves identification of pelvic lymph nodes compared with T2-weighted images alone. Using fusion images, 29% additional nodes were detected compared with T2-weighted images alone [47]. The improved nodal identification may aid in treatment planning.

For the vast majority of rectal carcinomas, MRI is currently the most accurate modality on which to base treatment decisions for patients with rectal cancer. Traditionally, the decision to apply preoperative treatment for rectal cancer patients has been based on the T- and Nstage. Lately, other MRI findings such as the radial distance of the tumor to the CRM and extramural vascular invasion score have been identified as important risk factors for local failure and survival. Every center that treats patients with rectal cancer should develop a multidisciplinary team featuring a description of the MRI findings and their implementation in the treatment strategy with the aim of increasing resectability, reducing the local recurrence and treatment morbidity, and improving the quality of life.

neoadjuvant CRT or an upfront regimen of chemotherapy before chemoradiation prior to operation. In contrast, patients with a free margin > 2 mm from mesorectal fascia may undergo surgery [total mesorectal excision (TME)] alone, avoiding preoperative chemoradiation. Interestingly, MRI-based therapy for CRM positive tumors was able to reduce the frequency of neoadjuvant therapy for rectal carcinoma by 35% without the risk of worsening the oncological results [40]. However, omitting preoperative chemoradiation for all CRM-negative tumors on MRI needs to be further investigated in prospective clinical trials before it is adopted

The presence of involved lymph nodes is an indicator for the likelihood of systemic disease and local recurrence [41]. Therefore node-positive disease is generally an indication for preoperative chemoradiation. However, radiological evaluation of lymph node metastatic involvement remains a challenge. Results of anatomic studies show that over half of the metastatic nodes from rectal cancer are within 3 cm of the primary tumor and are smaller than 5 mm in size [42]. With a standard TME, the perirectal nodes are removed with the primary tumor, but the internal iliac and obturator nodes are left in place. Moriya *et al* [43] reported that as many as 28% of lymph node-positive distal rectal cancers have involvement of lateral nodes and in 6% of cases, these were the only nodes involved. This means that in 6% of patients, the disease was incorrectly staged postoperatively as node-negative at TME. For pre-operative lymph node imaging, MRI at present is only moderately accurate, although this could change with advances in new MR techniques. Currently, the reported accuracy rate of MRI for nodal staging ranges from 71% to 91% [42]. On MRI, lymph nodes typically have lower signal intensity than the perirectal fat but higher signal intensity than arteries and veins. In patients with mucinous carcinoma, metastatic lymph nodes are visualized as hyperintense nodules alone or as hyperintense areas within hypointense nodules. A node is considered enlarged if the major axis length is more than 5 mm (mesorectal), 7 mm (internal iliac), 10 mm (external iliac), or 9 mm (common iliac) [44]. However, the morphological features or signal intensity of the nodes on MRI may more accurately determine metastatic involvement rather than measurement of size. Brown *et al* [45] demonstrated that an irregular border or mixed signal intensity of lymph nodes on MRI improved the specificity of predicting nodal status from 68% (based on size alone) to 97%. One of the more promising advances of MRI may be the use of new lymphographic agents that help assess tumor spread to lymph nodes. In a recent study, gadofosveset-enhanced MRI improved the specificity of nodal staging from 82% achieved with standard MRI to 97% [46]. Fusion of diffusion-weighted MR with T2-weighted images improves identification of pelvic lymph nodes compared with T2-weighted images alone. Using fusion images, 29% additional nodes were detected compared with T2-weighted images

alone [47]. The improved nodal identification may aid in treatment planning.

For the vast majority of rectal carcinomas, MRI is currently the most accurate modality on which to base treatment decisions for patients with rectal cancer. Traditionally, the decision to apply preoperative treatment for rectal cancer patients has been based on the T- and Nstage. Lately, other MRI findings such as the radial distance of the tumor to the CRM and extramural vascular invasion score have been identified as important risk factors for local

as standard therapy.

38 Colorectal Cancer - Surgery, Diagnostics and Treatment

**N staging**

**Figure 6.** MRI – a view of T-3 carcinoma - 3-D reconstruction after real-time software rendering.

#### **CT, MRI and intraoperative ultrasound for evaluation of the systematic progression in colorectal cancer**

The morbidity rate for patients with cancer depends on the early detection of liver metastases. The presence of liver metastases makes of the primary tumour non-resectable for oncologic reasons, except for tumour palliative treatment (for example resection for obstruction of the gastrointestinal tract). For a few malignancies, as in colorectal carcinoma, resection of liver metastases has been shown to improve the survival of the patients. The hepatic metastases are divided into synchronous (i.e. occurring at the time of diagnosis of the primary tumour) and metachronous (occurring after diagnosis of the primary tumour). The surgical resection of the metastases depends on the division, number, size, regional distribution and all clinical parameters of the patient, which makes resectable only 30% of all colorectal patients with metastases. The 5-year survival rate of these patients is more than 30% in comparison to a survival of less than 5% of patients with liver metastases not amenable to liver surgery [1–4].

The goal of imaging modalities is to assess the presence or absence of liver metastases in surgical candidates. Different studies indicate ferumoxide-enhanced magnetic resonance (MR) imaging as more sensitive and specific than contrast-enhanced computed tomography (CT) in detection of hepatic metastases. The different MR pulse sequences and MR contrast media agents makes MRI the modality of choice for non-invasive lesion characterization.

#### **Preoperative assessment of surgical candidates**

Preoperative assessment of metastatic liver involvement should be performed for all surgery candidates. This preoperative staging is conceivable by contrast-enhanced CT and/or MRI in

Deciding in management of rectal cancer is the differentiation of the mesorectal fasciacircumstance, which is possible using phased-array coils (confirmed from the multicentre

Diagnostic Modalities in Colorectal Cancer –Endoscopy, Ct and Pet Scanning, Magnetic Resonance...

http://dx.doi.org/10.5772/57508

41

MRI may not be the examination of choice for every patient. Patients with contraindications to MRI (e.g. implantable pacemakers), or unable to tolerate MRI (e.g. due to claustrophobia) would preferably undergo preoperative imaging with CT. Motion related imaging artifacts that can severely dampen the diagnostic quality of MRI will occur in patients who are unable

FDG PET is not a routine investigation for primary cancer due to its limited spatial resolution. PET cannot define the T-category of the primary tumor, but PET is superior to other imaging modalities in detecting of lymph node and distant metastases- an important prognostic factor. After PET-CT investigation the patient could be upstaged in 17% because of identifying unsuspected systemic and lymph node metastases. But the specificity of PET in nodal staging

The principle of positron emission tomography (PET) (and Fluoro-deoxy-glucose (FDG) used as tracer or enhancer) is based on the differential metabolic profile of tumors - higher metabolic activity, change in the tumor biology. FDG/PET is mainly useful in the assess‐ ment of local recurrence and metastases. Besides in neoplastic cells FDG accumulates in areas of inflammation, infection, in organs of increased metabolic activity such as brain, myocardium, liver or kidneys leading to false positive results. Interpretation of PET without anatomic correlation is difficult which results in necessity of fusing PET with CT images-PET-CT fusion scans are invented. This offers a detailed anatomical and functional imaging. The combination provides additional value to localize the hot spots. The false positive rates are due to other diseases and physiological processes. PET scans improve the manage‐ ment plan for rectal cancer. The addition of FDG-PET changes patient management in up to 30% of patients with potentially resectable liver metastases, mainly by detecting previously unknown extrahepatic disease. Furthermore, FDG-PET is useful in the followup of patients who underwent surgical procedures of the liver, since it is sensitive in detecting residual or relapse malignancy in scarred liver tissue following both resection and local ablative techniques. For follow-up during systemic therapy, early FDG-PET appears predictive for response to therapy. FDG-PET, computerized tomography and magnetic resonance imaging are complementary techniques in staging and restaging patients with advanced colorectal cancer. A combination of FDG-PET and CT scanning characteristics seems promising, and integrated PET/ CT is becoming more widely available, although the exact clinical value and efficacy is not yet fully established. In addition, assessment of these modalities in joint reading sessions with radiologist, nuclear medicine physician, medical and surgical oncologists significantly impacts upon patient management. This review evaluates the potential of FDG-PET and combined PET/CT in patients with colorectal liver

European MERCURY study)(21,23).

to breath hold for longer than 20 seconds.

**FDG PET in the Initial Staging of CRC**

does not be higher than multi-detector CT scan (MDCT).

metastases and discusses potential future possibilities.

**Figure 7.** Intraoperative ultrasound of the liver

most oncologic centers. All imaging modalities present different false-positive or falsenegative diagnoses- for helical CT- in 42%, intraoperative US- in 22.8%, mangafodipirenhanced MRI- in 10%, ferumoxide-enhanced MRI technique is accurate as CT during arterioportography (CTAP)- in 19%. Another study found that FDG-PET CT is the most sensitive method for detection of metastases. There is no firm statement which is the best imaging modality, further more the choice depends on local equipment, availability, and operator expertise. MDCT is preferred as a screening method for hepatic lesions because of its ability to reduce respiration-related artifacts, to shorten scan time, to perform multiphase scanning. The disadvantage is the high radiation exposure.

#### **Clinical Role of Intraoperative US**

Intraoperative US provide more diagnostic and staging information to the surgeon during hepatic resection. Intraoperative US supplies 35% more information about the lesion type, localization and expansion to adjacent tissues, relation to vascular structures, providing more specificity in the evaluation of liver lesions. In addition intraoperative US represent 25% more lesions than did preoperative US, CT, or angiography. This results in correction in disease staging, which affects the surgical management and postoperative treatment. The intraoper‐ ative US has a positive effect on patient care, surgical planning, and clinical outcome.

#### **Magnetic resonance imaging**

The standard phased array MRI produces good quality images with good contrast resolution and a relatively large field of view, so it is the modality of choice for preoperative staging of rectal primary tumor. MRI is reliable for assessment of the tumor and its locoregional exten‐ sion, for identifying recurrence and for planning radiation therapy. The disadvantage of MRI is impossibility in evaluation nodal metastases.

Deciding in management of rectal cancer is the differentiation of the mesorectal fasciacircumstance, which is possible using phased-array coils (confirmed from the multicentre European MERCURY study)(21,23).

MRI may not be the examination of choice for every patient. Patients with contraindications to MRI (e.g. implantable pacemakers), or unable to tolerate MRI (e.g. due to claustrophobia) would preferably undergo preoperative imaging with CT. Motion related imaging artifacts that can severely dampen the diagnostic quality of MRI will occur in patients who are unable to breath hold for longer than 20 seconds.

#### **FDG PET in the Initial Staging of CRC**

most oncologic centers. All imaging modalities present different false-positive or falsenegative diagnoses- for helical CT- in 42%, intraoperative US- in 22.8%, mangafodipirenhanced MRI- in 10%, ferumoxide-enhanced MRI technique is accurate as CT during arterioportography (CTAP)- in 19%. Another study found that FDG-PET CT is the most sensitive method for detection of metastases. There is no firm statement which is the best imaging modality, further more the choice depends on local equipment, availability, and operator expertise. MDCT is preferred as a screening method for hepatic lesions because of its ability to reduce respiration-related artifacts, to shorten scan time, to perform multiphase

Intraoperative US provide more diagnostic and staging information to the surgeon during hepatic resection. Intraoperative US supplies 35% more information about the lesion type, localization and expansion to adjacent tissues, relation to vascular structures, providing more specificity in the evaluation of liver lesions. In addition intraoperative US represent 25% more lesions than did preoperative US, CT, or angiography. This results in correction in disease staging, which affects the surgical management and postoperative treatment. The intraoper‐

The standard phased array MRI produces good quality images with good contrast resolution and a relatively large field of view, so it is the modality of choice for preoperative staging of rectal primary tumor. MRI is reliable for assessment of the tumor and its locoregional exten‐ sion, for identifying recurrence and for planning radiation therapy. The disadvantage of MRI

ative US has a positive effect on patient care, surgical planning, and clinical outcome.

scanning. The disadvantage is the high radiation exposure.

**Clinical Role of Intraoperative US**

**Figure 7.** Intraoperative ultrasound of the liver

40 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Magnetic resonance imaging**

is impossibility in evaluation nodal metastases.

FDG PET is not a routine investigation for primary cancer due to its limited spatial resolution. PET cannot define the T-category of the primary tumor, but PET is superior to other imaging modalities in detecting of lymph node and distant metastases- an important prognostic factor. After PET-CT investigation the patient could be upstaged in 17% because of identifying unsuspected systemic and lymph node metastases. But the specificity of PET in nodal staging does not be higher than multi-detector CT scan (MDCT).

The principle of positron emission tomography (PET) (and Fluoro-deoxy-glucose (FDG) used as tracer or enhancer) is based on the differential metabolic profile of tumors - higher metabolic activity, change in the tumor biology. FDG/PET is mainly useful in the assess‐ ment of local recurrence and metastases. Besides in neoplastic cells FDG accumulates in areas of inflammation, infection, in organs of increased metabolic activity such as brain, myocardium, liver or kidneys leading to false positive results. Interpretation of PET without anatomic correlation is difficult which results in necessity of fusing PET with CT images-PET-CT fusion scans are invented. This offers a detailed anatomical and functional imaging. The combination provides additional value to localize the hot spots. The false positive rates are due to other diseases and physiological processes. PET scans improve the manage‐ ment plan for rectal cancer. The addition of FDG-PET changes patient management in up to 30% of patients with potentially resectable liver metastases, mainly by detecting previously unknown extrahepatic disease. Furthermore, FDG-PET is useful in the followup of patients who underwent surgical procedures of the liver, since it is sensitive in detecting residual or relapse malignancy in scarred liver tissue following both resection and local ablative techniques. For follow-up during systemic therapy, early FDG-PET appears predictive for response to therapy. FDG-PET, computerized tomography and magnetic resonance imaging are complementary techniques in staging and restaging patients with advanced colorectal cancer. A combination of FDG-PET and CT scanning characteristics seems promising, and integrated PET/ CT is becoming more widely available, although the exact clinical value and efficacy is not yet fully established. In addition, assessment of these modalities in joint reading sessions with radiologist, nuclear medicine physician, medical and surgical oncologists significantly impacts upon patient management. This review evaluates the potential of FDG-PET and combined PET/CT in patients with colorectal liver metastases and discusses potential future possibilities.

#### **Suggested investigations for tumor staging of rectal cancer**

CT scanning is still the current standard for distant staging, but not to stage the local neoplasm. The combination of CT and PET offers both anatomical and functional imaging, so it is sufficient for recurrent rectal cancers. MRI and EUS should be considered as the initial modalities to stage the local tumor. For T1-T2 lesions EUS is more appropriate, whereas MRI is used in advanced rectal cancer. MRI has been shown to be highly accurate in predicting a clear circumferential resection margin in patients undergoing TME.

#### **Suggested investigation for nodal staging of rectal cancer**

Significant malignant lymph nodes (more than 1cm in diameter), in conjunction with size, shape and morphology, are identified through MRI, CT and EUS studies. The enlarged lymph node can be as a result of the inflammatory process but normal size nodes can have microme‐ tastases. Moreover the halves of nodes less than 5 mm are proved to be malignant. One novel technique involves use of a contrast media containing superparamagnetic iron oxide particles SPIO which accumulates in normal lymph nodes, but not in malignant nodes due to poor uptake. Then, using T2 weighted imaging, these nodes can be identified. Initial studies are promising but further research is needed [35].

**Figure 9.** Positron emission tomography of the body – an observation of perirectal lymphadenopathy

and in the future other modalities might be available.

CT chest for lung metastases.

Optical colonoscopy (OC) and virtual colonoscopy (VC) (i.e. CT colonoscopy and MR colono‐ scopy) are constantly developing and adapting to the new clinical needs. The optical colono‐ scopy has the advantage of being both diagnostic and therapeutic procedure for patients with positive findings on screening tests. The virtual colonoscopy is much less invasive method and can be used for mass screening because of the high prevalence of the colorectal cancer. As a screening test the VC has advantages over OC and other options such as FOBT, FIT, stool DNA testing, and DCBE. These methods can make a good combination of VC screening with OC follow-up on the positive findings. The current imaging modalities for VC are CT and MRI

Diagnostic Modalities in Colorectal Cancer –Endoscopy, Ct and Pet Scanning, Magnetic Resonance...

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43

The imaging standard for accurate diagnostics for colorectal cancer includes ultrasound (US), CT and MRI. The nuclear medicine has its role in finding extra-regional localization of the main disease by FDG-PET and FDG-PET/CT. The protocol for liver metastases includes CT as a first choice, which is followed by US. Lung-metastases are evaluated by X-ray or chest CT. The extrahepatic metastases are assessed by CT. The present guidelines could be adjusted by conducting comparative studies on different strategies for colon and rectal cancer, such as CT liver/abdomen vs. MRI liver/abdomen for liver and extrahepatic metastases, X-ray chest and

The screening of asymptomatic patients is justified due to the high prevalence of colon carcinoma and the mortality can be effectively reduced by removing adenomatous polyps. Although effective, this method consumes large resources if applied to the whole target population. The currently available screening options have limitations. The VC has the option to identify patients with adenomatous polyps. The combination of VC screening and OC

follow-up might prove as a cost-effective measure against colorectal cancer.

**5. Conclusion**

**Figure 8.** Positron emission tomography of the liver – an observation of metastasis from colorectal origin

**Figure 9.** Positron emission tomography of the body – an observation of perirectal lymphadenopathy

## **5. Conclusion**

**Suggested investigations for tumor staging of rectal cancer**

42 Colorectal Cancer - Surgery, Diagnostics and Treatment

clear circumferential resection margin in patients undergoing TME.

**Suggested investigation for nodal staging of rectal cancer**

promising but further research is needed [35].

CT scanning is still the current standard for distant staging, but not to stage the local neoplasm. The combination of CT and PET offers both anatomical and functional imaging, so it is sufficient for recurrent rectal cancers. MRI and EUS should be considered as the initial modalities to stage the local tumor. For T1-T2 lesions EUS is more appropriate, whereas MRI is used in advanced rectal cancer. MRI has been shown to be highly accurate in predicting a

Significant malignant lymph nodes (more than 1cm in diameter), in conjunction with size, shape and morphology, are identified through MRI, CT and EUS studies. The enlarged lymph node can be as a result of the inflammatory process but normal size nodes can have microme‐ tastases. Moreover the halves of nodes less than 5 mm are proved to be malignant. One novel technique involves use of a contrast media containing superparamagnetic iron oxide particles SPIO which accumulates in normal lymph nodes, but not in malignant nodes due to poor uptake. Then, using T2 weighted imaging, these nodes can be identified. Initial studies are

**Figure 8.** Positron emission tomography of the liver – an observation of metastasis from colorectal origin

Optical colonoscopy (OC) and virtual colonoscopy (VC) (i.e. CT colonoscopy and MR colono‐ scopy) are constantly developing and adapting to the new clinical needs. The optical colono‐ scopy has the advantage of being both diagnostic and therapeutic procedure for patients with positive findings on screening tests. The virtual colonoscopy is much less invasive method and can be used for mass screening because of the high prevalence of the colorectal cancer. As a screening test the VC has advantages over OC and other options such as FOBT, FIT, stool DNA testing, and DCBE. These methods can make a good combination of VC screening with OC follow-up on the positive findings. The current imaging modalities for VC are CT and MRI and in the future other modalities might be available.

The imaging standard for accurate diagnostics for colorectal cancer includes ultrasound (US), CT and MRI. The nuclear medicine has its role in finding extra-regional localization of the main disease by FDG-PET and FDG-PET/CT. The protocol for liver metastases includes CT as a first choice, which is followed by US. Lung-metastases are evaluated by X-ray or chest CT. The extrahepatic metastases are assessed by CT. The present guidelines could be adjusted by conducting comparative studies on different strategies for colon and rectal cancer, such as CT liver/abdomen vs. MRI liver/abdomen for liver and extrahepatic metastases, X-ray chest and CT chest for lung metastases.

The screening of asymptomatic patients is justified due to the high prevalence of colon carcinoma and the mortality can be effectively reduced by removing adenomatous polyps. Although effective, this method consumes large resources if applied to the whole target population. The currently available screening options have limitations. The VC has the option to identify patients with adenomatous polyps. The combination of VC screening and OC follow-up might prove as a cost-effective measure against colorectal cancer.

The challenges of VC are the associated radiation and the differentiation of the colonic materials from the colon wall. The MRI-based VC has no radiation and has better potential in differentiation of colonic materials from the colonic wall, but it has lower spatial resolution and is prone to motion artifacts. CT and MRI VC require sophisticated software processing to construct the colon model and real-time fly-through inside the lumen. More sophisticated image processing is important for the differentiation of adenomatous from hyperplastic ones. The extraction of the colon wall can be performed by the new method of electronic colon cleansing and analysis of texture features from image intensity of the wall. These processing methods are step toward computer-aided detection and diagnosis. Despite recent advances in chemotherapeutic agents, the prognosis for metastatic colon cancer remains poor. Over the past two decades, hepatic metastasectomy has emerged as a promising technique for improv‐ ing survival in patients with metastatic colon cancer and in some cases providing long-term cure. To maximize safety and efficacy of metastasectomy, appropriate pre-operative imaging is needed. Advancements in computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have led to improved detection of occult lesions and better definition of surgical anatomy. While CT, PET and MRI have a comparable sensitivity for detection of large liver metastases, MRI excels at detection of subcentimeter liver metastases compared to CT and FDG-PET, especially with the combination of diffusion weighted imaging (DWI) and hepatocyte-specific contrast agents. CT may be useful as a screening modality or in preoperative planning such as volumetric estimation of the remnant liver size or in defining preoperative arterial anatomy for hepatic artery infusion pump placement. While technologic advancements have led to unprecedented image quality and clarity, this does not replace the need for a dedicated, competent radiologist with experience in hepatic imaging.

[2] Jemal A, Siegel R, Ward E, et al. Cancer Statistics – 2008. A Cancer Journal for Clini‐

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[3] Hill M, Morrison B, Bussey H. Etiology of Adenoma Carcinoma Sequence in the

[4] Rickert R, Auerbach O, Garfinkel L, et al. Adenomatous Lesions of the Large Bowel –

[5] Grandqvist S. Distribution of Polyps of the Large Bowel in Relation to Age: A colono‐ scopic study. Scandinavian Journal of Gastroenterology (SJG) 1981;16(11):1025–1031.

[6] Stryker S, Wolff B, Culp C, et al. Natural History of Untreated Colonic Polyps. Gas‐

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962–966.

## **Author details**

Valentin Ignatov1 , Nikola Kolev1 , Anton Tonev1 , Shteryu Shterev1 , Elitsa Encheva4 , Tanya Kirilova2 , Tsvetelina Teneva3 and Krassimir Ivanov1

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


## **References**

[1] American Cancer Society. Cancer Facts & Figures 2008. Atlanta: American Cancer So‐ ciety; 2008.

[2] Jemal A, Siegel R, Ward E, et al. Cancer Statistics – 2008. A Cancer Journal for Clini‐ cians 2008;58 (1):71–96.

The challenges of VC are the associated radiation and the differentiation of the colonic materials from the colon wall. The MRI-based VC has no radiation and has better potential in differentiation of colonic materials from the colonic wall, but it has lower spatial resolution and is prone to motion artifacts. CT and MRI VC require sophisticated software processing to construct the colon model and real-time fly-through inside the lumen. More sophisticated image processing is important for the differentiation of adenomatous from hyperplastic ones. The extraction of the colon wall can be performed by the new method of electronic colon cleansing and analysis of texture features from image intensity of the wall. These processing methods are step toward computer-aided detection and diagnosis. Despite recent advances in chemotherapeutic agents, the prognosis for metastatic colon cancer remains poor. Over the past two decades, hepatic metastasectomy has emerged as a promising technique for improv‐ ing survival in patients with metastatic colon cancer and in some cases providing long-term cure. To maximize safety and efficacy of metastasectomy, appropriate pre-operative imaging is needed. Advancements in computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have led to improved detection of occult lesions and better definition of surgical anatomy. While CT, PET and MRI have a comparable sensitivity for detection of large liver metastases, MRI excels at detection of subcentimeter liver metastases compared to CT and FDG-PET, especially with the combination of diffusion weighted imaging (DWI) and hepatocyte-specific contrast agents. CT may be useful as a screening modality or in preoperative planning such as volumetric estimation of the remnant liver size or in defining preoperative arterial anatomy for hepatic artery infusion pump placement. While technologic advancements have led to unprecedented image quality and clarity, this does not replace the

need for a dedicated, competent radiologist with experience in hepatic imaging.

, Anton Tonev1

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

3 Department of Image diagnostics, University Hospital "St. Marina"- Varna, Bulgaria

4 Department of Radiology, University Hospital "St. Marina" – Varna, Bulgaria

and Krassimir Ivanov1

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

[1] American Cancer Society. Cancer Facts & Figures 2008. Atlanta: American Cancer So‐

, Shteryu Shterev1

, Elitsa Encheva4

,

**Author details**

Valentin Ignatov1

Tanya Kirilova2

Bulgaria

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ciety; 2008.

, Nikola Kolev1

44 Colorectal Cancer - Surgery, Diagnostics and Treatment

, Tsvetelina Teneva3


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line by September 24:

18046031]


**Chapter 3**

**Role of Magnetic Resonance Imaging in Locally**

This chapter will give an overview of the magnetic resonance imaging (MRI) modalities used in locally advanced rectal cancer (LARC) staging with an emphasis on the role of MRI and its

**2.** The role of MRI in diagnosis, staging, evaluation of response of neoadjuvant treatment,

This chapter will be organised in the following sections. First, in order to better define the role of MRI in LARC management, we will briefly describe the epidemiological scenario and therapeutic options, with an emphasis on issues in which MRI is relevant. Second, we will describe morphologic and functional MRI including DCE-MRI and DW-MRI. Finally, a systematic review of the literature concerning MRI, CT and PET for LARC management will

> © 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.

significance for planning an effective therapeutic strategy for the individual patient.

Specifically, the aim of this chapter is to present a brief review about: **1.** Methodologies of Magnetic Resonance Imaging in LARC staging

**i.** Dynamic Contrast Enhanced MRI (DCE-MRI)

**ii.** Diffusion Weighted MRI (DW-MRI)

**Advanced Rectal Cancer**

Antonio Avallone, Paolo Delrio,

http://dx.doi.org/10.5772/56831

**a.** Morphologic MRI

follow-up post surgery.

be presented.

**b.** Functional MRI

**1. Introduction**

Roberta Fusco, Mario Sansone, Mario Petrillo,

Fabiana Tatangelo and Antonella Petrillo

Additional information is available at the end of the chapter

## **Role of Magnetic Resonance Imaging in Locally Advanced Rectal Cancer**

Roberta Fusco, Mario Sansone, Mario Petrillo, Antonio Avallone, Paolo Delrio, Fabiana Tatangelo and Antonella Petrillo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56831

## **1. Introduction**

This chapter will give an overview of the magnetic resonance imaging (MRI) modalities used in locally advanced rectal cancer (LARC) staging with an emphasis on the role of MRI and its significance for planning an effective therapeutic strategy for the individual patient.

Specifically, the aim of this chapter is to present a brief review about:

	- **a.** Morphologic MRI
	- **b.** Functional MRI
		- **i.** Dynamic Contrast Enhanced MRI (DCE-MRI)
		- **ii.** Diffusion Weighted MRI (DW-MRI)

This chapter will be organised in the following sections. First, in order to better define the role of MRI in LARC management, we will briefly describe the epidemiological scenario and therapeutic options, with an emphasis on issues in which MRI is relevant. Second, we will describe morphologic and functional MRI including DCE-MRI and DW-MRI. Finally, a systematic review of the literature concerning MRI, CT and PET for LARC management will be presented.

## **2. Epidemiology**

Colorectal cancer is the third most common cancer worldwide [1], which includes cancers of the colon, rectum, rectosigmoid junction and anus. Specifically, in men it represents the third commonest neoplasm after prostate and lung cancers while in women it is the second major cause of morbidity and mortality, following breast cancer.

Adequate preoperative imaging of the pelvis is therefore important to identify those patients who are candidates for multimodality treatment, including preoperative chemoradiation protocols, intraoperative radiotherapy, and extended surgical resections. Much effort should be made to select patients with these advanced tumors for treatment in specialized referral centers. This has been shown to reduce morbidity and mortality and improve long-term

Role of Magnetic Resonance Imaging in Locally Advanced Rectal Cancer

http://dx.doi.org/10.5772/56831

55

Two main therapeutic options can be considered according to different pathological stages

**1.** Total mesorectal excision (TME): using this surgical technique, the rectum is resected together with all surrounding lymphatic pathways, lymph nodes, mesorectal fatty tissue, and the mesorectal fascia while the parietal pelvis fascia and the pelvic splanchnic nerves are spared. This surgical technique minimizes the chance of tumor being left inside; **2.** Adjuvant/neoadjuvant therapy: the aims of adjuvant or neoadjuvant therapy are to enable or facilitate total tumor resection even in advanced disease, to prevent local tumor

The majority of patients with primary rectal cancer have a tumor located within the mesorectal fascia, which is generally treated with total mesorectal excision (TME). Results of TME surgery are excellent with a significant reduction in local recurrences when preoperative short-term radiotherapy (5 x 5 Gy) is delivered one week prior to surgery [27]. In ≈10% of all rectal cancer patients the tumor extends into or beyond the enveloping fascia of the mesorectal compart‐

Often these tumors infiltrate adjacent structures and therefore have a higher risk to develop a

Patients with these primary locally advanced or recurrent rectal cancer are difficult to treat with surgery alone, but outcome has significantly improved using multimodality treatment. Although preoperative and adjuvant therapy is important in these patients, the mainstay of treatment in rectal cancer is complete surgical removal of the tumor. In both locally advanced and recurrent rectal cancers, this involves not only the removal of the total mesorectum, but

Although postoperative chemoradiotherapy (CRT) has long been recommended for locally advanced and node positive rectal cancer patients, preoperative treatment is now widely used worldwide. In many European centers, radiotherapy only was used as neoadjuvant treatment for locally advanced rectal cancer, but the addition of chemotherapy has recently demonstrated to improve local control in two large randomized trials [30,31]. Addition of 5-FU and leuco‐ vorin to preoperative radiation slightly increased the amount of acute toxicity in T3 to T4 resectable rectal cancer patients [32]. However, it increased the number of complete responses

Not only new chemotherapeutic drugs, but also a vascular endothelial cell growth factor- (VEGF-) specific monoclonal antibody in combination with chemoradiation was recently reported by Willet et al [32] to lead to considerable downstaging of the tumor. Other modalities

recurrence, and to minimize the risk of distant metastases.

en bloc resection of involved structures is often needed.

and decreased the local recurrence rate after 5 years.

survival rates.

ment.

local recurrence [28].

presented [13-35]:

In recent years, mortality rates have decreased due to several factors, including less exposure risk factors, more possibility of prevention and "early diagnosis" followed by an effective management of the disease. In particular, major changes in therapeutic management are given by the standardization of operative procedures and the introduction of adjuvant and neoad‐ juvant therapy [2-7], able to reduce recurrence risk and tumor size.

Cancers are characterized by profound spatial and temporal heterogeneity in their biologic characteristics. Most invasive cancers typically have alterations in cell physiology that promote malignant growth [2-7]. Rectal cancer is the result of a complex interaction between genetic and environmental factors and it is defined as a tumor whose aboral margin measured with the rigid rectoscope is 16 cm or less from the anocutaneous line. This distance serves to classify rectal cancer into tumours of the upper third (12–16 cm), the middle third (6–12 cm), and the lower third (<6 cm) [26] according to the Union for International Cancer Control (UICC).

The mesorectal fascia is an important anatomic landmark for the diagnostic evaluation of local tumor extent [26]. It is a connective tissue sheath that surrounds the rectum and the perirectal fatty tissue and acts as a natural barrier for tumor spread.

A locally advanced tumor often describes a tumor extending beyond the rectal wall with infiltration to surrounding organs or structures, and/or perforation of the visceral peritoneum. It includes bulky T3 tumors with threatened circumferential margins or T4 tumors, tumors with growth onto the peritoneal surface. A radiological T4 tumor is considered when detected growing outside the mesorectal fascia, while a T3 tumor refers to a tumor invading through muscularis propria [26].

These tumors have traditionally been looked upon as "unresectable", although previous staging, due to the wide tumor extension. However, when it is possible, these tumors cannot be resected without leaving microscopic or gross residual disease at the local site because of tumor adherence or fixation to that site.

## **3. Therapeutic options**

In LARC accurate and detailed anatomic information in tumor extent is essential not only for the selection of the patients for neoadjuvant chemotherapy and radiation therapy to achieve tumor shrinkage but also for the optimal surgical procedure planning. Moreover, the treatment for patients with locally advanced and recurrent rectal cancer differs significantly from patients with rectal cancer restricted to the mesorectum.

Adequate preoperative imaging of the pelvis is therefore important to identify those patients who are candidates for multimodality treatment, including preoperative chemoradiation protocols, intraoperative radiotherapy, and extended surgical resections. Much effort should be made to select patients with these advanced tumors for treatment in specialized referral centers. This has been shown to reduce morbidity and mortality and improve long-term survival rates.

**2. Epidemiology**

54 Colorectal Cancer - Surgery, Diagnostics and Treatment

muscularis propria [26].

**3. Therapeutic options**

tumor adherence or fixation to that site.

with rectal cancer restricted to the mesorectum.

Colorectal cancer is the third most common cancer worldwide [1], which includes cancers of the colon, rectum, rectosigmoid junction and anus. Specifically, in men it represents the third commonest neoplasm after prostate and lung cancers while in women it is the second major

In recent years, mortality rates have decreased due to several factors, including less exposure risk factors, more possibility of prevention and "early diagnosis" followed by an effective management of the disease. In particular, major changes in therapeutic management are given by the standardization of operative procedures and the introduction of adjuvant and neoad‐

Cancers are characterized by profound spatial and temporal heterogeneity in their biologic characteristics. Most invasive cancers typically have alterations in cell physiology that promote malignant growth [2-7]. Rectal cancer is the result of a complex interaction between genetic and environmental factors and it is defined as a tumor whose aboral margin measured with the rigid rectoscope is 16 cm or less from the anocutaneous line. This distance serves to classify rectal cancer into tumours of the upper third (12–16 cm), the middle third (6–12 cm), and the lower third (<6 cm) [26] according to the Union for International Cancer Control (UICC).

The mesorectal fascia is an important anatomic landmark for the diagnostic evaluation of local tumor extent [26]. It is a connective tissue sheath that surrounds the rectum and the perirectal

A locally advanced tumor often describes a tumor extending beyond the rectal wall with infiltration to surrounding organs or structures, and/or perforation of the visceral peritoneum. It includes bulky T3 tumors with threatened circumferential margins or T4 tumors, tumors with growth onto the peritoneal surface. A radiological T4 tumor is considered when detected growing outside the mesorectal fascia, while a T3 tumor refers to a tumor invading through

These tumors have traditionally been looked upon as "unresectable", although previous staging, due to the wide tumor extension. However, when it is possible, these tumors cannot be resected without leaving microscopic or gross residual disease at the local site because of

In LARC accurate and detailed anatomic information in tumor extent is essential not only for the selection of the patients for neoadjuvant chemotherapy and radiation therapy to achieve tumor shrinkage but also for the optimal surgical procedure planning. Moreover, the treatment for patients with locally advanced and recurrent rectal cancer differs significantly from patients

cause of morbidity and mortality, following breast cancer.

fatty tissue and acts as a natural barrier for tumor spread.

juvant therapy [2-7], able to reduce recurrence risk and tumor size.

Two main therapeutic options can be considered according to different pathological stages presented [13-35]:


The majority of patients with primary rectal cancer have a tumor located within the mesorectal fascia, which is generally treated with total mesorectal excision (TME). Results of TME surgery are excellent with a significant reduction in local recurrences when preoperative short-term radiotherapy (5 x 5 Gy) is delivered one week prior to surgery [27]. In ≈10% of all rectal cancer patients the tumor extends into or beyond the enveloping fascia of the mesorectal compart‐ ment.

Often these tumors infiltrate adjacent structures and therefore have a higher risk to develop a local recurrence [28].

Patients with these primary locally advanced or recurrent rectal cancer are difficult to treat with surgery alone, but outcome has significantly improved using multimodality treatment. Although preoperative and adjuvant therapy is important in these patients, the mainstay of treatment in rectal cancer is complete surgical removal of the tumor. In both locally advanced and recurrent rectal cancers, this involves not only the removal of the total mesorectum, but en bloc resection of involved structures is often needed.

Although postoperative chemoradiotherapy (CRT) has long been recommended for locally advanced and node positive rectal cancer patients, preoperative treatment is now widely used worldwide. In many European centers, radiotherapy only was used as neoadjuvant treatment for locally advanced rectal cancer, but the addition of chemotherapy has recently demonstrated to improve local control in two large randomized trials [30,31]. Addition of 5-FU and leuco‐ vorin to preoperative radiation slightly increased the amount of acute toxicity in T3 to T4 resectable rectal cancer patients [32]. However, it increased the number of complete responses and decreased the local recurrence rate after 5 years.

Not only new chemotherapeutic drugs, but also a vascular endothelial cell growth factor- (VEGF-) specific monoclonal antibody in combination with chemoradiation was recently reported by Willet et al [32] to lead to considerable downstaging of the tumor. Other modalities such as the use of intensity-modulated radiotherapy (IMRT), which has the potential of more accurate delivery of higher radiotherapy dosages, thus avoiding the damage of critical structures surrounding the tumor, are being tested in rectal cancer.

Among the imaging methods available Magnetic Resonance Imaging (MRI) is currently the modality of choice because of its capacity to perform local staging, since it enables evaluation of anatomic aspects and prognostic factors that are key to choosing the appropriate surgical

Role of Magnetic Resonance Imaging in Locally Advanced Rectal Cancer

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57

MRI is an imaging technique based on the different magnetic properties of tissues in the body. The exposure to a high intensity magnetic field determines the alignment of the hydrogen nuclei (protons) along the magnetic field axis itself. The emission of radio frequency pulses causes a shift from this alignment, which tends to reconstitute as soon as the impulse is interrupted. This phenomenon leads to a variation in energy level of the charges, which can be translated into a signal whose decoding is the basis of the generation of magnetic resonance images. All this is based on specific parameters that describe these steps of energy levels (including the so-called "relaxation times T1 and T2"), as well as on the concentration of protons

Pulses sequences are used to obtain the different MR images, sequences consisting of radio frequency pulses with different characteristics in terms of duration, frequency and type of

In the various biological tissues, the characteristics of the magnetic resonance signal are influenced mainly by the content of hydrogen atoms (whose nuclei are composed of only one proton). Since water is the most abundant molecule in the body and contains hydrogen atoms, it can be reasonably stated that the increase or the decrease of water in a given tissue is almost always at the basis of changes in signal intensity when using sequences of magnetic resonance

Where tissue contrast depends primarily on electron density, the tissue contrast obtained by MRI can be extensively varied by imaging the intrinsic tissue properties, as spin-lattice and spin-spin relaxation times, protons density, magnetization transfer, separately or in combina‐ tion, using a number of pulse sequences, which in turn can be altered by an essentially infinite number of different experimental conditions. These MR parameters can be exploited and tailored to facilitate optimal tumor visualization and evaluation. Another feature of MRI is that cortical bone does not give rise to an MR signal and therefore appears hypointense. This is because cortical bone contains calcium and there are few hydrogen protons to provide an MR signal. Furthermore, MRI can obtain detailed anatomical images in any desired plane, also acquiring 3D or volumetric image sets. Therefore, the superior soft tissue definition provided by MRI, together with its unrestricted multiplanar, volumetric, vascular and functional

Computed Tomography (CT) scanning is an imaging technique able to reproduce a 3D image of internal organs by irradiating X-ray. In LARC treatment CT shows the effective tumor size and its possible dissemination to internal organs. Although CT imaging provides excellent

approach and determining the need for neoadjuvant treatment.

**3.2. MRI physical basics**

within a given tissue.

imaging.

sampling of the resulting signal.

information has benefits for 3D treatment planning.

**3.3. Comparison of MRI and CT**

Total pelvic exenteration (TPE) is a widely used technique for resection of locally advanced or recurrent rectal tumors invading the bladder and/or prostate. Longterm survival with excellent local control is possible after TPE for primary locally advanced rectal cancer [33-35]. The majority of resections in primary cancer are without microscopic or macroscopic residual tumor mass, which clearly justifies the use of TPE in selected patients with primary disease. Although current guidelines for colorectal cancer surgery advocate TPE, only one third of the patients in a recent study based on SEER (survival, epidemiology and end results) data underwent the appropriate surgical resection.

These patients had a clinically significant overall survival benefit with no increase in shortterm mortality compared with similar patients who did not receive a multi-visceral resection. Local control in rectal cancer patients is related to the dose of irradiation, but because of toxicity to radiosensitive organs (such as small bowels), the external radiation dose should not exceed 60 Gy. A combination of external radiation and intraoperative radiation therapy (IORT) allows the safe delivery of higher effective doses of irradiation than can be delivered with externalbeam only techniques. IORT is used when resection margins are narrow or involved with tumor cells and can be applied very specifically to an area at risk, under direct visual control, and with the ability to shield the surrounding structures from radiation. The biological effectiveness of single-dose IORT is considered to be as effective as 2 to 3 times the equivalent dose of fractionated radiotherapy.

## **3. Role of MRI vs other modalities**

#### **3.1. Generalities**

Imaging techniques play a pivotal role in the strategies for management of locally advanced rectal cancer patients. The role of diagnostic imaging is to perform a loco-regional staging as accurate as possible in both evaluation of infiltration and extension degrees of disease. Image features also enable preoperative assessment of important prognostic outlines, which may guide patient selection for neoadjuvant therapies. Moreover, imaging plays an important role in therapeutic assessment, surveillance after surgery, and evaluation of suspected disease fallout. To date, imaging innovations have led to improvements in spatial and contrast resolution, increased data acquisition speeds, and enabled complex image to achieve excellence in anatomic resolution.

There are many different imaging modalities suitable for rectal cancer staging, tumour location and restaging but not all of them have the same accuracy for each indication. An optimal visualization of tumor volume and of its surrounding anatomical structures is necessary for any local cancer treatment. This issue is particularly important for radiotherapy treatment planning in order that a geographical miss can be avoided and the tumor adequately treated. Among the imaging methods available Magnetic Resonance Imaging (MRI) is currently the modality of choice because of its capacity to perform local staging, since it enables evaluation of anatomic aspects and prognostic factors that are key to choosing the appropriate surgical approach and determining the need for neoadjuvant treatment.

#### **3.2. MRI physical basics**

such as the use of intensity-modulated radiotherapy (IMRT), which has the potential of more accurate delivery of higher radiotherapy dosages, thus avoiding the damage of critical

Total pelvic exenteration (TPE) is a widely used technique for resection of locally advanced or recurrent rectal tumors invading the bladder and/or prostate. Longterm survival with excellent local control is possible after TPE for primary locally advanced rectal cancer [33-35]. The majority of resections in primary cancer are without microscopic or macroscopic residual tumor mass, which clearly justifies the use of TPE in selected patients with primary disease. Although current guidelines for colorectal cancer surgery advocate TPE, only one third of the patients in a recent study based on SEER (survival, epidemiology and end results) data

These patients had a clinically significant overall survival benefit with no increase in shortterm mortality compared with similar patients who did not receive a multi-visceral resection. Local control in rectal cancer patients is related to the dose of irradiation, but because of toxicity to radiosensitive organs (such as small bowels), the external radiation dose should not exceed 60 Gy. A combination of external radiation and intraoperative radiation therapy (IORT) allows the safe delivery of higher effective doses of irradiation than can be delivered with externalbeam only techniques. IORT is used when resection margins are narrow or involved with tumor cells and can be applied very specifically to an area at risk, under direct visual control, and with the ability to shield the surrounding structures from radiation. The biological effectiveness of single-dose IORT is considered to be as effective as 2 to 3 times the equivalent

Imaging techniques play a pivotal role in the strategies for management of locally advanced rectal cancer patients. The role of diagnostic imaging is to perform a loco-regional staging as accurate as possible in both evaluation of infiltration and extension degrees of disease. Image features also enable preoperative assessment of important prognostic outlines, which may guide patient selection for neoadjuvant therapies. Moreover, imaging plays an important role in therapeutic assessment, surveillance after surgery, and evaluation of suspected disease fallout. To date, imaging innovations have led to improvements in spatial and contrast resolution, increased data acquisition speeds, and enabled complex image to achieve excellence in

There are many different imaging modalities suitable for rectal cancer staging, tumour location and restaging but not all of them have the same accuracy for each indication. An optimal visualization of tumor volume and of its surrounding anatomical structures is necessary for any local cancer treatment. This issue is particularly important for radiotherapy treatment planning in order that a geographical miss can be avoided and the tumor adequately treated.

structures surrounding the tumor, are being tested in rectal cancer.

underwent the appropriate surgical resection.

56 Colorectal Cancer - Surgery, Diagnostics and Treatment

dose of fractionated radiotherapy.

**3.1. Generalities**

anatomic resolution.

**3. Role of MRI vs other modalities**

MRI is an imaging technique based on the different magnetic properties of tissues in the body. The exposure to a high intensity magnetic field determines the alignment of the hydrogen nuclei (protons) along the magnetic field axis itself. The emission of radio frequency pulses causes a shift from this alignment, which tends to reconstitute as soon as the impulse is interrupted. This phenomenon leads to a variation in energy level of the charges, which can be translated into a signal whose decoding is the basis of the generation of magnetic resonance images. All this is based on specific parameters that describe these steps of energy levels (including the so-called "relaxation times T1 and T2"), as well as on the concentration of protons within a given tissue.

Pulses sequences are used to obtain the different MR images, sequences consisting of radio frequency pulses with different characteristics in terms of duration, frequency and type of sampling of the resulting signal.

In the various biological tissues, the characteristics of the magnetic resonance signal are influenced mainly by the content of hydrogen atoms (whose nuclei are composed of only one proton). Since water is the most abundant molecule in the body and contains hydrogen atoms, it can be reasonably stated that the increase or the decrease of water in a given tissue is almost always at the basis of changes in signal intensity when using sequences of magnetic resonance imaging.

Where tissue contrast depends primarily on electron density, the tissue contrast obtained by MRI can be extensively varied by imaging the intrinsic tissue properties, as spin-lattice and spin-spin relaxation times, protons density, magnetization transfer, separately or in combina‐ tion, using a number of pulse sequences, which in turn can be altered by an essentially infinite number of different experimental conditions. These MR parameters can be exploited and tailored to facilitate optimal tumor visualization and evaluation. Another feature of MRI is that cortical bone does not give rise to an MR signal and therefore appears hypointense. This is because cortical bone contains calcium and there are few hydrogen protons to provide an MR signal. Furthermore, MRI can obtain detailed anatomical images in any desired plane, also acquiring 3D or volumetric image sets. Therefore, the superior soft tissue definition provided by MRI, together with its unrestricted multiplanar, volumetric, vascular and functional information has benefits for 3D treatment planning.

#### **3.3. Comparison of MRI and CT**

Computed Tomography (CT) scanning is an imaging technique able to reproduce a 3D image of internal organs by irradiating X-ray. In LARC treatment CT shows the effective tumor size and its possible dissemination to internal organs. Although CT imaging provides excellent definition between structures with different electron density or X-ray attenuation character‐ istics, it distinguishes poorly between structures with similar electron density such as different soft tissue structures, including tumors, unless there is an obvious fat or air interface [60]. The major advantage of MRI compared with CT is in its superior ability to demonstrate and characterize soft tissues that have similar electron densities. In this manner, MRI may provide better delineation not only of the tumor extent, but also of the adjacent critical soft tissue organs. This will allow conformal planning to enhance its therapeutic ratio by more accurately targeting the tumor, avoiding the organs at risk and subsequently improving local control.

allow to detection of the residual tumor after neoadjuvant therapy and to diagnose recurrences,

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59

As regards the topographic relationship of the tumor with the mesorectal fascia can be adequately established with morphologic MRI [26]. The advent of powerful gradient systems and, above all, the development of high-resolution phased array surface coil systems in recent years brought the breakthrough in the staging of rectal cancer by MRI. The use of these phasedarray surface coils combines a very high spatial resolution with a large FOV that allows not only detailed evaluation of the intestinal wall but also depicts surrounding anatomy including

A standard phased-array morphologic MRI protocol for LARC staging (including T-N stage and CRM evaluation) consists of T2-weighted coronal, transversal and sagittal turbospin-echo

**Figure 1.** (a) A heterogeneous irregular thickening along the entire rectal wall is well shown on T2w axial pre-pCRT scan (arrowheads). (b) After pCRT, a hypo-intense spiculated area with thin digitations into peri-rectal fat is visible on T2w axial scan (arrowheads). (c) In the same patient, multiple irregular rectal wall thickening are shown on T2w sagit‐ tal pre-pCRT scan (arrowheads). (d) A single hypo-intense area, showed also in (b) is pointed by arrowheads, suspect‐

distinguishing them from fibrosis.

MR sequences with high spatial resolution (Fig. 1) [26].

ing for a residual post-pCRT tumor focus (arrowheads).

**4.1. Morphological MRI**

the mesorectal fascia.

#### **3.4. Comparison of MRI and PET/CT**

In LARC patient management detection of tumor sites throughout the body is needed with high sensitivity and specificity in order to have accurate information about the local extent. As discussed in the previous section, an accurate tumour visualization can be performing using MRI techniques. An additional value should be given to consider the combination of Positron Emission Tomography (PET) and CT [61]. PET/CT is a diagnostic procedure that allows to obtain morphological images of the human body provided by CT and images of the tissue metabolic processes provided by PET by means of a co-registration system.

Tissues appear differently on PET and on CT images. CT displays anatomy with high spatial resolution, but with low contrast resolution for soft tissues, while PET visualizes pathological sites with high contrast resolution but a limited spatial resolution and surrounding normal anatomicalstructuresarehardlyvisualized.Thecombinationofmetabolicactivitywithanatomic localization achievable with PET/CT improve accuracy over that of PET or CT alone [62].

## **4. Role of MRI in LARC**

In the recent years MRI has undergone significant transformations resulting from technolog‐ ical innovation that have taken place as the introduction of high-field magnets, powerful gradients, multi-channel phased array coils and endorectal coils improvement. These techno‐ logical developments have certainly allowed the executing of high quality diagnostic studies due to the high spatial resolution and contrast obtained, to the possibility of identification and distinction of rectal wall layers, and to the possibility of assessing perirectal and sphinteric structures. Mainly, superficial endorectal coils are currently able to identify various layers of lower rectum wall. MRI is thus the ideal technique for rectal cancer staging, combining the capabilities of an accurate loco-regional staging to the outlook and multi-planar properties.

In conclusion, MRI can currently stage with high accuracy the T parameter (related to the degree of tumor infiltration) due to the possibility offered by the endorectal coil to recognize the wall layers, resulting also extremely useful in planning surgery and in prognostic stratifi‐ cation, owing to the ability to accurately identify mesorectum and the distance between mesorectal fascia and neoplasia. Furthermore the high temporal resolution of last generation devices allows to perform perfusion and dynamic studies after gadolinium administration that allow to detection of the residual tumor after neoadjuvant therapy and to diagnose recurrences, distinguishing them from fibrosis.

#### **4.1. Morphological MRI**

definition between structures with different electron density or X-ray attenuation character‐ istics, it distinguishes poorly between structures with similar electron density such as different soft tissue structures, including tumors, unless there is an obvious fat or air interface [60]. The major advantage of MRI compared with CT is in its superior ability to demonstrate and characterize soft tissues that have similar electron densities. In this manner, MRI may provide better delineation not only of the tumor extent, but also of the adjacent critical soft tissue organs. This will allow conformal planning to enhance its therapeutic ratio by more accurately targeting the tumor, avoiding the organs at risk and subsequently improving local control.

In LARC patient management detection of tumor sites throughout the body is needed with high sensitivity and specificity in order to have accurate information about the local extent. As discussed in the previous section, an accurate tumour visualization can be performing using MRI techniques. An additional value should be given to consider the combination of Positron Emission Tomography (PET) and CT [61]. PET/CT is a diagnostic procedure that allows to obtain morphological images of the human body provided by CT and images of the tissue

Tissues appear differently on PET and on CT images. CT displays anatomy with high spatial resolution, but with low contrast resolution for soft tissues, while PET visualizes pathological sites with high contrast resolution but a limited spatial resolution and surrounding normal anatomicalstructuresarehardlyvisualized.Thecombinationofmetabolicactivitywithanatomic localization achievable with PET/CT improve accuracy over that of PET or CT alone [62].

In the recent years MRI has undergone significant transformations resulting from technolog‐ ical innovation that have taken place as the introduction of high-field magnets, powerful gradients, multi-channel phased array coils and endorectal coils improvement. These techno‐ logical developments have certainly allowed the executing of high quality diagnostic studies due to the high spatial resolution and contrast obtained, to the possibility of identification and distinction of rectal wall layers, and to the possibility of assessing perirectal and sphinteric structures. Mainly, superficial endorectal coils are currently able to identify various layers of lower rectum wall. MRI is thus the ideal technique for rectal cancer staging, combining the capabilities of an accurate loco-regional staging to the outlook and multi-planar properties.

In conclusion, MRI can currently stage with high accuracy the T parameter (related to the degree of tumor infiltration) due to the possibility offered by the endorectal coil to recognize the wall layers, resulting also extremely useful in planning surgery and in prognostic stratifi‐ cation, owing to the ability to accurately identify mesorectum and the distance between mesorectal fascia and neoplasia. Furthermore the high temporal resolution of last generation devices allows to perform perfusion and dynamic studies after gadolinium administration that

metabolic processes provided by PET by means of a co-registration system.

**3.4. Comparison of MRI and PET/CT**

58 Colorectal Cancer - Surgery, Diagnostics and Treatment

**4. Role of MRI in LARC**

As regards the topographic relationship of the tumor with the mesorectal fascia can be adequately established with morphologic MRI [26]. The advent of powerful gradient systems and, above all, the development of high-resolution phased array surface coil systems in recent years brought the breakthrough in the staging of rectal cancer by MRI. The use of these phasedarray surface coils combines a very high spatial resolution with a large FOV that allows not only detailed evaluation of the intestinal wall but also depicts surrounding anatomy including the mesorectal fascia.

A standard phased-array morphologic MRI protocol for LARC staging (including T-N stage and CRM evaluation) consists of T2-weighted coronal, transversal and sagittal turbospin-echo MR sequences with high spatial resolution (Fig. 1) [26].

**Figure 1.** (a) A heterogeneous irregular thickening along the entire rectal wall is well shown on T2w axial pre-pCRT scan (arrowheads). (b) After pCRT, a hypo-intense spiculated area with thin digitations into peri-rectal fat is visible on T2w axial scan (arrowheads). (c) In the same patient, multiple irregular rectal wall thickening are shown on T2w sagit‐ tal pre-pCRT scan (arrowheads). (d) A single hypo-intense area, showed also in (b) is pointed by arrowheads, suspect‐ ing for a residual post-pCRT tumor focus (arrowheads).

An adequate, state-of-the-art MRI staging classification is capable to predict whether a tumorfree CRM is likely to be achieved or not [26]. In this way one would be able to differentiate patients with minimal mesorectal infiltration in whom neoadjuvant therapy is not mandatory from patients who would definitely benefit from neoadjuvant therapy because the mesorectal fascia is infiltrated or at risk.

the potential to improve the management of treatment for patients with rectal cancer

Role of Magnetic Resonance Imaging in Locally Advanced Rectal Cancer

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61

Angiogenesis is a key factor for the growth and dissemination of solid tumors and is a prognostic marker in CRC. Neovascularization arises early in the adenoma–carcinoma sequence via upregulation of vascular endothelial growth factor. Tumor angiogenesis is characterized by structurally abnormal blood vessels that are thin, fragile, tortuous, and hyperpermeable. They have a chaotic, heterogeneous intratumoral distribution. Abnormal

DCE-MRI techniques inform on tissue perfusion and vascular leakage (Fig. 2). T1- or relaxivitybased MR sequences are sensitive to the presence of dilute contrast medium in the extrava‐ scular– extracellular space. In most tumors, low-molecular-weight contrast media readily diffuse from the blood into the extravascular– extracellular space at a rate determined by

The most commonly used model for analyzing DCE-MRI data uses two compartments where the contrast agent resides (blood plasma and extravascular– extracellular space). Ktrans (volume transfer constant between the blood plasma and the extravascular–extracellular space, the washin rate, measured in minutes−1) and kep (rate constant between the extravascular– extracellular space back to the blood plasma, the washout rate, measured in minutes−1)

Physiologically, Ktrans indicates a variable combination of the flow and permeability properties. For blood vessels where leakage is rapid (that is, when the extraction fraction during the first pass of the contrast agent is high, as typically is found in tumors), perfusion will determine contrast agent distribution and Ktrans approximates to tissue blood flow per unit volume. There are circumstances in which transport out of the vasculature does not significantly deplete intravascular contrast medium concentration (that is, tissues with lower first-pass extraction fraction). This is typically found after treatment with chemotherapy or late after radiotherapy and in fibrotic lesions, and in these situations, Ktrans approximates to the product of permea‐

At present, the use of diffusion-weighted imaging (DWI) incorporated into a standard MR protocol is gradually increasing because of its proven benefit not only for tumor detection/ characterization but also for monitoring treatment response (8–12). Diffusion-weighted imaging measures water diffusion characteristics, which are dependent on multiple factors such as cell density, vascularity, viscosity of extracellular fluid, and cell membrane integri‐ ty (12). By quantifying these properties and expressing them as an apparent diffusion coefficient (ADC), DWI could potentially be used as an imaging biomarker to better select patients with poor prognosis who will truly benefit from a more aggressive neoadjuvant treatment (8-12). In literature it was demonstrated that ADC values of rectal cancers significantly correlate with prognostic factors including the MRF status, the nodal stage and

vascularity often extends beyond the tumor boundaries into surrounding tissues.

perfusion and the capillary permeability and surface area.

determine the transport between these two compartments.

bility and the surface area (permeability surface area product).

*4.2.2. Diffusion-weighted imaging DWI-MRI*

the histological differentiation grade.

[6-7,24-25].

The common use of total mesorectal excision (TME) and the shift from a postoperative to a preoperative chemo-radiotherapy (pre-CRT) approach have substantially reduced the risk of local recurrences, increasing curative resection and the rate of anal sphincter preservation and improving local control and overall survival rates [13-18].

#### **4.2. Functional MRI**

Although morphological tumour assessment performed by MRI has been repeatedly shown to be the most accurate modality in evaluating the presence of a positive circumferential resection margin (CRM), MRI is considered not to be conclusive in pre-CRT tumor response evaluation since histopathological downstage is not always associated with tumour effective reduction [17]. The main difficulty regarding post-chemoradiation MRI includes discrimina‐ tion of active tumour and post-treatment fibrosis, particularly when differentiating stage T2 and stage T3 carcinomas, according to different recurrence and overall survival rates between Low Risk (T1/T2N0) and Intermediate Risk (T3/N0) as reported by Gunderson et al. [23-24].

Several studies have shown the potential of functional [diffusion- or perfusion] weighted imaging to predict the response to adjuvant or neoadjuvant therapy [5–7,19].

In fact, it has long been known that the pathophysiology and aggressiveness of a tumor are determined not only by the macroscopic tumor extent but also by other factors such as tumor microcirculation and angiogenesis.

#### *4.2.1. DCE-MRI*

Previous considerations support a Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) approach that could gain a renewed role to MRI adding functional data to the morphological examination. DCE-MRI has been reported by many authors as a tool potentially able to permit an evaluation of pre-CRT effectiveness basing on the strict relationship between tumor growth and angiogenesis [6-7,24-25].

DCE-MRI is gaining a large consensus as a technique for diagnosis, staging and assessment of therapy response for different types of tumours, due to its capability to detect highly active angiogenesis. It is well known that angiogenesis is a key factor in the growth and dissemination of cancer; characterization of the angiogenic status of the tumour on an individual patient basis could allow for a more targeted approach to treatment of rectal cancer [24].

More specifically, in the case of rectal cancer, previous trials have provided the proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of the treatment for this disease. In vivo imaging techniques capable to assess tumour perfusion have the potential to improve the management of treatment for patients with rectal cancer [6-7,24-25].

Angiogenesis is a key factor for the growth and dissemination of solid tumors and is a prognostic marker in CRC. Neovascularization arises early in the adenoma–carcinoma sequence via upregulation of vascular endothelial growth factor. Tumor angiogenesis is characterized by structurally abnormal blood vessels that are thin, fragile, tortuous, and hyperpermeable. They have a chaotic, heterogeneous intratumoral distribution. Abnormal vascularity often extends beyond the tumor boundaries into surrounding tissues.

DCE-MRI techniques inform on tissue perfusion and vascular leakage (Fig. 2). T1- or relaxivitybased MR sequences are sensitive to the presence of dilute contrast medium in the extrava‐ scular– extracellular space. In most tumors, low-molecular-weight contrast media readily diffuse from the blood into the extravascular– extracellular space at a rate determined by perfusion and the capillary permeability and surface area.

The most commonly used model for analyzing DCE-MRI data uses two compartments where the contrast agent resides (blood plasma and extravascular– extracellular space). Ktrans (volume transfer constant between the blood plasma and the extravascular–extracellular space, the washin rate, measured in minutes−1) and kep (rate constant between the extravascular– extracellular space back to the blood plasma, the washout rate, measured in minutes−1) determine the transport between these two compartments.

Physiologically, Ktrans indicates a variable combination of the flow and permeability properties. For blood vessels where leakage is rapid (that is, when the extraction fraction during the first pass of the contrast agent is high, as typically is found in tumors), perfusion will determine contrast agent distribution and Ktrans approximates to tissue blood flow per unit volume. There are circumstances in which transport out of the vasculature does not significantly deplete intravascular contrast medium concentration (that is, tissues with lower first-pass extraction fraction). This is typically found after treatment with chemotherapy or late after radiotherapy and in fibrotic lesions, and in these situations, Ktrans approximates to the product of permea‐ bility and the surface area (permeability surface area product).

#### *4.2.2. Diffusion-weighted imaging DWI-MRI*

An adequate, state-of-the-art MRI staging classification is capable to predict whether a tumorfree CRM is likely to be achieved or not [26]. In this way one would be able to differentiate patients with minimal mesorectal infiltration in whom neoadjuvant therapy is not mandatory from patients who would definitely benefit from neoadjuvant therapy because the mesorectal

The common use of total mesorectal excision (TME) and the shift from a postoperative to a preoperative chemo-radiotherapy (pre-CRT) approach have substantially reduced the risk of local recurrences, increasing curative resection and the rate of anal sphincter preservation and

Although morphological tumour assessment performed by MRI has been repeatedly shown to be the most accurate modality in evaluating the presence of a positive circumferential resection margin (CRM), MRI is considered not to be conclusive in pre-CRT tumor response evaluation since histopathological downstage is not always associated with tumour effective reduction [17]. The main difficulty regarding post-chemoradiation MRI includes discrimina‐ tion of active tumour and post-treatment fibrosis, particularly when differentiating stage T2 and stage T3 carcinomas, according to different recurrence and overall survival rates between Low Risk (T1/T2N0) and Intermediate Risk (T3/N0) as reported by Gunderson et al. [23-24].

Several studies have shown the potential of functional [diffusion- or perfusion] weighted

In fact, it has long been known that the pathophysiology and aggressiveness of a tumor are determined not only by the macroscopic tumor extent but also by other factors such as tumor

Previous considerations support a Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) approach that could gain a renewed role to MRI adding functional data to the morphological examination. DCE-MRI has been reported by many authors as a tool potentially able to permit an evaluation of pre-CRT effectiveness basing on the strict relationship between

DCE-MRI is gaining a large consensus as a technique for diagnosis, staging and assessment of therapy response for different types of tumours, due to its capability to detect highly active angiogenesis. It is well known that angiogenesis is a key factor in the growth and dissemination of cancer; characterization of the angiogenic status of the tumour on an individual patient basis

More specifically, in the case of rectal cancer, previous trials have provided the proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of the treatment for this disease. In vivo imaging techniques capable to assess tumour perfusion have

could allow for a more targeted approach to treatment of rectal cancer [24].

imaging to predict the response to adjuvant or neoadjuvant therapy [5–7,19].

fascia is infiltrated or at risk.

60 Colorectal Cancer - Surgery, Diagnostics and Treatment

**4.2. Functional MRI**

microcirculation and angiogenesis.

tumor growth and angiogenesis [6-7,24-25].

*4.2.1. DCE-MRI*

improving local control and overall survival rates [13-18].

At present, the use of diffusion-weighted imaging (DWI) incorporated into a standard MR protocol is gradually increasing because of its proven benefit not only for tumor detection/ characterization but also for monitoring treatment response (8–12). Diffusion-weighted imaging measures water diffusion characteristics, which are dependent on multiple factors such as cell density, vascularity, viscosity of extracellular fluid, and cell membrane integri‐ ty (12). By quantifying these properties and expressing them as an apparent diffusion coefficient (ADC), DWI could potentially be used as an imaging biomarker to better select patients with poor prognosis who will truly benefit from a more aggressive neoadjuvant treatment (8-12). In literature it was demonstrated that ADC values of rectal cancers significantly correlate with prognostic factors including the MRF status, the nodal stage and the histological differentiation grade.

exploited in clinical practice to provide indirect assessments of tissue properties such as cellularity, gland formation, perfusion, and cell death. In general, the greater the cell density per high power field, the more impeded will be tissue water diffusion. Diffusion-weighted signal is derived from the motion of water molecules within the extravascular–extracellular space and intravascular space with some component from intracellular space water. The relative contribution of each space to the derived signal varies from tissue to tissue. In highly vascular tumors, intravascular water diffusion will account for a significant proportion of the diffusion-weighted signal. In highly glandular tissues, such as the pancreas and salivary

**Figure 3.** (a) Axial diffusion weigthed imaging b=0, (b) Axial diffusion weigthed imaging b=800. Hyperintensity diffu‐

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By performing DWI using different b values, quantitative analysis is possible with the calculation of the apparent diffusion coefficient (ADC, measured in μm/s). Areas of restricted diffusion show low ADC values. ADC values are inversely correlated with tumor cellularity

Areas retaining high signal intensity on high-b-value images usually (but not always) indicate highly cellular tissues such as tumors. Normal tissues including lymph nodes, spleen, nervous tissues, adrenal glands, bowel mucosa, and endometrium may show the same findings. Lower-signal-intensity regions are seen in most organized normal tissues, cystic spaces, and vessels. However, high signal intensities on high-b-value images are not always reliable indicators of increased cellularity on their own. Occasionally, fluid, edema, or mucinous materials remain of high signal intensity because of high proton density. This observation is called T2-shine through, but this effect can be detected easily by noting

There is growing interest in the application of DWI for the evaluation of CRC. DWI aids in detection of lesions, particularly when lesions are small. High-b-value DWI may be a useful

DWI has been shown to be feasible as an early marker of treatment response because cell death and vascular alterations typically occur before size changes. Increases in ADC values with

glands, significant signal contributions arise from glandular water.

sion weigthed imaging is consistent with the diagnosis of tumor.

and reductions in ADC correlate with response to cytotoxic therapy.

corresponding high signal on ADC maps.

tool for detecting and defining tumor extent.

**Figure 2.** T1w post-contrast scan obtained on the same patient in fig. 8, before (a)-(b) and after (c)-(d) pre-CRT. The analysis of TIC calculated on a ROI, drawn outside the rectal wall where on T2w scans (fig. 8) tumor clearly spreads into peri-rectal fat pad, confirm this suspect showing a rapid CA intake and a fast discharge (b). After pre-CRT, on the same areas showed on T2w scans (fig. 8) no pathological CA uptake is present confirming that hypo-intense tissue visible on T2w scans are tumor nests but only residual inflammation due to pre-CRT. This patient was considered as a Responder. Histopathology showed a TRG 1.

The movement of water molecules in biologic tissues is restricted because their motion is modified and limited by interactions with cell membranes and macromolecules. Watermolecule motion in tissues can be assessed by applying diffusion- weighting gradients to T2 weighted sequences. This process entails the application of two balanced gradients placed symmetrically about a focusing 180° pulse. Water molecules that have not moved during the time taken to apply the first gradient will have acquired phase shifts that are exactly cancelled out by the proceeding second gradient; thus, there is no net additional signal loss induced by the application of the paired diffusion gradients. For water molecules that have moved during the application of the first gradient, however, the acquired phase shifts will not be cancelled out by the second gradient; residual phase incoherence will result in net losses of signal. Hence, the motion of water molecules is detected as attenuation of the measured signal intensity on DWI (Fig. 3).

The sensitivity of the DWI sequence to water motion can be varied by changing the parameter known as the b value (measured in s/mm2), which is proportional to the gradient amplitude, duration of the applied gradient, and time interval between the paired gradients. DWI can be

**Figure 3.** (a) Axial diffusion weigthed imaging b=0, (b) Axial diffusion weigthed imaging b=800. Hyperintensity diffu‐ sion weigthed imaging is consistent with the diagnosis of tumor.

exploited in clinical practice to provide indirect assessments of tissue properties such as cellularity, gland formation, perfusion, and cell death. In general, the greater the cell density per high power field, the more impeded will be tissue water diffusion. Diffusion-weighted signal is derived from the motion of water molecules within the extravascular–extracellular space and intravascular space with some component from intracellular space water. The relative contribution of each space to the derived signal varies from tissue to tissue. In highly vascular tumors, intravascular water diffusion will account for a significant proportion of the diffusion-weighted signal. In highly glandular tissues, such as the pancreas and salivary glands, significant signal contributions arise from glandular water.

By performing DWI using different b values, quantitative analysis is possible with the calculation of the apparent diffusion coefficient (ADC, measured in μm/s). Areas of restricted diffusion show low ADC values. ADC values are inversely correlated with tumor cellularity and reductions in ADC correlate with response to cytotoxic therapy.

The movement of water molecules in biologic tissues is restricted because their motion is modified and limited by interactions with cell membranes and macromolecules. Watermolecule motion in tissues can be assessed by applying diffusion- weighting gradients to T2 weighted sequences. This process entails the application of two balanced gradients placed symmetrically about a focusing 180° pulse. Water molecules that have not moved during the time taken to apply the first gradient will have acquired phase shifts that are exactly cancelled out by the proceeding second gradient; thus, there is no net additional signal loss induced by the application of the paired diffusion gradients. For water molecules that have moved during the application of the first gradient, however, the acquired phase shifts will not be cancelled out by the second gradient; residual phase incoherence will result in net losses of signal. Hence, the motion of water molecules is detected as attenuation of the measured signal intensity on

**Figure 2.** T1w post-contrast scan obtained on the same patient in fig. 8, before (a)-(b) and after (c)-(d) pre-CRT. The analysis of TIC calculated on a ROI, drawn outside the rectal wall where on T2w scans (fig. 8) tumor clearly spreads into peri-rectal fat pad, confirm this suspect showing a rapid CA intake and a fast discharge (b). After pre-CRT, on the same areas showed on T2w scans (fig. 8) no pathological CA uptake is present confirming that hypo-intense tissue visible on T2w scans are tumor nests but only residual inflammation due to pre-CRT. This patient was considered as a Responder.

The sensitivity of the DWI sequence to water motion can be varied by changing the parameter known as the b value (measured in s/mm2), which is proportional to the gradient amplitude, duration of the applied gradient, and time interval between the paired gradients. DWI can be

DWI (Fig. 3).

Histopathology showed a TRG 1.

62 Colorectal Cancer - Surgery, Diagnostics and Treatment

Areas retaining high signal intensity on high-b-value images usually (but not always) indicate highly cellular tissues such as tumors. Normal tissues including lymph nodes, spleen, nervous tissues, adrenal glands, bowel mucosa, and endometrium may show the same findings. Lower-signal-intensity regions are seen in most organized normal tissues, cystic spaces, and vessels. However, high signal intensities on high-b-value images are not always reliable indicators of increased cellularity on their own. Occasionally, fluid, edema, or mucinous materials remain of high signal intensity because of high proton density. This observation is called T2-shine through, but this effect can be detected easily by noting corresponding high signal on ADC maps.

There is growing interest in the application of DWI for the evaluation of CRC. DWI aids in detection of lesions, particularly when lesions are small. High-b-value DWI may be a useful tool for detecting and defining tumor extent.

DWI has been shown to be feasible as an early marker of treatment response because cell death and vascular alterations typically occur before size changes. Increases in ADC values with treatment reflect decreases in cellularity and thus provide indirect assessment of chemothera‐ py induced cell death. It has been reported that transient decreases in ADC may occur early in treatment related to cellular swelling, reduction in blood flow, or reduction in the extravascu‐ lar– extracellular space due to dehydration. However, early decreases in ADC values are not consistently seen, and it has recently been reported that increases in ADC value with therapy response occur within 3–7 days in responding CRC patients treated with chemotherapy.

of the total 27 patients, 11 (41%) had pathologic complete response; 16 (59%) had suboptimal response. They evaluate the ability of change in 4 specific PET parameters to predict pathologic response: the maximum SUV in the region of interest, SUVmax; the average SUV throughout the entire region of interest, SUVavg; the summed metabolic rate of the tumor, TLG; the virtual

Chien-Chih Chen et al. [37] evaluated the correlation between pathological verified tumor stage and clinical stage predicted by MRI. The overall predictive accuracy in T stage was 52%, whereas overstaging and understaging occurred in 38% and 10% of patients, respectively. Another study regard the MRI accuracy was conducted by Dresen et al. [45] using T2- weighted MR images obtained before and after radiation therapy and correlating findings with histo‐

Kristiansen et al. [39] investigated the possibility of using PET/CT to predict the histopatho‐ logic response in 30 patients with LARC treated with a combination of radiotherapy and concurrent Uftoral® and leucovorine. PET/CT correctly identified six of eight patients,

To evaluate the correlation between the change of SUVmax and of apparent diffusion coefficient (ADC) before and after neoadjuvant therapy, thirty patients with locally advanced rectal cancer were recruited in Ippolito et al. [40] analysis, in which all the patients underwent a whole body 18F-FDG PET/CT scan and a pelvic MR examination including DW imaging for

Table 1 summarizes the main characteristics of the examined methodologies in locally

**Table 1.** Summary of the main characteristics of includes studies about different methodologies used in LARC diseases. Per each study the table reports: imaging modality used; number of patients examined; parameters

**Study Modality No.Patients Parameters**

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TNM TNM TNM SUV SUV SUV TRG,SUV SUV TNM TNM SUV,TLG,VRS ADC SUV TNM TNM SUV

MRI MRI CT PET PET PET/CT PET/CT PET/CT MRI MRI PET MRI PET/CT MRI CT PET/CT

graded global assessment of response, VRS.

specificity 75%, with complete pathologic response.

pathology results.

staging therapy.

advanced rectal cancer studies.

C. C. Chen et al. [37] T. Denecke et al. [46]

G. L. Cascini et al. [41] C. Capirci et al. [38] C. Kristiansen et al. [39] R. Rosenberg et al. [44] A. Suppiah et al. [36] R. C. Dresen et al. [45] T. Leibold et al. [47] D. Ippolito et al. [40]

J. Martellucci et al. [42]

M. J. M. Duréndez et al. [43]

examined; sensitivity and specificity methodology values.

Responders had a lower ADC at presentation than non responders. Higher pretreatment ADC values in nonresponders may reflect necrotic tumors that are more resistant to therapy because of concomitant hypoxia. Similarly, for CRC liver metastases, a higher pretreatment ADC is also predictive of poor response.

## **5. A systematic review**

#### **5.1. Methodologies**

A systematic literature search was performed to identify English-language studies and articles concerning different diagnostic imaging methodologies available in locally advanced rectal cancer disease after radiation therapy. Data were identified using PubMed database with the following keywords: "locally advanced rectal cancer, magnetic resonance imaging, CT planning, PET imaging". This yielded 309 titles. Articles, reviews and studies that did not present data about specificity and sensibility of tests treated were excluded. Due to the small number of studies for each imaging modality, there was not set a minimum number of patients as an inclusion criteria. For this reason, a total number of 12 titles were considered as studies included in the research.

Details regarding the number of patients, imaging modality investigated, the accuracy values and parameters examined of the studies were recorded. Cascini et al. [41] evaluated 18F-FDG PET to assess the effect of chemoradiation therapy in thirty-three patients with LARC proved disease. They correlate the change in tumor 18F-FDG standardized uptake value (SUV) during and after preoperative radiotherapy with the pathologic response achieved.

The accuracy of CT and MRI in restaging rectal cancer after preoperative chemoradiation in order to plan optimal therapy was performed in Martellucci et al. [42] study, in which thirtyseven consecutive patients undergoing neoadjuvant therapy were evaluated. Considering the depth of invasion after treatment only in neoplasia with stage T3 they found CT agree with histopathology in 19 cases and MRI in 10/12 cases.

Denecke et al. [46] compare CT, MRI and FDG-PET examining a total of twenty-three patients with T3/4 rectal cancer. Response criteria were a change in T category and tumour volume for CT and MRI and a change in glucose uptake for FDG-PET. Their results in sensitivity and specificity suggest that PET is superior to CT and MRI in predicting response to preoperative multimodal treatment of LARC.

A prospective analysis to evaluate tumor response with 18F-FDG PET in twenty-seven patients with biopsy-proven rectal adenocarcinoma was conducted by Leibold et al. [47]. They found

of the total 27 patients, 11 (41%) had pathologic complete response; 16 (59%) had suboptimal response. They evaluate the ability of change in 4 specific PET parameters to predict pathologic response: the maximum SUV in the region of interest, SUVmax; the average SUV throughout the entire region of interest, SUVavg; the summed metabolic rate of the tumor, TLG; the virtual graded global assessment of response, VRS.

treatment reflect decreases in cellularity and thus provide indirect assessment of chemothera‐ py induced cell death. It has been reported that transient decreases in ADC may occur early in treatment related to cellular swelling, reduction in blood flow, or reduction in the extravascu‐ lar– extracellular space due to dehydration. However, early decreases in ADC values are not consistently seen, and it has recently been reported that increases in ADC value with therapy response occur within 3–7 days in responding CRC patients treated with chemotherapy.

Responders had a lower ADC at presentation than non responders. Higher pretreatment ADC values in nonresponders may reflect necrotic tumors that are more resistant to therapy because of concomitant hypoxia. Similarly, for CRC liver metastases, a higher pretreatment ADC is

A systematic literature search was performed to identify English-language studies and articles concerning different diagnostic imaging methodologies available in locally advanced rectal cancer disease after radiation therapy. Data were identified using PubMed database with the following keywords: "locally advanced rectal cancer, magnetic resonance imaging, CT planning, PET imaging". This yielded 309 titles. Articles, reviews and studies that did not present data about specificity and sensibility of tests treated were excluded. Due to the small number of studies for each imaging modality, there was not set a minimum number of patients as an inclusion criteria. For this reason, a total number of 12 titles were considered as studies

Details regarding the number of patients, imaging modality investigated, the accuracy values and parameters examined of the studies were recorded. Cascini et al. [41] evaluated 18F-FDG PET to assess the effect of chemoradiation therapy in thirty-three patients with LARC proved disease. They correlate the change in tumor 18F-FDG standardized uptake value (SUV) during

The accuracy of CT and MRI in restaging rectal cancer after preoperative chemoradiation in order to plan optimal therapy was performed in Martellucci et al. [42] study, in which thirtyseven consecutive patients undergoing neoadjuvant therapy were evaluated. Considering the depth of invasion after treatment only in neoplasia with stage T3 they found CT agree with

Denecke et al. [46] compare CT, MRI and FDG-PET examining a total of twenty-three patients with T3/4 rectal cancer. Response criteria were a change in T category and tumour volume for CT and MRI and a change in glucose uptake for FDG-PET. Their results in sensitivity and specificity suggest that PET is superior to CT and MRI in predicting response to preoperative

A prospective analysis to evaluate tumor response with 18F-FDG PET in twenty-seven patients with biopsy-proven rectal adenocarcinoma was conducted by Leibold et al. [47]. They found

and after preoperative radiotherapy with the pathologic response achieved.

histopathology in 19 cases and MRI in 10/12 cases.

multimodal treatment of LARC.

also predictive of poor response.

64 Colorectal Cancer - Surgery, Diagnostics and Treatment

**5. A systematic review**

**5.1. Methodologies**

included in the research.

Chien-Chih Chen et al. [37] evaluated the correlation between pathological verified tumor stage and clinical stage predicted by MRI. The overall predictive accuracy in T stage was 52%, whereas overstaging and understaging occurred in 38% and 10% of patients, respectively. Another study regard the MRI accuracy was conducted by Dresen et al. [45] using T2- weighted MR images obtained before and after radiation therapy and correlating findings with histo‐ pathology results.

Kristiansen et al. [39] investigated the possibility of using PET/CT to predict the histopatho‐ logic response in 30 patients with LARC treated with a combination of radiotherapy and concurrent Uftoral® and leucovorine. PET/CT correctly identified six of eight patients, specificity 75%, with complete pathologic response.

To evaluate the correlation between the change of SUVmax and of apparent diffusion coefficient (ADC) before and after neoadjuvant therapy, thirty patients with locally advanced rectal cancer were recruited in Ippolito et al. [40] analysis, in which all the patients underwent a whole body 18F-FDG PET/CT scan and a pelvic MR examination including DW imaging for staging therapy.


Table 1 summarizes the main characteristics of the examined methodologies in locally advanced rectal cancer studies.

**Table 1.** Summary of the main characteristics of includes studies about different methodologies used in LARC diseases. Per each study the table reports: imaging modality used; number of patients examined; parameters examined; sensitivity and specificity methodology values.

#### **5.2. Summary ROC curves and Forest Plots**

In order to assess individual methodology in LARC treatment, Summary Receiver Operating Characteristic (SROC) curves have been realized, Fig. 4. ROC curves is a statistic technique for displaying, organizing and selecting classifiers based on their performance.

modality, while a summary ROC curve for a worthless modality is represented by the bisector,

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Another additional graphical representation realized is the Forest Plot, Fig. 5, which shows the sensitivity and specificity estimates of the results for each study. It is composed of a plot of the measure of effect for each of these studies incorporating confidence intervals represented by horizontal bars. The confidence interval expresses the precision level associated with the parameter estimation: the more is small, the more indicates that the prediction is accurate. In this analysis confidence intervals are computed with a probability of containing the true effect size equal to 95%. The blue square represents the point estimate, i.e. the sensitivity or specif‐

**Figure 5.** Forest Plot of MRI, CT, PET and PET/CT sensitivity and specificity estimates and their confidence intervals

also named change line.

icity.

(95%).

**Figure 4.** Estimated Summary ROC curves and original data points for four imaging techniques. MRI= magnetic reso‐ nance imaging, CT= computed tomography, PET= Positron emission tomography, PET/CT= positron emission tomog‐ raphy and computed tomography.

ROC analysis was performed through the study of the function that links the probability to obtain a true-positive result in the disease like class, i.e. the sensitivity, to the probability to obtain a false-positive result in the non-diseased class, linked to the specificity. In this way a graphical 2D representation that shows the false-positive proportion in x-axis and true-positive proportion in y-axis, relatively to values obtained from each test applied.

For each modality, a model was obtained that was adjusted for significant variables that were set to 1, indicating the ideal design versus 0, as appropriate, Fig. 4. The position of the summary ROC curve indicates the difference in diagnostic performance among the imaging modalities. A summary ROC curve located near the upper left corner indicate rte better diagnostic modality, while a summary ROC curve for a worthless modality is represented by the bisector, also named change line.

Another additional graphical representation realized is the Forest Plot, Fig. 5, which shows the sensitivity and specificity estimates of the results for each study. It is composed of a plot of the measure of effect for each of these studies incorporating confidence intervals represented by horizontal bars. The confidence interval expresses the precision level associated with the parameter estimation: the more is small, the more indicates that the prediction is accurate. In this analysis confidence intervals are computed with a probability of containing the true effect size equal to 95%. The blue square represents the point estimate, i.e. the sensitivity or specif‐ icity.

**5.2. Summary ROC curves and Forest Plots**

66 Colorectal Cancer - Surgery, Diagnostics and Treatment

raphy and computed tomography.

In order to assess individual methodology in LARC treatment, Summary Receiver Operating Characteristic (SROC) curves have been realized, Fig. 4. ROC curves is a statistic technique for

**Figure 4.** Estimated Summary ROC curves and original data points for four imaging techniques. MRI= magnetic reso‐ nance imaging, CT= computed tomography, PET= Positron emission tomography, PET/CT= positron emission tomog‐

ROC analysis was performed through the study of the function that links the probability to obtain a true-positive result in the disease like class, i.e. the sensitivity, to the probability to obtain a false-positive result in the non-diseased class, linked to the specificity. In this way a graphical 2D representation that shows the false-positive proportion in x-axis and true-positive

For each modality, a model was obtained that was adjusted for significant variables that were set to 1, indicating the ideal design versus 0, as appropriate, Fig. 4. The position of the summary ROC curve indicates the difference in diagnostic performance among the imaging modalities. A summary ROC curve located near the upper left corner indicate rte better diagnostic

proportion in y-axis, relatively to values obtained from each test applied.

displaying, organizing and selecting classifiers based on their performance.

**Figure 5.** Forest Plot of MRI, CT, PET and PET/CT sensitivity and specificity estimates and their confidence intervals (95%).

#### **5.3. Discussion**

The objective of this statistical analysis was to evaluate the diverse methodologies (MRI, PET, PET/CT, CT) in LARC management. In particular, in our analysis we considered the accuracy in assessing the therapy response.

[3] Choi HJ, Hyun MS, Jung GJ, Kim SS, Hong SH. Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and re‐

Role of Magnetic Resonance Imaging in Locally Advanced Rectal Cancer

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69

[4] Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascu‐ lar endothelial growth factor, microvascular hyperpermeability, and angiogenesis.

[5] Dzik-Jurasz A, Domenig C, George M et al (2002) Diffusion MRI for prediction of re‐

[6] Devries AF, Griebel J, Kremser C et al (2001) Tumor microcirculation evaluated by dynamic magnetic resonance imaging predicts therapy outcome for primary rectal

[7] DeVries AF, Kremser C, Hein PA et al (2003) Tumor microcirculation and diffusion predict therapy outcome for primary rectal carcinoma. Int J Radiat Oncol Biol Phys

[8] Koh DM, Padhani AR. Diffusion-weighted MRI: a new functional clinical technique

[9] Koh DM, Collins DJ. Diffusion-weighted MRI in the body: applications and challeng‐

[10] Patterson DM, Padhani AR, Collins DJ. Technology insight: water diffusion MRI-a potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol

[11] Padhani AR, Liu G, Koh DM, et al. Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 2009;11:102–125.

[12] deSouza NM, Riches SF, Vanas NJ, et al. Diffusion-weighted magnetic resonance imaging: a potential non-invasive marker of tumour aggressiveness in localized pros‐

[13] Avallone A, Delrio P, Guida C, Tatangelo F, Petrillo A, Marone P, Cascini LG, Morri‐ ca B, Lastoria S, Parisi V, Budillon A, Comella P. (2006). Biweekly oxaliplatin, ralti‐ trexed, 5-fluorouracil and folinic acid combination chemotherapy during preoperative radiation therapy for locally advanced rectal cancer: a phase I-II study,

[14] Avallone A, Delrio P, Pecori B, Tatangelo F, Petrillo A, Scott N, Marone P, Aloi L, Sandomenico C, Lastoria S, Iaffaioli VR, Scala D, Iodice G, Budillon A., Comella P. (2011). Oxaliplatin plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy for locally advanced rectal carcinoma: long-term outcome, Int J

[15] Delrio P, Avallone A, Guida C, Lastoria S, Tatangelo F, Cascini GM, Marone P, Petril‐ lo, A, Budillon A, Marzo MD, Palaia R, Albino V, Rosa VD, Parisi V. (2005). Multidis‐

sponse of rectal cancer to chemoradiation. Lancet 360 (9329):307–308

currence. Oncology 1998; 55:575–581.

carcinoma. Cancer Res 61(6):2513–2516

for tumor imaging. Br J Radiol 2006;79: 633–635.

tate cancer. Clin Radiol 2008;63:774–782.

Brit J Cancer 94(12): 1809–1815.

Radiat Oncol 79(3): 670–676.

es in oncology. AJR Am J Roentgenol 2007; 188:1622–1635.

56(4):958–96

2008;5:220–233.

Am J Pathol 1995;146:1029–1039.

Although, the ROC curves analysis showed that PET has the best accuracy in term of sensitivity and specificity it should be noticed that only three studies have been retrieved from the literature.

However, in agreement with the intuitive considerations MRI and PET/ CT showed a high diagnostic accuracy and their results are also more reliable than PET because the statistical analysis has been carried out on a larger number of studies (6 studies for MRI with a total of 239 patients and 5 studies for PET/CT with a total of 176 patients).

The number of studies for CT is very small to draw detailed conclusions.

In conclusion we could state that a greater number of studies should be performed in the future for each modalities to improve the reliability of any conclusion.

## **Author details**

Roberta Fusco1,3, Mario Sansone2 , Mario Petrillo3 , Antonio Avallone4 , Paolo Delrio3 , Fabiana Tatangelo3 and Antonella Petrillo1

1 Department of Diagnostic Imaging, Radiant and Metabolic Therapy, "Istituto Nazionale dei Tumori Fondazione G. Pascale " – IRCCS, Naples, Italy

2 Department of Electrical Engineering and Information Technologies University 'Federico II' of Naples, Italy

3 Department of Radiology, Second University of Naples, Italy

4 Gastrointestinal Medical Oncology, "Istituto Nazionale dei Tumori Fondazione G. Pas‐ cale " – IRCCS, Naples, Italy

## **References**


[3] Choi HJ, Hyun MS, Jung GJ, Kim SS, Hong SH. Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and re‐ currence. Oncology 1998; 55:575–581.

**5.3. Discussion**

literature.

**Author details**

Fabiana Tatangelo3

II' of Naples, Italy

**References**

277–300.

1971;285:1182–1186.

cale " – IRCCS, Naples, Italy

Roberta Fusco1,3, Mario Sansone2

in assessing the therapy response.

68 Colorectal Cancer - Surgery, Diagnostics and Treatment

The objective of this statistical analysis was to evaluate the diverse methodologies (MRI, PET, PET/CT, CT) in LARC management. In particular, in our analysis we considered the accuracy

Although, the ROC curves analysis showed that PET has the best accuracy in term of sensitivity and specificity it should be noticed that only three studies have been retrieved from the

However, in agreement with the intuitive considerations MRI and PET/ CT showed a high diagnostic accuracy and their results are also more reliable than PET because the statistical analysis has been carried out on a larger number of studies (6 studies for MRI with a total of

In conclusion we could state that a greater number of studies should be performed in the future

1 Department of Diagnostic Imaging, Radiant and Metabolic Therapy, "Istituto Nazionale

2 Department of Electrical Engineering and Information Technologies University 'Federico

4 Gastrointestinal Medical Oncology, "Istituto Nazionale dei Tumori Fondazione G. Pas‐

[1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60(5):

[2] Folkman J Tumor angiogenesis: therapeutic implications. N Engl J Med

, Antonio Avallone4

, Paolo Delrio3

,

239 patients and 5 studies for PET/CT with a total of 176 patients).

for each modalities to improve the reliability of any conclusion.

and Antonella Petrillo1

dei Tumori Fondazione G. Pascale " – IRCCS, Naples, Italy

3 Department of Radiology, Second University of Naples, Italy

The number of studies for CT is very small to draw detailed conclusions.

, Mario Petrillo3


ciplinary approach to locally advanced rectal cancer: results of a single institution trial, Suppl Tumori 4(3): S8.

[25] Kremser C, Trieb T, Rudisch A, Judmaier W, de Vries A. Dynamic t(1) mapping pre‐ dicts outcome of chemoradiation therapy in primary rectal carcinoma: sequence im‐

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[26] Beets-Tan RG, Beets GL. Rectal cancer: review with emphasis on MR imaging. Radi‐

[27] Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med

[28] Vermaas M, Ferenschild FT, Nuyttens JJ, et al. Preoperative radiotherapy improves

[29] Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J

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therapy in Locally Advanced Rectal Cancer Using18FDG-PET/CT. Society of Surgical Oncology 7 March 2012;19:2178-2185.

**Chapter 4**

**Role of Tumour Markers in Diagnosis and Follow up of**

Colorectal cancer is the second most common cancer in terms of incidence in men and women. Another concern is the high rate of morbidity and mortality in patients with this cancer. Therefore, researchers are constantly searching for new diagnostic methods that would enable the early detection of recurrent, clinically asymptomatic periods. The development of clinical immunodiagnostics has enriched oncology with the possibility of determining the quantity of glycoproteins and glycolipids in the blood of patients with cancer. These are called neoplastic markers. The usefulness of a neoplastic marker assay has been confirmed in diagnosing alimentary tract neoplasms, mainly in the early post-operative detection of a recurrence of

According to an account published by The European Group on Tumor Markers (EGTM) of 2003, CEA is the main marker that is used in detecting colorectal cancer. It is important to point out, however, that approximately 10-15 % of patients do not produce CEA at all or that it is secreted in only minimal amounts. In such cases, the normal level of CEA concentration does not exclude the existence of a neoplasm even at an advanced stage. Therefore, the use of CA

Carcinoembryonic antigen is a glycoprotein that contains about 60% carbohydrates. CEAshave epitopes that are specific to the neoplasm and epitopes that connect antibodies against nonspecific cross-reacting antigens (NCA, NCA2, BGP).Its upper normalrange is 3 ng/ml[1, 2]

> © 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.

**Colorectal Cancer — Potential for Future Research**

Additional information is available at the end of the chapter

**1.1. Immunodiagnostics of Colorectal cancer — CEA and CA 19-9**

neoplastic disease and in the evaluation of the efficacy of surgery.

19-9 as a tumor marker in diagnostics has been proposed.

*1.1.1. Characteristic of CEA tumour marker*

Robert Partyka

**1. Introduction**

http://dx.doi.org/10.5772/57514


## **Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research**

Robert Partyka

therapy in Locally Advanced Rectal Cancer Using18FDG-PET/CT. Society of Surgical

[57] Itatani Y, Akiyoshi T, Kuroyanagi H, Yamakawa K, Noaki R, Konishi T, Fujimoto Y, Ueno M, Oya M, Suenaga M, Yamaguchi T. Total mesorectal excision of initially un‐ resectable locally advanced rectal cancer infiltrating the pelvic wall after treatment with FOLFOX4 plus bevacizumab and preoperative chemoradiation: report of a case.

[58] O'Neill BDP, Brown G, Heald RJ, Cunningham D, Tait DM. Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer. The lancet oncology July

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[60] Beets-Tan RG, Beets GL, Borstlap SC, Oei Tk, Teune TM, von Meyenfeldt MF, et al. Preoperative assessment of local tumour extent in advanced rectal cancer: CT or

[61] Wiering B, Ruers TJ, Oyen WJ. Role of FDG\_PET in the diagnosis and treatment of

[62] Park IJ, Kim HC, Yu CS, et al. Efficacy of PET/CT in the accurate evaluation of pri‐

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Oncology 7 March 2012;19:2178-2185.

74 Colorectal Cancer - Surgery, Diagnostics and Treatment

Surg Today 12 November 2011;42(75-79).

hanced-magnetic-resonance-imaging-in-rectal-cancer.

high- resolution MRI? Abdominal Imaging 2000;25(5):533-41.

mary colorectal carcinoma. Eur J Surg Oncol 2006; 32:941-947.

2007;8:625-633.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57514

## **1. Introduction**

#### **1.1. Immunodiagnostics of Colorectal cancer — CEA and CA 19-9**

Colorectal cancer is the second most common cancer in terms of incidence in men and women. Another concern is the high rate of morbidity and mortality in patients with this cancer. Therefore, researchers are constantly searching for new diagnostic methods that would enable the early detection of recurrent, clinically asymptomatic periods. The development of clinical immunodiagnostics has enriched oncology with the possibility of determining the quantity of glycoproteins and glycolipids in the blood of patients with cancer. These are called neoplastic markers. The usefulness of a neoplastic marker assay has been confirmed in diagnosing alimentary tract neoplasms, mainly in the early post-operative detection of a recurrence of neoplastic disease and in the evaluation of the efficacy of surgery.

According to an account published by The European Group on Tumor Markers (EGTM) of 2003, CEA is the main marker that is used in detecting colorectal cancer. It is important to point out, however, that approximately 10-15 % of patients do not produce CEA at all or that it is secreted in only minimal amounts. In such cases, the normal level of CEA concentration does not exclude the existence of a neoplasm even at an advanced stage. Therefore, the use of CA 19-9 as a tumor marker in diagnostics has been proposed.

#### *1.1.1. Characteristic of CEA tumour marker*

Carcinoembryonic antigen is a glycoprotein that contains about 60% carbohydrates. CEAshave epitopes that are specific to the neoplasm and epitopes that connect antibodies against nonspecific cross-reacting antigens (NCA, NCA2, BGP).Its upper normalrange is 3 ng/ml[1, 2]

#### *1.1.2. Characteristic of CA 19-9 tumour marker*

The CA 19-9 Antigen is associated with gastrointestinal cancers. It occurs in the sialyated Lewis A blood group antigen that is produced in a small amount in the salivary and bronchial glands as well as in the pancreatic and bile ducts. This marker is very useful in the diagnosis of gastrointestinal cancers such as gastric, pancreatic, bile duct cancers and pancreatitis. Its upper normal range is 37 U/ml, but in approximately 1% of healthy people, concentrations reaching 120 U/ml have been detected [1, 2].

according to the stage of the disease and were: Dukes A group – CEA (*x*¯=1.82 ng/ml, CA 19-9 *x*¯=12.45 U/ml, Dukes B group – CEA *x*¯=5.97 ng/ml, CA 19-9 *x*¯=15.37 U/ml, Dukes C group – CEA *x*¯=7.42 ng/ml, CA 19-9 *x*¯=55.73 U/ml, Dukes D group – CEA *x*¯=17.97 ng/ml, CA 19-9 70.42 U/ml. In the post-operative follow-up, in which the Dukes D group was excluded, a recurrence was found in 53 patients, an elevation of CEA was found in 47 patients (88.6%) and CA 19-9 was found in 36 patients (67.9%). The recurrence was detected in 100% of the patients when an elevation of CEA CA 19-9 was accepted as a criterion. The results are shown in Figure 3.

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

**Numbers of patients Dukes scale TNM scale**

61 B 61 – T3N0M0

**Table 1.** The stages of the disease on the Dukes and TNM scales. Table I describes the results of the division of patients according to the

stage of the disease on the TNM scale. The pre-operative CEA and CA 19-9

7.42

17.97

3 – T1N0M0 5 – T2N0M0

http://dx.doi.org/10.5772/57514

77

37 – T3N1M0 57 – T3N2M0

2 – T4N2M1 5 – T4N2M1

CEA

CA 19‐9

8 A

94 C

7 D

concentrations is presented in Figure 1 and Figure 2.

*mean*

*concentration*

*mean*

*concentration*

1.82

**Figure 1.** Mean concentration of CEA markers in pre-operative patients.

Fig. 1. Mean concentration of CEA markers in pre-operative patients.

5.97

ABCD

*Dukes' scale*

55.73

70.42

Fig. 2. Mean concentration of CA 19-9 markers in pre-operative patients.

ABCD

*Dukes' scale*

12.45 15.37

A pre-operative elevation of the CEA concentration in serum was found

in 182 patients (71%). CEA did not exceed the normal range in the Dukes A

#### **1.2. Aim of the study**

The purpose of the study was to estimate the usefulness of selected neoplastic markers – conditioned by their location in the pre-operative and post-operative histological evaluations of patients with gastrointestinal cancers.

#### **1.3. Material and methods**

256 patients, both won men and women, aged 19-86, in whom colorectal cancer was diagnosed and histopathology was confirmed, were included into the research that was performed between 1991-1998.

Patients were divided into two groups according to the progression of the disease on the TMN scale and patients with a proctologic neoplasm on the Dukes and TMN scales. Neoplasm markers were marked in serum using commercial kits (blood samples were collected from the cubital vein and stored at -20°C after centrifugation). CEA and CA 19-9 were detected using the MEIA method using an Abbott's kit (USA). The upper normal range in healthy subjects is 3 ng/ml for CEA and 37 U/ml for CA 19-9.

The detection of neoplastic markers was performed in the Independent Laboratory of Clinical Immunodiagnostics at State Hospital No. 5 in Sosnowiec, Poland. Blood samples were collected preoperatively, in the first, second and third months after surgery and next after every 3 months for 2-5 years.

#### **1.4. Results**

The detection of neoplastic markers was extended about lab tests, abdominal ultrasonography; CT was performed in certain cases. Results were worked out using the t-Student test, the Cochran-Cox test, variance analysis (ANOVA) and the Shapiro-Wilk test for hardly large test.

Table I describes the results of the division of patients according to the stage of the disease on the TNM scale. The pre-operative CEA and CA 19-9 concentrations is presented in Figure 1 and Figure 2.

A pre-operative elevation of the CEA concentration in serum was found in 182 patients (71%). CEA did not exceed the normal range in the Dukes A group. CA 19-9 was increased in 83 (32%) patients in the Dukes C and D groups. The mean concentration of CEA and CA 19-9 changed according to the stage of the disease and were: Dukes A group – CEA (*x*¯=1.82 ng/ml, CA 19-9 *x*¯=12.45 U/ml, Dukes B group – CEA *x*¯=5.97 ng/ml, CA 19-9 *x*¯=15.37 U/ml, Dukes C group – CEA *x*¯=7.42 ng/ml, CA 19-9 *x*¯=55.73 U/ml, Dukes D group – CEA *x*¯=17.97 ng/ml, CA 19-9 70.42 U/ml. In the post-operative follow-up, in which the Dukes D group was excluded, a recurrence was found in 53 patients, an elevation of CEA was found in 47 patients (88.6%) and CA 19-9 was found in 36 patients (67.9%). The recurrence was detected in 100% of the patients when an elevation of CEA CA 19-9 was accepted as a criterion. The results are shown in Figure 3.


stage of the disease on the TNM scale. The pre-operative CEA and CA 19-9

**Table 1.** The stages of the disease on the Dukes and TNM scales. Table I describes the results of the division of patients according to the

concentrations is presented in Figure 1 and Figure 2.

*1.1.2. Characteristic of CA 19-9 tumour marker*

76 Colorectal Cancer - Surgery, Diagnostics and Treatment

120 U/ml have been detected [1, 2].

of patients with gastrointestinal cancers.

3 ng/ml for CEA and 37 U/ml for CA 19-9.

every 3 months for 2-5 years.

**1.4. Results**

and Figure 2.

**1.2. Aim of the study**

**1.3. Material and methods**

between 1991-1998.

The CA 19-9 Antigen is associated with gastrointestinal cancers. It occurs in the sialyated Lewis A blood group antigen that is produced in a small amount in the salivary and bronchial glands as well as in the pancreatic and bile ducts. This marker is very useful in the diagnosis of gastrointestinal cancers such as gastric, pancreatic, bile duct cancers and pancreatitis. Its upper normal range is 37 U/ml, but in approximately 1% of healthy people, concentrations reaching

The purpose of the study was to estimate the usefulness of selected neoplastic markers – conditioned by their location in the pre-operative and post-operative histological evaluations

256 patients, both won men and women, aged 19-86, in whom colorectal cancer was diagnosed and histopathology was confirmed, were included into the research that was performed

Patients were divided into two groups according to the progression of the disease on the TMN scale and patients with a proctologic neoplasm on the Dukes and TMN scales. Neoplasm markers were marked in serum using commercial kits (blood samples were collected from the cubital vein and stored at -20°C after centrifugation). CEA and CA 19-9 were detected using the MEIA method using an Abbott's kit (USA). The upper normal range in healthy subjects is

The detection of neoplastic markers was performed in the Independent Laboratory of Clinical Immunodiagnostics at State Hospital No. 5 in Sosnowiec, Poland. Blood samples were collected preoperatively, in the first, second and third months after surgery and next after

The detection of neoplastic markers was extended about lab tests, abdominal ultrasonography; CT was performed in certain cases. Results were worked out using the t-Student test, the Cochran-Cox test, variance analysis (ANOVA) and the Shapiro-Wilk test for hardly large test.

Table I describes the results of the division of patients according to the stage of the disease on the TNM scale. The pre-operative CEA and CA 19-9 concentrations is presented in Figure 1

A pre-operative elevation of the CEA concentration in serum was found in 182 patients (71%). CEA did not exceed the normal range in the Dukes A group. CA 19-9 was increased in 83 (32%) patients in the Dukes C and D groups. The mean concentration of CEA and CA 19-9 changed

Fig. 2. Mean concentration of CA 19-9 markers in pre-operative patients.

ABCD

*Dukes' scale*

A pre-operative elevation of the CEA concentration in serum was found

in 182 patients (71%). CEA did not exceed the normal range in the Dukes A

55.73

70.42

CA 19‐9

 Fig. 1. Mean concentration of CEA markers in pre-operative patients. **Figure 1.** Mean concentration of CEA markers in pre-operative patients.

12.45 15.37

*mean*

*concentration*

*mean*

*concentration*

1.82

ABCD

*Dukes' scale*

5.97

Table I describes the results of the division of patients according to the

17.97

CEA

recurrence of a neoplastic process in the asymptomatic phase and to estimate the effectiveness of supplementary therapy, a determination of markers in the serum of patients plays a crucial

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

http://dx.doi.org/10.5772/57514

79

Gold and Freedman [10] isolated carcinoembryonic antigen in colon cancer in 1966. They thought that it was specific to colorectal adenocarcinomas. The process of a quantitative determination of CEA in systemic fluids was described shortly thereafter, which indicat‐ ed that more cancers produce CEA than had been previously thought. Moreover, it was found that its serum concentration may be higher than the normal range in non-neoplas‐ tic diseases such as pneumonia, bronchitis, tuberculosis, infections of the urinary tract and

CEA is increased in non-neoplastic diseases of the intestines like colitis ulcerosa and Crohn's disease [1, 4, 11]. This information appeared to reduce the clinical value of a CEA assay; however, the development of monoclonal antibodies against CEA improved the specificity of the assays. This antigen is not present in the serum of all patients, even in a case of a recurrence, which was shown in studies that lasted for several years. Therefore, it is important to enhance clinical immunodiagnostics through the use of other markers (epitopes), which can use the information provided by the assay of CEA. The studies included 256 patients divided accord‐ ing to the stage of the cancer on the Dukes and TNM scales. Two neoplastic cancers CEA and CA 19-9 were determined in all 256 patients. Increased CEA was found in 182 patients (71%)

An analysis of the results revealed that in addition to CEA, CA 19-9 is an especially helpful marker. This agrees with the reports of Dienst et al. [12], who found increased concentrations of CEA in 49-58.5% of patients and increased concentrations of CA 19-9 in 21-67% of patients. However, Filela et al. [5] observed increased concentrations of CEA in 61% of patients and increased concentrations of CA 19-9 in 35% of patients. The concentration of both markers changed depending on the stage of the disease. CEA and CA 19-9 concentrations were within normal limits in the Dukes A group; the mean concentration of CEA was above the normal limits, 5.97 ng/ml, and CA 19-9 was within the normal limits in the Dukes B group. In the Dukes C group, the mean concentration of CEA was 7.42 ng/ml and the mean concentration of CA 19-9 was 55.73 U/ml. Similar results can be found in literature. Szymendera [2], Nowacki [7] and Lindmark et al. [13] revealed that in the advanced stages of colon cancer, a percentage of patients have elevated CEA and CEA concentrations. However, about 10-15% of patients do

The literature reveals that about 11-13% of patients with histopathologically confirmed colorectal cancer do not "produce" CEA and that an assay of these markers can lead to false negative results [2, 4, 9]. In these cases, the presence of advanced cancer is not excluded by a CEA concentration within the normal limits. CA 19-9 is the marker of first choice in this group of patients. The addition of CA 19-9 to an assay of CEA increased the sensitivity from 71% to 83.6% in our studies; however, 12.5% of patients with CEA within the normal limits had elevated CA 19-9. A positive correlation of CEA, CA 19-9 and the Dukes scale was revealed. Similar results were obtained by other authors. Fillela et al. [5] revealed that multifactoral analysis indicates the prognostic significance of CA 19-9 independent of the Dukes scale. New

role [1, 2, 4, 5, 6, 7, 8, 9].

also in 30% of smokers [1, 10].

not secrete CEA.

and CA 19-9 was found in 83 patients (32%).

7.42

stage of the disease on the TNM scale. The pre-operative CEA and CA 19-9

concentrations is presented in Figure 1 and Figure 2.

 Fig. 2. Mean concentration of CA 19-9 markers in pre-operative patients. **Figure 2.** Mean concentration of CA 19-9 markers in pre-operative patients. in 100% of the patients when an elevation of CEA CA 19-9 was accepted as a criterion. The results are shown in Figure 3.

Fig. 3. Percentage of CEA and CA 19-9 concentration in patients with a recurrence. **Figure 3.** Percentage of CEA and CA 19-9 concentration in patients with a recurrence.

#### **1.5. Discussion**

**Discussion** Although the dreams of Bates et al. [3] to find an ideal marker for an active neoplastic process, i.e. that they have a different effect depending Although the dreams of Bates et al. [3] to find an ideal marker for an active neoplastic process, i.e. that they have a different effect depending on the location of an organ and are absent in healthy people, were frustrated, neoplastic markers are now widely used in clinical diagnos‐ tics, usually for patients who have undergone surgery to remove cancerous tissue. Studies that lasted several years revealed that in order to estimate the efficacy of surgery, to detect a

on the location of an organ and are absent in healthy people, were frustrated,

neoplastic markers are now widely used in clinical diagnostics, usually

recurrence of a neoplastic process in the asymptomatic phase and to estimate the effectiveness of supplementary therapy, a determination of markers in the serum of patients plays a crucial role [1, 2, 4, 5, 6, 7, 8, 9].

Table I describes the results of the division of patients according to the

17.97

CEA

CA 19‐9

7.42

stage of the disease on the TNM scale. The pre-operative CEA and CA 19-9

concentrations is presented in Figure 1 and Figure 2.

78 Colorectal Cancer - Surgery, Diagnostics and Treatment

*% of*

*elevated*

*concentration*

*mean*

**Discussion**

**1.5. Discussion**

*concentration*

*mean*

*concentration*

1.82

Fig. 1. Mean concentration of CEA markers in pre-operative patients.

5.97

ABCD

*Dukes' scale*

55.73

group. CA 19-9 was increased in 83 (32%) patients in the Dukes C and D

groups. The mean concentration of CEA and CA 19-9 changed according

to the stage of the disease and were: Dukes A group – CEA (�̅=1.82 ng/ml, CA

19-9 �̅=12.45 U/ml, Dukes B group – CEA �̅=5.97 ng/ml, CA 19-9 �̅=15.37

U/ml, Dukes C group – CEA �̅=7.42 ng/ml, CA 19-9 �̅=55.73 U/ml, Dukes D

group – CEA �̅=17.97 ng/ml, CA 19-9 70.42 U/ml. In the post-operative followup, in which the Dukes D group was excluded, a recurrence was found

in 53 patients, an elevation of CEA was found in 47 patients (88.6%)

and CA 19-9 was found in 36 patients (67.9%). The recurrence was detected

in 100% of the patients when an elevation of CEA CA 19-9 was accepted

70.42

Fig. 2. Mean concentration of CA 19-9 markers in pre-operative patients.

ABCD

*Dukes' scale*

12.45 15.37

**Figure 2.** Mean concentration of CA 19-9 markers in pre-operative patients.

as a criterion. The results are shown in Figure 3.

**86.6**

**Figure 3.** Percentage of CEA and CA 19-9 concentration in patients with a recurrence.

A pre-operative elevation of the CEA concentration in serum was found

Fig. 3. Percentage of CEA and CA 19-9 concentration in patients with a recurrence.

**19‐9**

**56.6**

**CEA or CA 19‐9**

**100**

**CEA CA 19‐9 CEA and CA**

Although the dreams of Bates et al. [3] to find an ideal marker

for an active neoplastic process, i.e. that they have a different effect depending

Although the dreams of Bates et al. [3] to find an ideal marker for an active neoplastic process, i.e. that they have a different effect depending on the location of an organ and are absent in healthy people, were frustrated, neoplastic markers are now widely used in clinical diagnos‐ tics, usually for patients who have undergone surgery to remove cancerous tissue. Studies that lasted several years revealed that in order to estimate the efficacy of surgery, to detect a

on the location of an organ and are absent in healthy people, were frustrated,

neoplastic markers are now widely used in clinical diagnostics, usually

in 182 patients (71%). CEA did not exceed the normal range in the Dukes A

**67.9**

Gold and Freedman [10] isolated carcinoembryonic antigen in colon cancer in 1966. They thought that it was specific to colorectal adenocarcinomas. The process of a quantitative determination of CEA in systemic fluids was described shortly thereafter, which indicat‐ ed that more cancers produce CEA than had been previously thought. Moreover, it was found that its serum concentration may be higher than the normal range in non-neoplas‐ tic diseases such as pneumonia, bronchitis, tuberculosis, infections of the urinary tract and also in 30% of smokers [1, 10].

CEA is increased in non-neoplastic diseases of the intestines like colitis ulcerosa and Crohn's disease [1, 4, 11]. This information appeared to reduce the clinical value of a CEA assay; however, the development of monoclonal antibodies against CEA improved the specificity of the assays. This antigen is not present in the serum of all patients, even in a case of a recurrence, which was shown in studies that lasted for several years. Therefore, it is important to enhance clinical immunodiagnostics through the use of other markers (epitopes), which can use the information provided by the assay of CEA. The studies included 256 patients divided accord‐ ing to the stage of the cancer on the Dukes and TNM scales. Two neoplastic cancers CEA and CA 19-9 were determined in all 256 patients. Increased CEA was found in 182 patients (71%) and CA 19-9 was found in 83 patients (32%).

An analysis of the results revealed that in addition to CEA, CA 19-9 is an especially helpful marker. This agrees with the reports of Dienst et al. [12], who found increased concentrations of CEA in 49-58.5% of patients and increased concentrations of CA 19-9 in 21-67% of patients. However, Filela et al. [5] observed increased concentrations of CEA in 61% of patients and increased concentrations of CA 19-9 in 35% of patients. The concentration of both markers changed depending on the stage of the disease. CEA and CA 19-9 concentrations were within normal limits in the Dukes A group; the mean concentration of CEA was above the normal limits, 5.97 ng/ml, and CA 19-9 was within the normal limits in the Dukes B group. In the Dukes C group, the mean concentration of CEA was 7.42 ng/ml and the mean concentration of CA 19-9 was 55.73 U/ml. Similar results can be found in literature. Szymendera [2], Nowacki [7] and Lindmark et al. [13] revealed that in the advanced stages of colon cancer, a percentage of patients have elevated CEA and CEA concentrations. However, about 10-15% of patients do not secrete CEA.

The literature reveals that about 11-13% of patients with histopathologically confirmed colorectal cancer do not "produce" CEA and that an assay of these markers can lead to false negative results [2, 4, 9]. In these cases, the presence of advanced cancer is not excluded by a CEA concentration within the normal limits. CA 19-9 is the marker of first choice in this group of patients. The addition of CA 19-9 to an assay of CEA increased the sensitivity from 71% to 83.6% in our studies; however, 12.5% of patients with CEA within the normal limits had elevated CA 19-9. A positive correlation of CEA, CA 19-9 and the Dukes scale was revealed. Similar results were obtained by other authors. Fillela et al. [5] revealed that multifactoral analysis indicates the prognostic significance of CA 19-9 independent of the Dukes scale. New information about the CA 19-9 antigen has been revealed in recent years. CA 19-9 is sialofu‐ cololactotetraosyl and is included in the group of E-selectines. E-selectines enable a rise of remote metastases that is caused by the adhesion of neoplastic cells to epithelial cells in macrocirculation vessels. A pre-operative statistical analysis showed that the probability of recurrence is higher in cases where there is a higher CEA concentration before a treatment. However, Filela et al. [5] revealed that the risk of recurrence is 2.95 times greater in preoperative patients with an increased concentration of CA 19-9 than in patients with a normal concentration of CA 19-9. 170 of 256 the patients who underwent surgery were tested in the follow-up phase. Patients in the Dukes D group were not tested. A recurrence was observed in 53 of the 170 patients (31%). The mean concentration of CEA was 20.71 ng/ml in the Dukes B group and 20.55 ng/ml in the Dukes C group. The mean concentration of CA 19-9 was 61.61 U/ml and 197.18 U/ml, respectively. A recurrence was detected in 100% of the patients when an increased concentration of CEA or CA 19-9 was used as a criterion. A recurrence was detected in 88.6% of patients when only CEA was estimated and 67.9% of patients when only CA 19-9 was estimated. The differentiation of a local neoplasm and remote metastases is difficult. Szymendera [2] reported that a concentration of CEA that is greater than 20 indicates metastases in the liver, while a small concentration of CEA or CA 19-9 might indicate meta‐ stases in the bones or lymph nodes.

who have undergone cancer surgery (esp. of the digestive tract, but also for breast and ovarian

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81

**2.1. Characteristic of tissue polypeptide specific antigen (TPS) — Soluble fragments of**

**2.2. Clinical results of serum concentration of TPS in patients with colorectal cancer**

**1.** To estimate pre-operative CEA and TPS concentrations in the blood serum of patients with colorectal cancer and rectal carcinomas depending on the advancement of their

**2.** To attempt to determine whether TPS provides additional information that cannot be

178 patients (101 men and 77 women) aged 22-86 years who had been diagnosed with colorectal cancer and had undergone surgery in the years 1991-2002 were included in the study. The patients were being treated at the Department of General Surgery and Coloproctology of the Medical University of Silesia in Sosnowiec. The CEA concentration was determined in the patients' blood serum using the MEIA method and commercial sets from Abbott (USA). TPS was determined using the enzyme-immunological method (EIA) and sets from BEKI (Sweden). The normal concentration of CEA was determined as 3 ng/ml and in the case of TPS – 90 U/l.

The criteria for choosing patients for the research: 178 patients whose pre-operative diagnostics confirmed the existence of a colon or rectal adenocarcinoma in a histopatholog‐

The criteria for excluding patients from the research. The research excluded patients who were

**•** an inflammation of the large intestine (colitis ulcerosa, Leśniowski-Crohn disease),

TPS (tissue polypeptide specific antigen) is a new marker of cellular proliferation. The antibody directed against TPS enables the determination of the concentration of the soluble fragments of cytokeratin 18 [14]. TPS was introduced into oncological immunodiagnostics by Bjorklund. It has one of the two active epitopes of TPA (tissue polypeptide antigen) that are detectable by the monoclonal antibody M3. TPS is a singular conjugated polypeptide chain that is created in the S and G2 phases of the cellular cycle and is released immediately after mitosis. It has 33 antigen determiners, two of which are connected with the activity of a tumor. TPS is strictly connected with the proliferation of neoplastic cells and is a function of the velocity of cell

cancer) proceeding the clinical symptoms of metastasis for 2-7 months.

**cytokeratine 18**

divisions [15].

*2.2.1. Aim of the study*

disease.

ical examination.

diagnosed with:

**•** chronic kidney diseases,

*2.2.2. Material and methods*

obtained from CEA tests only.

#### **1.6. Conclusions**


The continuous development of immunodiagnostic methods and the production of monoclo‐ nal antibodies can bring new neoplastic markers into diagnostics. One of these is the TPS (Tissue Polipeptide Specific Antigen). Its structure is similar to the TPA (Tissue Polipeptide Antigen). Reports in the last 2-3 years suggest the great value of the determination of TPS in the serum of patients, including patients with gastrointestinal cancers, especially for the early detection of release and estimation of therapy effectiveness. TPS is a marker of cell proliferation and an increase in its concentration in serum often precedes the markers of a tumor

## **2. Scientific literature indicates interest of a cellular proliferation marker — TPS**

A review of medical reports from recent years shows an increasing interest in estimating TPS levels mainly in oncologic diagnostics. Estimating TPS- concentration (which is a marker connected with the proliferation of neoplastic cells) is very important for monitoring patients who have undergone cancer surgery (esp. of the digestive tract, but also for breast and ovarian cancer) proceeding the clinical symptoms of metastasis for 2-7 months.

#### **2.1. Characteristic of tissue polypeptide specific antigen (TPS) — Soluble fragments of cytokeratine 18**

TPS (tissue polypeptide specific antigen) is a new marker of cellular proliferation. The antibody directed against TPS enables the determination of the concentration of the soluble fragments of cytokeratin 18 [14]. TPS was introduced into oncological immunodiagnostics by Bjorklund. It has one of the two active epitopes of TPA (tissue polypeptide antigen) that are detectable by the monoclonal antibody M3. TPS is a singular conjugated polypeptide chain that is created in the S and G2 phases of the cellular cycle and is released immediately after mitosis. It has 33 antigen determiners, two of which are connected with the activity of a tumor. TPS is strictly connected with the proliferation of neoplastic cells and is a function of the velocity of cell divisions [15].

#### **2.2. Clinical results of serum concentration of TPS in patients with colorectal cancer**

#### *2.2.1. Aim of the study*

information about the CA 19-9 antigen has been revealed in recent years. CA 19-9 is sialofu‐ cololactotetraosyl and is included in the group of E-selectines. E-selectines enable a rise of remote metastases that is caused by the adhesion of neoplastic cells to epithelial cells in macrocirculation vessels. A pre-operative statistical analysis showed that the probability of recurrence is higher in cases where there is a higher CEA concentration before a treatment. However, Filela et al. [5] revealed that the risk of recurrence is 2.95 times greater in preoperative patients with an increased concentration of CA 19-9 than in patients with a normal concentration of CA 19-9. 170 of 256 the patients who underwent surgery were tested in the follow-up phase. Patients in the Dukes D group were not tested. A recurrence was observed in 53 of the 170 patients (31%). The mean concentration of CEA was 20.71 ng/ml in the Dukes B group and 20.55 ng/ml in the Dukes C group. The mean concentration of CA 19-9 was 61.61 U/ml and 197.18 U/ml, respectively. A recurrence was detected in 100% of the patients when an increased concentration of CEA or CA 19-9 was used as a criterion. A recurrence was detected in 88.6% of patients when only CEA was estimated and 67.9% of patients when only CA 19-9 was estimated. The differentiation of a local neoplasm and remote metastases is difficult. Szymendera [2] reported that a concentration of CEA that is greater than 20 indicates metastases in the liver, while a small concentration of CEA or CA 19-9 might indicate meta‐

**1.** Simultaneous detection of CEA and CA 19-9 should be the first immunodiagnostic test in

**2.** The use of carcinoembryonic antigen is advisable in order to monitor the course of the disease in the case of an increased serum concentration of CEA and CA 19-9.

**3.** An increased concentration of CA 19-9 along with a normal lack of CEA in the serum of

The continuous development of immunodiagnostic methods and the production of monoclo‐ nal antibodies can bring new neoplastic markers into diagnostics. One of these is the TPS (Tissue Polipeptide Specific Antigen). Its structure is similar to the TPA (Tissue Polipeptide Antigen). Reports in the last 2-3 years suggest the great value of the determination of TPS in the serum of patients, including patients with gastrointestinal cancers, especially for the early detection of release and estimation of therapy effectiveness. TPS is a marker of cell proliferation

patients with colorectal adenocarcinomas is unfavorable prognostically.

and an increase in its concentration in serum often precedes the markers of a tumor

**2. Scientific literature indicates interest of a cellular proliferation marker**

A review of medical reports from recent years shows an increasing interest in estimating TPS levels mainly in oncologic diagnostics. Estimating TPS- concentration (which is a marker connected with the proliferation of neoplastic cells) is very important for monitoring patients

stases in the bones or lymph nodes.

80 Colorectal Cancer - Surgery, Diagnostics and Treatment

patients suspected of having colorectal cancer.

**1.6. Conclusions**

**— TPS**


#### *2.2.2. Material and methods*

178 patients (101 men and 77 women) aged 22-86 years who had been diagnosed with colorectal cancer and had undergone surgery in the years 1991-2002 were included in the study. The patients were being treated at the Department of General Surgery and Coloproctology of the Medical University of Silesia in Sosnowiec. The CEA concentration was determined in the patients' blood serum using the MEIA method and commercial sets from Abbott (USA). TPS was determined using the enzyme-immunological method (EIA) and sets from BEKI (Sweden). The normal concentration of CEA was determined as 3 ng/ml and in the case of TPS – 90 U/l.

The criteria for choosing patients for the research: 178 patients whose pre-operative diagnostics confirmed the existence of a colon or rectal adenocarcinoma in a histopatholog‐ ical examination.

The criteria for excluding patients from the research. The research excluded patients who were diagnosed with:


In cases where the division according to the degree of advancement in the whole group of 178 patients was not taken into account, the sensitivity for pre-operative CEA concentration was 72.5% and for TPS – 65.2%. When only cases with increased levels of CEA and TPS concen‐

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

The concentration of CEA was: 2.34 ng/ml in the Dukes A subgroup, 5.71 ng/ml in the Dukes B subgroup, 8.66 ng/ml in the Dukes C subgroup and 19.97 ng/ml in the Dukes D subgroup,

**A** 8 2,34 0,362284 0,128087 2,03462 2,64038

**B** 62 5,71 4,385849 0,557003 4,59636 6,82396

**C** 89 8,66 7,035047 0,745713 7,17906 10,14296

**D** 19 19,97 9,826148 2,254273 15,23553 24,70763

Another characteristic was observed in the case of the determination of TPS concentration. The highest average pre-operative TPS concentration was found in the Dukes C subgroup – 226.7 U/l. It was 107.4 U/l in the Dukes A subgroup and 181.2 U/l in the Dukes B subgroup. However, the average amount measured in the Dukes D subgroup was 167.37 U/l, which may be

**Table 4.** CEA concentration in patients before surgery in relation to the degree of the advancement of the cancer

**Standard deviation**

**A** 8 107,41 60,0221 21,22102 57,2328 157,5922

**B** 62 181,20 75,9138 9,64106 161,9283 200,4853

**C** 89 226,71 126,6201 13,42170 200,0392 253,3848

**D** 19 167,37 145,3267 33,34024 97,3295 237,4200

**Table 5.** TPS concentration in patients before operation in relation to the degree of the advancement of the cancer

A recurrence of the disease was detected in 47 patients (Dukes B and C). When the concentra‐ tion of CEA was used, recurrence was detected in 89.4% of patients and when the concentration of TPS was used, recurrence was detected in 80.85% of patients. If the criterion was an elevated

**Standard error -95% CI +95% CI**

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83

**Standard error -95% CI +95% CI**

**Standard deviation**

trations were taken into account, the sensitivity of the test increased to 82.6%.

respectively. (Table IV)

**Number of patients**

**Average amount**

connected with a decrease in proliferation. (Table V)

**Average amount**

**Number of patients**

**Dukes**

according to Dukes.

**Dukes**

according to Dukes.


The largest number of patients in the research was in the Dukes C group – 89 patients (50%). The fewest number of patients was in the Dukes A group – 8 patients (10.11%)(Table II)


**Table 2.** The degree of the clinical advancement of colon and rectal carcinomas according to Dukes.

#### *2.2.2.1. Statistical methods*

All results were statistically measured using the Statistica 6.0 program from StatSoft Inc.

#### *2.2.3. Results*

No increased abnormal CEA concentration was found in any patient in the Dukes A subgroup. An increased amount of CEA was found in 37 cases (59.7%) in the Dukes B subgroup, in 75 patients (83.9%) in the Dukes C subgroup and in 17 cases (89.57%) in the Dukes D subgroup.

Another profile was observed when determining TPS. An increased concentration was found in 3 patients (37.5%) in the Dukes A subgroup. An increased concentration was found in 48 cases (77.4%) in the Dukes B subgroup, in 59 cases (65.5%) in the Dukes C subgroup and in 6 cases (31.6%) in the Dukes D subgroup. (Table III)


**Table 3.** The percentage of patients with an increased abnormal concentration of CEA and TPS in relation to the Dukes scale.

In cases where the division according to the degree of advancement in the whole group of 178 patients was not taken into account, the sensitivity for pre-operative CEA concentration was 72.5% and for TPS – 65.2%. When only cases with increased levels of CEA and TPS concen‐ trations were taken into account, the sensitivity of the test increased to 82.6%.

**•** chronic liver diseases,

thyroid cysts),

**•** chronic infections.

*2.2.2.1. Statistical methods*

*2.2.3. Results*

Dukes scale.

**•** diabetes, or

**•** an inflammation of the rheumatoid joints,

82 Colorectal Cancer - Surgery, Diagnostics and Treatment

**•** autoimmunological diseases caused by autoimmunity (Hashimoto, Graves-Basedov,

The largest number of patients in the research was in the Dukes C group – 89 patients (50%). The fewest number of patients was in the Dukes A group – 8 patients (10.11%)(Table II)

62 B 62 – T3N0M0

3 – T1N0M0 5 – T2N0M0

53 – T3N1M0 36 – T3N2M0

11 – T4N2M1 8 – T4N2M1

**Numbers of patients Dukes scale TNM scale**

8 A

89 C

19 D

cases (31.6%) in the Dukes D subgroup. (Table III)

**Table 2.** The degree of the clinical advancement of colon and rectal carcinomas according to Dukes.

All results were statistically measured using the Statistica 6.0 program from StatSoft Inc.

No increased abnormal CEA concentration was found in any patient in the Dukes A subgroup. An increased amount of CEA was found in 37 cases (59.7%) in the Dukes B subgroup, in 75 patients (83.9%) in the Dukes C subgroup and in 17 cases (89.57%) in the Dukes D subgroup. Another profile was observed when determining TPS. An increased concentration was found in 3 patients (37.5%) in the Dukes A subgroup. An increased concentration was found in 48 cases (77.4%) in the Dukes B subgroup, in 59 cases (65.5%) in the Dukes C subgroup and in 6

**Dukes CEA [%] TPS [%] A** 0,00 37,5 **B** 59,68 77,41935 **C** 83,91 65,51724 **D** 89,47 31,57895

**Table 3.** The percentage of patients with an increased abnormal concentration of CEA and TPS in relation to the

The concentration of CEA was: 2.34 ng/ml in the Dukes A subgroup, 5.71 ng/ml in the Dukes B subgroup, 8.66 ng/ml in the Dukes C subgroup and 19.97 ng/ml in the Dukes D subgroup, respectively. (Table IV)


**Table 4.** CEA concentration in patients before surgery in relation to the degree of the advancement of the cancer according to Dukes.

Another characteristic was observed in the case of the determination of TPS concentration. The highest average pre-operative TPS concentration was found in the Dukes C subgroup – 226.7 U/l. It was 107.4 U/l in the Dukes A subgroup and 181.2 U/l in the Dukes B subgroup. However, the average amount measured in the Dukes D subgroup was 167.37 U/l, which may be connected with a decrease in proliferation. (Table V)


**Table 5.** TPS concentration in patients before operation in relation to the degree of the advancement of the cancer according to Dukes.

A recurrence of the disease was detected in 47 patients (Dukes B and C). When the concentra‐ tion of CEA was used, recurrence was detected in 89.4% of patients and when the concentration of TPS was used, recurrence was detected in 80.85% of patients. If the criterion was an elevated concentration of CEA or TPS, recurrence was detected in of 100% patients. The concentration of CEA in patients with a recurrence was *x*¯=12.82 ± 4.73 ng/ml in the Dukes B group and *x*¯=13.5 ± 7.69 ng/ml in the Dukes C group. The concentration of TPS was *x*¯=282.95 ± 56.08 U/l in the Dukes B group and C *x*¯= 313.77 ± 116.62 U/l in the Dukes C group.

**3. Apoptosis and proliferation – Bcl-2**

toring of patients with colorectal cancer.

**3.1. Material and methods**

the studies.

**3.2. Results**

(Figures 4, 5 and 6)

about apoptosis concern immunohistochemistry studies.

The mechanism of malignancy is considered to be an imbalance between apoptosis and the processes of proliferation. A phenotype that is resistant to apoptosis is one of the major features of cancer cells. Recently, attention has been drawn to the function of a number of proteins that inhibit the process of apoptosis within a tumor. To date, only a few works connected with the assessment of apoptosis proteins serum concentrations have been published. Most of the works

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85

This study attempts to find an answer to the question of whether the serum concentration of antiapoptotic the Bcl-2 protein provides additional information for the post-operative moni‐

The research was conducted on 46 patients (21 with a B Astler-Coller's stage cancer and 25 with a C Astler-Coller's stage cancer) was it colon cancer, who underwent surgery (resection RO). Their ages ranged from 47 to 85 (average age 67); sex (19 women, 27 men). The patients were divided into 2 groups: I –patients with a recurrence of cancer and II – patients without a recurrence of cancer. The control group consisted of 20 healthy people, mainly medical staff. The average CEA concentration in this group was 1.6 ng/ml+/- 0.43; TPS: 48.67U/l+/- 9.1; Bcl2: 0.31ng/ml+/- 0.13. The period of the observation of the patients and conducting the research was 1-5 years. The recurrence of the disease or the lack of a recurrence was confirmed using a physical examination and additional examinations during the oncological follow-up. Ten ml of venous shunt blood was collected from each patient. The serum was frozen at -20°C after centrifuging-. The blood for testing was collected one day before the surgery and 1, 3, 6 and 12 months after the surgery. CEA was measured using MEIA method and a commercial set from ABBOT (USA). The standard concentration for a healthy person was adopted as 3ng/ml. TPS was measured using the EIA method and sets from Beki Diagnostic Bromma (Sweden). The standard for a healthy person does not exceed 90 U/I. Bcl-2 concentration was labeled using the ELISA method using SORIN-BIOMEDICA tests (Italy). A standard for healthy people is 0.5 ng/ml. The results obtained were analyzed statistically. Calculations were done using Microsoft Excel 2003. The Ethical Committee at the Silesian Medical University approved

Of the 46 patients who underwent surgery, a recurrence was detected in 14 patients including 6 with an initial stage of a tumor – B according to the Dukes classification as modified by Astler-Coller and 8 – degree C. The detection time of the recurrence was from 6 to 23 months. Most of the recurrences were distant metastases: 9 in the liver and 2 in the lungs. A local recurrence was observed in the intestinal stapling or retroperitoneal space in 3 patients. (Table VI) and

#### *2.2.4. Discussion*

In diagnosing carcinomas of the digestive system, particularly in the case of colon and rectal carcinomas, the carcinoembryonic antigen (CEA) still remains the "gold standard" [16, 17, 18]. However, great expectations are connected with the introduction of the soluble fragments of cytokeratin 18 (TPS) into the immunodiagnostics of colorectal cancer because TPS reflects the velocity of cell divisions [19].

Our results of pre-operative CEA concentrations are similar to those that have been reported by other researchers. Treska et al. obtained the highest sensitivity of CEA assessment from 45% to 80% depending on the degree of the progression of cancer [20]. Similar results were reported by Turoldo et al. and Marchena et al. [21, 22].

The main aim of the presented research was to estimate the usefulness of determining TPS concentration. The TPS sensitivity was 65.17% in our own clinical research. The highest preoperative sensitivity equaling 70% was reported by Plebani et al. [23].

We also observed that the sensitivity of the test increased when the results of the determination of TPS and CEA were combined. An abnormal pre-operative CEA concentration was recorded in 129 patients (72.47%). When determining TPS concentration, 116 patients were found to have increased abnormal levels (65.17%). When the established criterion was an increased level of TPS or CEA, then the sensitivity of the test increased to 82.31%. Lindmark et al. using the CEA, CA 19-9, CA 50 and TPS tests proved their correlation with one another; however, only the TPS concentration test had the highest diagnostic sensitivity [18].

It is important to stress that adding TPS determination to the standard tests used for detecting and monitoring colon and rectal carcinomas has recently been approved by the European Group of Tumor Markers. According to the EGTM tests, adding TPS determination to the list of "mass tumor" markers enables an increase in sensitivity, particularly in the earlier stages of colorectal cancer [24].

#### *2.2.5. Conclusions*


## **3. Apoptosis and proliferation – Bcl-2**

The mechanism of malignancy is considered to be an imbalance between apoptosis and the processes of proliferation. A phenotype that is resistant to apoptosis is one of the major features of cancer cells. Recently, attention has been drawn to the function of a number of proteins that inhibit the process of apoptosis within a tumor. To date, only a few works connected with the assessment of apoptosis proteins serum concentrations have been published. Most of the works about apoptosis concern immunohistochemistry studies.

This study attempts to find an answer to the question of whether the serum concentration of antiapoptotic the Bcl-2 protein provides additional information for the post-operative moni‐ toring of patients with colorectal cancer.

#### **3.1. Material and methods**

concentration of CEA or TPS, recurrence was detected in of 100% patients. The concentration of CEA in patients with a recurrence was *x*¯=12.82 ± 4.73 ng/ml in the Dukes B group and *x*¯=13.5 ± 7.69 ng/ml in the Dukes C group. The concentration of TPS was *x*¯=282.95 ± 56.08 U/l in the

In diagnosing carcinomas of the digestive system, particularly in the case of colon and rectal carcinomas, the carcinoembryonic antigen (CEA) still remains the "gold standard" [16, 17, 18]. However, great expectations are connected with the introduction of the soluble fragments of cytokeratin 18 (TPS) into the immunodiagnostics of colorectal cancer because TPS reflects

Our results of pre-operative CEA concentrations are similar to those that have been reported by other researchers. Treska et al. obtained the highest sensitivity of CEA assessment from 45% to 80% depending on the degree of the progression of cancer [20]. Similar results were reported

The main aim of the presented research was to estimate the usefulness of determining TPS concentration. The TPS sensitivity was 65.17% in our own clinical research. The highest pre-

We also observed that the sensitivity of the test increased when the results of the determination of TPS and CEA were combined. An abnormal pre-operative CEA concentration was recorded in 129 patients (72.47%). When determining TPS concentration, 116 patients were found to have increased abnormal levels (65.17%). When the established criterion was an increased level of TPS or CEA, then the sensitivity of the test increased to 82.31%. Lindmark et al. using the CEA, CA 19-9, CA 50 and TPS tests proved their correlation with one another; however, only

It is important to stress that adding TPS determination to the standard tests used for detecting and monitoring colon and rectal carcinomas has recently been approved by the European Group of Tumor Markers. According to the EGTM tests, adding TPS determination to the list of "mass tumor" markers enables an increase in sensitivity, particularly in the earlier stages

**1.** The profile of the activity of pre-operative TPS concentration in the blood serum of patients with colorectal cancer in relation to the degree of the advancement of the cancer is different

**2.** Determination of TPS concentration in patients with colorectal cancer provides essential information necessary to confirm the cancer, particularly at the earliest stages of its

Dukes B group and C *x*¯= 313.77 ± 116.62 U/l in the Dukes C group.

operative sensitivity equaling 70% was reported by Plebani et al. [23].

the TPS concentration test had the highest diagnostic sensitivity [18].

*2.2.4. Discussion*

the velocity of cell divisions [19].

84 Colorectal Cancer - Surgery, Diagnostics and Treatment

of colorectal cancer [24].

advancement.

from that observed for CEA.

*2.2.5. Conclusions*

by Turoldo et al. and Marchena et al. [21, 22].

The research was conducted on 46 patients (21 with a B Astler-Coller's stage cancer and 25 with a C Astler-Coller's stage cancer) was it colon cancer, who underwent surgery (resection RO). Their ages ranged from 47 to 85 (average age 67); sex (19 women, 27 men). The patients were divided into 2 groups: I –patients with a recurrence of cancer and II – patients without a recurrence of cancer. The control group consisted of 20 healthy people, mainly medical staff. The average CEA concentration in this group was 1.6 ng/ml+/- 0.43; TPS: 48.67U/l+/- 9.1; Bcl2: 0.31ng/ml+/- 0.13. The period of the observation of the patients and conducting the research was 1-5 years. The recurrence of the disease or the lack of a recurrence was confirmed using a physical examination and additional examinations during the oncological follow-up. Ten ml of venous shunt blood was collected from each patient. The serum was frozen at -20°C after centrifuging-. The blood for testing was collected one day before the surgery and 1, 3, 6 and 12 months after the surgery. CEA was measured using MEIA method and a commercial set from ABBOT (USA). The standard concentration for a healthy person was adopted as 3ng/ml. TPS was measured using the EIA method and sets from Beki Diagnostic Bromma (Sweden). The standard for a healthy person does not exceed 90 U/I. Bcl-2 concentration was labeled using the ELISA method using SORIN-BIOMEDICA tests (Italy). A standard for healthy people is 0.5 ng/ml. The results obtained were analyzed statistically. Calculations were done using Microsoft Excel 2003. The Ethical Committee at the Silesian Medical University approved the studies.

#### **3.2. Results**

Of the 46 patients who underwent surgery, a recurrence was detected in 14 patients including 6 with an initial stage of a tumor – B according to the Dukes classification as modified by Astler-Coller and 8 – degree C. The detection time of the recurrence was from 6 to 23 months. Most of the recurrences were distant metastases: 9 in the liver and 2 in the lungs. A local recurrence was observed in the intestinal stapling or retroperitoneal space in 3 patients. (Table VI) and (Figures 4, 5 and 6)

It was established that the Bcl-2 concentration was statistically significantly higher in the recurrence group than in the non-recurrence group when examined 1, 3, 6 and 12 months after the surgery. The TPS concentration was statistically significantly higher in the recurrence group than in the non-recurrence group when examined before and 3, 6 and 12 months after the surgery. The concentration of the antigen, i.e. CEA, was statistically significantly higher in the recurrence group in relation to the non-recurrence group, as was TPS in the pre-operative determinations and 3, 6 and 12 months after the surgery. Bcl-2, TPS and CEA serum concen‐ trations were unrelated to the Astler-Coller stage of colorectal cancer. However, insignificantly higher concentrations of CEA at degree C than at degree B were observed. There was also no dependence related to the sex, the age of a patient, the original location of the tumor and the recurrence. Correlations between the concentrations of the determined parameters in all patients (with a recurrence and without a recurrence) were also noticed. A strong correlation between the concentrations of Bcl-2 and TPS proteins occurred 12 months after the surgery in the recurrence group.


**Figure 4.** Results of the evaluation of post-operative CEA levels

**Figure 4.** Results of the evaluation of post-operative CEA levels

**Figure 4.** Results of the evaluation of post-operative CEA levels in the group without recurrence, with recurrence and

**Group**

**Group**

**Figure 5.** Results of the evaluation of post-operative Bcl-2 levels

**Figure 5.** Results of the evaluation of post-operative Bcl-2 levels in the group without recurrence, the recurrence and

**Figure 5.** Results of the evaluation of post-operative Bcl-2 levels

**Group**

**Group**

in the group without recurrence, the recurrence and the

in the group without recurrence, the recurrence and the

and the control group.

and the control group.

14.46

14.46

7.46

7.46

**Mean**

**Mean**

2.26

2.26

7.82

7.82

control group.

control group.

**Mean**

**Mean**

the control group.

the control group.

in the group without recurrence, with recurrence

in the group without recurrence, with recurrence

7.46

7.46

**P<0,001 P<0,001 P<0,001**

**P<0,001 P<0,001 P<0,001**

0.31

0.31

2.26 1.68

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

2.26 1.68

**P<0,001 P<0,01 P<0,001**

**P<0,001 P<0,01 P<0,001**

7.82

7.82

1.68

1.68

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14.46

14.46

0.31

0.31

**Table 6.** Values of the basic description parameters (0 – preoperative results and 1-, 3-, 6-, and 12 months after the surgery.

It was established that the Bcl-2 concentration was statistically significantly higher in the recurrence group than in the non-recurrence group when examined 1, 3, 6 and 12 months after the surgery. The TPS concentration was statistically significantly higher in the recurrence group than in the non-recurrence group when examined before and 3, 6 and 12 months after the surgery. The concentration of the antigen, i.e. CEA, was statistically significantly higher in the recurrence group in relation to the non-recurrence group, as was TPS in the pre-operative determinations and 3, 6 and 12 months after the surgery. Bcl-2, TPS and CEA serum concen‐ trations were unrelated to the Astler-Coller stage of colorectal cancer. However, insignificantly higher concentrations of CEA at degree C than at degree B were observed. There was also no dependence related to the sex, the age of a patient, the original location of the tumor and the recurrence. Correlations between the concentrations of the determined parameters in all patients (with a recurrence and without a recurrence) were also noticed. A strong correlation between the concentrations of Bcl-2 and TPS proteins occurred 12 months after the surgery in

**No recurrence Recurrence**

Bcl2\_0 8,09 6,82 0,41 24,39 10,39 6,78 0,57 23,02 Bcl2\_1 7,34 6,07 1,74 28,41 8,87 3,17 4,09 14,61 Bcl2\_3 7,40 6,58 0,50 29,79 12,15 8,14 0,55 30,00 Bcl2\_6 6,97 6,99 0,41 26,40 17,50 7,98 1,98 29,74 Bcl2\_12 8,38 7,67 1,47 25,09 20,52 7,03 12,14 29,81 CEA\_0 5,26 7,22 1,70 42,60 5,75 2,60 2,30 11,90 CEA\_1 2,61 1,00 1,10 6,30 2,46 0,53 1,70 3,00 CEA\_3 1,87 0,90 0,40 3,70 4,94 3,88 1,20 17,40 CEA\_6 2,21 2,19 0,30 11,90 10,72 5,74 3,70 20,30 CEA\_12 2,57 2,97 0,40 14,60 14,86 13,92 1,30 41,00 TPS\_0 98,9 19,1 60,4 160,3 118,1 31,1 60,7 168,9 TPS\_1 92,8 16,8 64,6 143,7 101,6 17,7 80,3 144,1 TPS\_3 95,9 27,0 64,7 188,3 125,2 31,0 90,7 193,7 TPS\_6 96,8 35,7 70,3 197,6 152,0 49,0 80,4 279,1 TPS\_12 96,6 37,9 70,4 207,4 152,4 34,2 100,0 190,4 Age 66,2 10,9 47,0 85,0 70,4 4,0 64,0 77,0

**Table 6.** Values of the basic description parameters (0 – preoperative results and 1-, 3-, 6-, and 12 months after the

**Average SD Min. Max. Average SD Min. Max.**

the recurrence group.

86 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Feature**

surgery.

**Figure 4.** Results of the evaluation of post-operative CEA levels in the group without recurrence, with recurrence **Figure 4.** Results of the evaluation of post-operative CEA levels in the group without recurrence, with recurrence and the control group. in the group without recurrence, with recurrence and the control group.

**Figure 4.** Results of the evaluation of post-operative CEA levels

and the control group.

control group.

control group.

**Figure 5.** Results of the evaluation of post-operative Bcl-2 levels **Figure 5.** Results of the evaluation of post-operative Bcl-2 levels in the group without recurrence, the recurrence and the **Figure 5.** Results of the evaluation of post-operative Bcl-2 levels in the group without recurrence, the recurrence and the control group.

in the group without recurrence, the recurrence and the

**3.4. Conclusions**

cancer.

proliferation of cancer cells.

**4. Angiogenesis – VEGF**

**4.1. Aim of the study**

colorectal cancer.

**4.2. Material and methods**

the group without a recurrence.

350 pg/ml.

studied.

metastasis of cancer and is the future of cancer therapy.

**1.** A statistically significant excess of Bcl-2 in patients who have a recurrence of colorectal cancer makes information saying about the suppression of cancer cells apoptosis. **2.** A statistically significant increase of the concentration of TPS in the group with a recur‐ rence seems to indicate that the suppression of apoptosis is conductive to an excessive

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

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89

**3.** The findings obtained can mean that the evaluation of Bcl-2 and TPS may be complemen‐ tary to CEA determinations in the post-operative follow-up of patients with colorectal

The process of angiogenesis, which is the creation of new blood vessels, plays an important role in the development and metastasis of cancer. It can be initiated by tumor cell hypoxia, tumor suppressor gene mutations and oncogenes. As a result of the accumulation of these processes, tumor cells activate the angiogenic factors. The main factor involved in angiogenesis is VEGF-A. Blocking angiogenesis is one of the ways of preventing the development and

**1.** An assessment of the concentration of VEGF-A in the blood serum of patients with

**2.** An attempt to answer the question of whether the determination of VEGF-A provides clinically meaningful information in the post-operative monitoring of patients.

117 patients underwent surgery for colorectal cancer in the years 2004-2009. Patients were divided according to the Dukes and TNM classifications. The control group consisted of 20 healthy volunteers. A recurrence was detected in 35 patients in the period of 623 months after the surgery, including 11 patients in the Dukes B group and 24 patients in the Dukes C group. Patients with a recurrence were grouped together, while the remaining 71 patients made up

The concentration of CEA and VEGF-A was determined in all of the patients before the surgery and 1, 3, 6 and 12 months after the surgery. CEA was determined by MEIA using Abbott kits (USA); the standard concentration in healthy people is 3 ng/ml. VEGF-A was determined by ELISA using BIOMEDICA Sorin kits (Italy); the standard concentration in healthy people is

The results were analyzed statistically. ROC curves were marked for the diagnostic parameters

**Figure 6.** Results of the evaluation of post-operative TPS levels in the group without recurrence, the recurrence and the control **Figure 6.** Results of the evaluation of post-operative TPS levels in the group without recurrence, the recurrence and the control group.

#### **3.3. Discussion**

group.

It was established that the Bcl-2 concentration was statistically significantly higher in the recurrence group than in the non-recurrence group when examined 1, 3, 6 and 12 months after the surgery. The TPS concentration The European Tumor Markers Association recommended CEA as a useful clinical marker in the diagnosis and monitoring of patients with colorectal cancer in 2003. To date, many scientific researchers have been shown that the addition of tumor markers in the diagnosis of patients with colorectal cancer is necessary. Colorectal cancer, like breast and lung cancer, reveals a high expression of the antiapoptotic proteins: Bcl-2, Bcl-XL, PED, Il-4, which are secreted by tumor cells, strengthens that expression and protects neoplastic cells by environmental death signals.

was statistically significantly higher in the recurrence group than in the non-recurrence group when examined before and 3, 6 and 12 months after the surgery. The concentration of the antigen, i.e. CEA, was statistically A low expression of BAX expression correlates with disease recurrence of the disease in preoperatively irradiated rectal carcinomas and is connected with a worse response. A decrease in the expression of BAX indicates the worst response to chemotherapy and reduces the life expectancy of patients [25, 26, 27].

significantly higher in the recurrence group in relation to the non-recurrence group, as was TPS in the pre-operative determinations and 3, 6 and 12 months after the surgery. Bcl-2, TPS and CEA serum concentrations were unrelated Our results show that an increase of Bcl-2 in the serum of patients with colorectal cancer is bad prognostically. A high concentration (*x*¯=14.46 ng/ml) was observed in the group with a recurrence of the disease. The concentration of the Bcl-2 protein has been correlated with TPS – a marker of cell proliferation. A high correlation in 12th month after surgery may confirm that the suppression of the apoptosis of cancer cells increases their proliferation.

to the Astler-Coller stage of colorectal cancer. However, insignificantly higher concentrations of CEA at degree C than at degree B were observed. At the present time the apoptotic process and the process of cell proliferation are the targets of many researchers in different areas of specialization.

There was also no dependence related to the sex, the age of a patient,

the original location of the tumor and the recurrence. Correlations between

the concentrations of the determined parameters in all patients

(with a recurrence and without a recurrence) were also noticed. A strong

#### **3.4. Conclusions**


## **4. Angiogenesis – VEGF**

The process of angiogenesis, which is the creation of new blood vessels, plays an important role in the development and metastasis of cancer. It can be initiated by tumor cell hypoxia, tumor suppressor gene mutations and oncogenes. As a result of the accumulation of these processes, tumor cells activate the angiogenic factors. The main factor involved in angiogenesis is VEGF-A. Blocking angiogenesis is one of the ways of preventing the development and metastasis of cancer and is the future of cancer therapy.

#### **4.1. Aim of the study**

**Figure 6.** Results of the evaluation of post-operative TPS levels

**Figure 6.** Results of the evaluation of post-operative TPS levels in the group without recurrence, the recurrence and

The European Tumor Markers Association recommended CEA as a useful clinical marker in the diagnosis and monitoring of patients with colorectal cancer in 2003. To date, many scientific researchers have been shown that the addition of tumor markers in the diagnosis of patients with colorectal cancer is necessary. Colorectal cancer, like breast and lung cancer, reveals a high expression of the antiapoptotic proteins: Bcl-2, Bcl-XL, PED, Il-4, which are secreted by tumor cells, strengthens that expression and protects neoplastic cells by environmental death

**Group**

**P<0,001 P<0,001 P<0,001**

96.6

58.3

132.5

58.3

group.

the life expectancy of patients [25, 26, 27].

of many researchers in different areas of specialization.

88 Colorectal Cancer - Surgery, Diagnostics and Treatment

**Mean**

the control group.

**3.3. Discussion**

signals.

95.6

132.5

in the group without recurrence, the recurrence and the control

It was established that the Bcl-2 concentration was statistically

significantly higher in the recurrence group than in the non-recurrence group

when examined 1, 3, 6 and 12 months after the surgery. The TPS concentration

was statistically significantly higher in the recurrence group than

A low expression of BAX expression correlates with disease recurrence of the disease in preoperatively irradiated rectal carcinomas and is connected with a worse response. A decrease in the expression of BAX indicates the worst response to chemotherapy and reduces

in the non-recurrence group when examined before and 3, 6 and 12 months after

the surgery. The concentration of the antigen, i.e. CEA, was statistically

significantly higher in the recurrence group in relation to the non-recurrence

Our results show that an increase of Bcl-2 in the serum of patients with colorectal cancer is bad prognostically. A high concentration (*x*¯=14.46 ng/ml) was observed in the group with a recurrence of the disease. The concentration of the Bcl-2 protein has been correlated with TPS – a marker of cell proliferation. A high correlation in 12th month after surgery may confirm

group, as was TPS in the pre-operative determinations and 3, 6 and 12 months

after the surgery. Bcl-2, TPS and CEA serum concentrations were unrelated

that the suppression of the apoptosis of cancer cells increases their proliferation.

to the Astler-Coller stage of colorectal cancer. However, insignificantly higher

At the present time the apoptotic process and the process of cell proliferation are the targets

concentrations of CEA at degree C than at degree B were observed.

There was also no dependence related to the sex, the age of a patient,

the original location of the tumor and the recurrence. Correlations between

the concentrations of the determined parameters in all patients

(with a recurrence and without a recurrence) were also noticed. A strong


#### **4.2. Material and methods**

117 patients underwent surgery for colorectal cancer in the years 2004-2009. Patients were divided according to the Dukes and TNM classifications. The control group consisted of 20 healthy volunteers. A recurrence was detected in 35 patients in the period of 623 months after the surgery, including 11 patients in the Dukes B group and 24 patients in the Dukes C group. Patients with a recurrence were grouped together, while the remaining 71 patients made up the group without a recurrence.

The concentration of CEA and VEGF-A was determined in all of the patients before the surgery and 1, 3, 6 and 12 months after the surgery. CEA was determined by MEIA using Abbott kits (USA); the standard concentration in healthy people is 3 ng/ml. VEGF-A was determined by ELISA using BIOMEDICA Sorin kits (Italy); the standard concentration in healthy people is 350 pg/ml.

The results were analyzed statistically. ROC curves were marked for the diagnostic parameters studied.

#### **4.3. Results**

The pre-operative mean CEA concentrations differed significantly in all three degrees of the severity of the disease (p<0.01). In the post-operative control, patients demonstrated statisti‐ cally significant differences in CEA concentrations 3, 6 and 12 months after surgery with the largest concentration at the month follow-up (p<0,001). (Figure 7).

In addition, a high, statistically significant correlation between VEGF-A and CEA was

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

ROC Graph Directional factor = 2,06 Proposed cut-off point = 3,1

**Figure 8.** ROC curve for the concentration of CEA determined at the 3-month follow-up.

0,0 0,2 0,4 0,6 0,8 1,0 **1-Specificity**

AUC = 0,936 SE = 0,036 95%CI 0,866 - 1

Pre-operatively, a high concentration of VEGF-A was found in each stage

557.7

**p<0,001**

of the disease; however, it showed no difference in levels of statistical

**p<0,001**

significance. Throughout the period of post-operative observation, patients

442.5

demonstrated a very high statistical significance between the group without

a recurrence and those with a recurrence of the neoplastic process (p<0,001).

331.6

**p<0,00**

**Figure 9.** Evaluation of the concentration of VEGF-A in the control group and in the group

**Figure 9.** Evaluation of the concentration of VEGF-A in the control group and in the group of patients with and with‐

of patients with and without a recurrence of a tumor in the subsequent stages

Before 1 3 6 12

**Month after surgery**

**p<0,01 p<0,00 p<0,00 p<0,00 p<0,00**

288.0

**p<0,0**

281.1

**p<0,01**

584.0

**p<0,001**

259.8

p>0,05

440.9

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91

**p<0,001**

The average concentration in patients without a recurrence

was 294.24 pg/ml, while in patients with a recurrence it was 501.89 pg/ml. ROC

curves showed the usefulness of VEGF-A in detecting a recurrence

a month after surgery and a concentration of 412 pg/ml, it is confirmed

(Figure 9)

0

100

200

300

**Mean concentration VEGF-A [pg/ml]**

400

500

600

demonstrated 3, 6 and 12 months after surgery (Figure 11 and 12).

3,1

0,0

No recurrence Recurrence

of observation.

out a recurrence of a tumor in the subsequent stages of observation.

Control group

247.2

(Figure 10).

**Figure 8.** ROC curve for the concentration of CEA determined at the 3-month follow-up.

562.6

**p<0,001**

447.4

**p<0,001**

0,2

0,4

0,6

**Sensitivity**

0,8

1,0

**Figure 7.** Evaluation of the concentration of CEA in the control group and in the groups of patients with and without a recurrence of a tumor in the subsequent stages **Figure 7.** Evaluation of the concentration of CEA in the control group and in the groups of patients with and withouta recurrence of a tumor in the subsequent stages of observation.

of observation. Most recurrences were detected during this period. The average Most recurrences were detected during this period. The average concentrations of CEA in patients without a recurrence was 2.18 ng/ml and in patients with a recurrence 7.58 ng/ml. The ROC curves analysis showed a concentration of CEA of 3.1 ng/ml as early as 3 months after the surgery, which confirms the recurrence of the cancer (Figure 8).

concentrations of CEA in patients without a recurrence was 2.18 ng/ml and in patients with a recurrence 7.58 ng/ml. The ROC curves analysis showed a concentration of CEA of 3.1 ng/ml as early as 3 months after the surgery, Pre-operatively, a high concentration of VEGF-A was found in each stage of the disease; however, it showed no difference in levels of statistical significance. Throughout the period of post-operative observation, patients demonstrated a very high statistical significance between the group without a recurrence and those with a recurrence of the neoplastic process (p<0,001). (Figure 9)

which confirms the recurrence of the cancer (Figure 8). The average concentration in patients without a recurrence was 294.24 pg/ml, while in patients with a recurrence it was 501.89 pg/ml. ROC curves showed the usefulness of VEGF-A in detecting a recurrence a month after surgery and a concentration of 412 pg/ml, it is confirmed (Figure 10).

In addition, a high, statistically significant correlation between VEGF-A and CEA was demonstrated 3, 6 and 12 months after surgery (Figure 11 and 12).

**4.3. Results**

90 Colorectal Cancer - Surgery, Diagnostics and Treatment

The pre-operative mean CEA concentrations differed significantly in all three degrees of the severity of the disease (p<0.01). In the post-operative control, patients demonstrated statisti‐ cally significant differences in CEA concentrations 3, 6 and 12 months after surgery with the

**Figure 7.** Evaluation of the concentration of CEA in the control group and in the groups

**Figure 7.** Evaluation of the concentration of CEA in the control group and in the groups of patients with and withouta recurrence of a tumor in the subsequent stages of observation.

Most recurrences were detected during this period. The average concentrations of CEA in patients without a recurrence was 2.18 ng/ml and in patients with a recurrence 7.58 ng/ml. The ROC curves analysis showed a concentration of CEA of 3.1 ng/ml as early as 3 months after

2.42

2.51

**p<0,0** p>0,0 **p<0,01**

of patients with and without a recurrence of a tumor in the subsequent stages

Before 1 3 6 12

**Month after surgery**

p>0,05 p>0,05 **p<0,00 p<0,00 p<0,00**

2.12

6.88

**p<0,001**

2.00

p>0,05

11.96

**p<0,001**

2.07

p>0,05

9.73

**p<0,001**

Most recurrences were detected during this period. The average

concentrations of CEA in patients without a recurrence was 2.18 ng/ml

Pre-operatively, a high concentration of VEGF-A was found in each stage of the disease; however, it showed no difference in levels of statistical significance. Throughout the period of post-operative observation, patients demonstrated a very high statistical significance between the group without a recurrence and those with a recurrence of the neoplastic process (p<0,001).

and in patients with a recurrence 7.58 ng/ml. The ROC curves analysis showed

a concentration of CEA of 3.1 ng/ml as early as 3 months after the surgery,

The average concentration in patients without a recurrence was 294.24 pg/ml, while in patients with a recurrence it was 501.89 pg/ml. ROC curves showed the usefulness of VEGF-A in detecting a recurrence a month after surgery and a concentration of 412 pg/ml, it is confirmed

which confirms the recurrence of the cancer (Figure 8).

the surgery, which confirms the recurrence of the cancer (Figure 8).

largest concentration at the month follow-up (p<0,001). (Figure 7).

No recurrence Recurrence

3.87

**p<0,001**

4.30

**p<0,001**

of observation.

Control group

2.11

0.00

2.00

4.00

6.00

**Mean concentration CEA [ng/ml]**

(Figure 9)

(Figure 10).

8.00

10.00

12.00

**Figure 8.** ROC curve for the concentration of CEA determined at the 3-month follow-up.

**Figure 8.** ROC curve for the concentration of CEA determined at the 3-month follow-up.

**Figure 9.** Evaluation of the concentration of VEGF-A in the control group and in the group of patients with and without a recurrence of a tumor in the subsequent stages **Figure 9.** Evaluation of the concentration of VEGF-A in the control group and in the group of patients with and with‐ out a recurrence of a tumor in the subsequent stages of observation.

The average concentration in patients without a recurrence

was 294.24 pg/ml, while in patients with a recurrence it was 501.89 pg/ml. ROC

curves showed the usefulness of VEGF-A in detecting a recurrence

a month after surgery and a concentration of 412 pg/ml, it is confirmed

of observation.

(Figure 10).

ROC Graph Directional factor = 2,02 Proposed cut-off point = 412

In addition, a high, statistically significant correlation between VEGF-A

**Figure 12.** Correlation between the concentrations of CEA and VEGF-A in patients

**Figure 12.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 6 months after surgery. **Figure 12.** Correlation between the concentrations of CEA and VEGF-A in patients

0.0 3.0 6.0 9.0 12.0 15.0 18.0 21.0

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

0.0 3.0 6.0 9.0 12.0 15.0 18.0 21.0

**Concentration of CEA [ng/ml]**

**Concentration of CEA [ng/ml]**

*r*=0,586; *p***<0,01**

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93

*r*=0,586; *p***<0,01**

*r*=0,932; *p***<0,001**

*r*=0,932; *p***<0,001**

**Figure 13.** Correlation between the concentrations of CEA and VEGF-A in patients

**Figure 13.** Correlation between the concentrations of CEA and VEGF-A in patients

**Figure 13.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 12

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0

**Concentration of CEA [ng/ml]**

**Concentration of CEA [ng/ml]**

with a recurrence of a tumor 12 months after surgery.

with a recurrence of a tumor 12 months after surgery.

with a recurrence of a tumor 6 months after surgery.

with a recurrence of a tumor 6 months after surgery.

0

0

0

0

200

200

400

400

**Concentration of VEGF-A [pg/ml]**

months after surgery.

**Concentration of VEGF-A [pg/ml]**

600

600

800

800

1000

1000

400

400

800

800

**Concentration of VEGF-A [pg/ml]**

**Concentration of VEGF-A [pg/ml]**

1200

1200

1600

1600

2000

2000

and CEA was demonstrated 3, 6 and 12 months after surgery (Figure 11 and 12).

**Figure 10.** ROC curve for the concentration of CEA determined at a one-month follow-up. **Figure 10.** ROC curve for the concentration of CEA determined at a one-month follow-up.

200 **Concentration of VEGF-A [pg/ml]***r*=0,595; *p***<0,01 Figure 11.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 3 months after surgery. **Figure 11.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 3 months after surgery.

0.0 3.0 6.0 9.0 12.0 15.0 18.0

**Concentration of CEA [ng/ml]**

**Figure 11.** Correlation between the concentrations of CEA and VEGF-A in patients

with a recurrence of a tumor 3 months after surgery.

0

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research http://dx.doi.org/10.5772/57514 93

**Figure 12.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 6 months after surgery. **Figure 12.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 6 months after surgery. **Figure 12.** Correlation between the concentrations of CEA and VEGF-A in patients

with a recurrence of a tumor 6 months after surgery.

**Figure 10.** ROC curve for the concentration of CEA determined at a one-month follow-up.

**Figure 10.** ROC curve for the concentration of CEA determined at a one-month follow-up.

0,0 0,2 0,4 0,6 0,8 1,0 **1-Specificity**

**Figure 10.** ROC curve for the concentration of CEA determined at a one-month follow-up.

AUC = 0,799 SE = 0,052 95%CI 0,696 - 0,901

AUC = 0,799 SE = 0,052 95%CI 0,696 - 0,901

0,0 0,2 0,4 0,6 0,8 1,0 **1-Specificity**

412

0,4

0,6

0,8

1,0

0,2

0,0

412

0,0

0,2

0,4

0,6

**Sensitivity**

0,8

**Sensitivity**

1,0

92 Colorectal Cancer - Surgery, Diagnostics and Treatment

ROC Graph Directional factor = 2,02 Proposed cut-off point = 412

ROC Graph Directional factor = 2,02 Proposed cut-off point = 412

and CEA was demonstrated 3, 6 and 12 months after surgery (Figure 11 and 12).

**Figure 11.** Correlation between the concentrations of CEA and VEGF-A in patients

0.0 3.0 6.0 9.0 12.0 15.0 18.0

**Figure 11.** Correlation between the concentrations of CEA and VEGF-A in patients

**Figure 11.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 3

0.0 3.0 6.0 9.0 12.0 15.0 18.0

**Concentration of CEA [ng/ml]**

**Concentration of CEA [ng/ml]**

*r*=0,595; *p***<0,01**

*r*=0,595; *p***<0,01**

with a recurrence of a tumor 3 months after surgery.

with a recurrence of a tumor 3 months after surgery.

0

months after surgery.

200

400

0

200

400

600

800

1000

**Concentration of VEGF-A [pg/ml]**

600

800

**Concentration of VEGF-A [pg/ml]**

1000

In addition, a high, statistically significant correlation between VEGF-A

and CEA was demonstrated 3, 6 and 12 months after surgery (Figure 11 and 12).

In addition, a high, statistically significant correlation between VEGF-A

**Figure 13.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 12 months after surgery. **Figure 13.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 12 months after surgery. **Figure 13.** Correlation between the concentrations of CEA and VEGF-A in patients with a recurrence of a tumor 12 months after surgery.

#### **4.4. Discussion**

Our results are similar to the results shown by Bombardieri [28], Treska [29], Kokocińska [30] and many others. CEA was discussed in the first part of this chapter. VEGF-A was examined in the blood of patients after the surgery.

In the future, proteins, gene products, phenotyping of patients (determining the phenotype of

Role of Tumour Markers in Diagnosis and Follow up of Colorectal Cancer — Potential for Future Research

http://dx.doi.org/10.5772/57514

95

Department of Anesthesiology, Intensive Treatment and Emergency Medicine, Medical Uni‐

The chapter was prepared based on results of research at the Institute of Tumor Markers,

[1] Kokocińska D.: Przygotowanie składników testu radioimmunologicznego i enzy‐ moimmunologicznego dla oznaczeń progesteronu, oczyszczanie i frakcjonowanie przeciwciał: IgG, F(ab)'2 przeciw progesteronowi i przeciw ferrytynie dla potrzeb di‐ agnostyki klinicznej. Rozprawa habilitacyjna, Katowice, Śl. AM 1993; XVI: 234.

[2] Szymendera JJ, Góźdź S: Rola krążących markerów nowotworowych w diagnostyce I monitorowaniu leczenia chorych na nowotwory. Nowotwory 1995; 45: 369-383.

[3] Bates SH, Longo DL: Use of serum tumor markers in cancer diagnosis and manage‐

[4] Dusza D: Dobór oznaczeń markerów nowotworowych u chorych na raka jelita gru‐

[5] Fillela X, Molina MD, Gran MD et al.: Prognostic value of CA 19-9 levels in colorectal

[6] Kokocińska D, Kuśmierski S: Antygen CA 72-4 – nowy marker choroby nowotworo‐

[7] Nowacki M: Przydatność kliniczna badań antygenu karcinoembrionalnego (CEA) w surowicy, określenie stopnia zaawansowania, rokowania, leczenia chirurgicznego

[8] Staab HJ, Brummendorf T, Hornung A et al.: The clinical validity of circulating tu‐ mor associated antigens CEA and CA 19-9 in primary diagnosis and follow-up pa‐

[9] Wilson MS, Schofieln PF: Markers to study human colonic cell proliferation. Gut

tients with gastrointestinal malignancies. Klin Wschr 1985; 63: 106-115.

which were then compared to the results obtained by other researchers.

bego i odbytnicy. Rozprawa doktorska. Śląska AM 1996.

wej układu pokarmowego. Medycyna 2000 1994; 45(46): 46-47.

nowotworów jelita grubego. Nowotwory 1983;1: 13.

patients) and molecular cytology should also be added.

ment. Semin Onkol 1987; 14: 102-138.

cancer. Ann Surg 1992; 210: 55-59.

1995; 36(1): 152.

**Author details**

Robert Partyka

**References**

versity of Silesia, Katowice, Poland

We did not find any statistically significant differences between the Dukes classification. In contrast, Fujisaki et al. [31] and Fuhrmann-Benzakein et al. [32] observed such a correlation. The highest concentration of VEGF was observed in patients with a liver metastasis.

Chung et al. [33] and Ohta et al. [34] reported that VEGF may be considered as a proliferation and prognostic factor. A high expression or concentration of VEGF indicates the possibility of the recurrence of a disease in a relatively short time.

Afify et al. [35] also indicated that the concentration of VEGF is very useful in detecting a recurrence of the disease and a metastasis to the liver.

However, Werther et al. and Karatzas et al. [36] reported that A high pre-operative concen‐ tration of VEGF suggests liver metastasis in the post-surgery period. Our results confirm those of Afify, Werther and Chung.

The results of our researches show a statistically significantly correlation between VEGF-A and CEA. It is possible that VEGF-A may stimulate the proliferation of tumor cells. To date, only Chung et al. and Ohta et al. have confirmed a connection of VEGF with the proliferation of tumor cells and with the development of cancer [33, 34].

All researches suggest that VEGF-A be added to the immunodiagnostics of CEA in patients with colorectal cancer.

## **5. Conclusions**


## **6. Summary**

A review of the scientific literature on colorectal diseases over the last 20 years indicates the continued development of Clinical Immunodiagnostics and the "gold standard", which is CEA, but also showed the usefulness and necessity of adding new markers: TPS, Bcl-2, VEGF and their receptors.

In the future, proteins, gene products, phenotyping of patients (determining the phenotype of patients) and molecular cytology should also be added.

## **Author details**

**4.4. Discussion**

in the blood of patients after the surgery.

94 Colorectal Cancer - Surgery, Diagnostics and Treatment

of Afify, Werther and Chung.

with colorectal cancer.

**5. Conclusions**

cancer.

**6. Summary**

and their receptors.

the recurrence of a disease in a relatively short time.

recurrence of the disease and a metastasis to the liver.

of tumor cells and with the development of cancer [33, 34].

Our results are similar to the results shown by Bombardieri [28], Treska [29], Kokocińska [30] and many others. CEA was discussed in the first part of this chapter. VEGF-A was examined

We did not find any statistically significant differences between the Dukes classification. In contrast, Fujisaki et al. [31] and Fuhrmann-Benzakein et al. [32] observed such a correlation.

Chung et al. [33] and Ohta et al. [34] reported that VEGF may be considered as a proliferation and prognostic factor. A high expression or concentration of VEGF indicates the possibility of

Afify et al. [35] also indicated that the concentration of VEGF is very useful in detecting a

However, Werther et al. and Karatzas et al. [36] reported that A high pre-operative concen‐ tration of VEGF suggests liver metastasis in the post-surgery period. Our results confirm those

The results of our researches show a statistically significantly correlation between VEGF-A and CEA. It is possible that VEGF-A may stimulate the proliferation of tumor cells. To date, only Chung et al. and Ohta et al. have confirmed a connection of VEGF with the proliferation

All researches suggest that VEGF-A be added to the immunodiagnostics of CEA in patients

**1.** A statistically significant increase in VEGF-A in patients with a recurrence of a tumor in the early post-operative period supports the usefulness of the inclusion of this marker for

**2.** The high correlation between CEA and VEGF-A seems to indicate that the concentration of VEGF-A has a close relationship with the proliferation of cells and the development of

A review of the scientific literature on colorectal diseases over the last 20 years indicates the continued development of Clinical Immunodiagnostics and the "gold standard", which is CEA, but also showed the usefulness and necessity of adding new markers: TPS, Bcl-2, VEGF

monitoring patients, especially in planning their antiangiogenic therapy.

The highest concentration of VEGF was observed in patients with a liver metastasis.

Robert Partyka

Department of Anesthesiology, Intensive Treatment and Emergency Medicine, Medical Uni‐ versity of Silesia, Katowice, Poland

The chapter was prepared based on results of research at the Institute of Tumor Markers, which were then compared to the results obtained by other researchers.

## **References**


[10] Gold P, Freedman SO: Specific carcinoembryonic antigens in the human digestive system. J Exp Med 1965; 122: 439-462.

European Group on Tumor Markers (EGTM) guidelines. Eur J Cancer 2003; 39(6):

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[25] Paul-Samojedny M, Kokocińska D, Samojedny A i wsp. Expression of cell survival/ death genes: bcl-2 and bax at the rate of colon cancer prognosis. Biochimica et Bio‐

[26] Schelwies K, Sturm I, Grabowski P et al.: Analysis of p53/BAX in primary colorectal carcinoma: low BAX protein expression is a negative prognostic factor In UICC stage

[27] Nehls O, Okech T, Hsieh CJ et al.: Low BAX protein expression correlates with dis‐ ease recurrence in preoperatively irradited rectal carcinoma. Int J Radiat Oncol Biol

[28] Bombardieri E, Saccani JG, Cocciolo MG, Mori M, Rusca M, Seregni E, Becchi G, Fon‐ tanesi M, Tardini A et al. Tissue polypeptide antigen and carcinoembryonic antigen in colon tumors: serum levels and immunohistochemical localization. Cancer Detect

[29] Treska V, Topolcan O, Stanislav K, Liska V, Holubec L. Preoperative tumor markers as prognostic factors of colorectal liver metastates. Hepatogastroenterology 2009;

[30] Kokocińska D, Jarząb B, Kawecki M, Donocik J, Kusmierski S. Antygeny CA 19-9, CEA, CA 50 I ferrytyna w nowotworach przewodu pokarmowego. Pol Przegl Chir

[31] Fujisaki K, Mitsuyama K, Toyonaga A, Matsuo K, Tanikawa K. Circulationg vascular endothelial growth factor in patients with colorectal cancer. Am J Gastroenterol 1998;

[32] Fuhfmann-Benzakein E, Ma MN, Rubia-Brandt L et al. Elevated levels of angiogenic

[33] Chung Y.S, Maeda K, Sowa M. Prognostic value of angiogenesis in gastrointestinal

[34] Ohta Y, Endo Y, Tanaka M, Shimizu J, Oda M, Hayashi Y, Watanabe Y, Sasaki T. Sag‐ nificance of vascular endothelial growth factor messenger RNA expression in pri‐

[35] Afify M, Samy N, Hashim M, Essam T. Clinical significance of vascular endothelial growth factor in Egyptian colorectal cancer patients. Int J Integf Biol 2008; 4(2):

[36] Karatzas G. Clinical significance of preoperative serum vascular endothelial growth factor levels in patients with colorectal cancer and effect of tumor surgery. Surgery

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[25] Paul-Samojedny M, Kokocińska D, Samojedny A i wsp. Expression of cell survival/ death genes: bcl-2 and bax at the rate of colon cancer prognosis. Biochimica et Bio‐ phisica Acta 2005; 1741: 25 – 29.

[10] Gold P, Freedman SO: Specific carcinoembryonic antigens in the human digestive

[11] Ogata S, Ho J, Chen A et al.: Tumor associated sialylated antigens are constitutively expressed in normal human colonic mucosa. Cancer Res 1995; 1; 36: 1869-1874. [12] Dienst C, Clodius T, Oldorp T: CA 19-9, CA 50 and CEA bei Pankreas und Gastroin‐ testinaltumoren vergleichende Untersuchungen. Bred Klein 1987; 82: 49-50.

[13] Lindmark G, Bergensrom R, Pahlman I et al.: The association of preoperative serum tumor markers with Dukes' stage and surival in colorectal cancer. Br J Cancer 1995;

[14] Bonfrer J, Groenveled E, Korse C, Van Dalen A, Oomen LC, Ivanyi D. (1994). Mono‐ clonal antibody M3 used in tissue polypeptide-specific antigen assay for the quantifi‐ cation if tissue polypeptide antigen recognizes keratin 18. Tumor Biol; 15(4): 210-222.

[15] Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tu‐

[16] Lucsaite R, Sauer-Eppel M, Oremek GM. Value of biomarkers in diagnosis of gastric

[17] Takagawa R, Fujii S, Ohta M, Nagano Y, Kunisaki C, Yamagishi S, Osada S, Ichikawa Y, Shimada H. Preoperative serum carcinoembryonic antigen level as a predictive factor of recurrence after curative resection of colorectal cancer. Ann Surg Oncol

[18] Lindmark G, Bergstrom R, Pahlman L, Grimelius B. The association of preoperative serum tumor markers with Dukes's stage and survival in colorectal cancer. Brit J of

[19] Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tu‐

[20] Treska V, Topolcan O, Stanislav K i wsp. Preoperative tumor markers as prognostic factors of colorectal liver metastases. Hepato-Gastroenterology 2009; 56(90): 317-320.

[21] Turoldo A, Balani A, Scaramucci M, Pistan V, Roseano M, Liguori G. Preoperative CEA: prognostic significance in colorectal carcinoma. Tumori 2003; 89(4): 95-97. [22] Marchena J, Acosta MA, Garcia-Anguiano F, Simpson H, Cruz F. Use of the preoper‐ ative levels of CEA in patients with colorectal cancer. Hepatogastroenterology 2003;

[23] Plebani M, De Paoli M, Basso D, Roveroni G, Giacomini A, Galeotti F, Corsini A. Se‐ rum tumor markers in colorectal cancer staging, grading, and follow-up. J Surg On‐

[24] Duffy MJ, van Dalen A, Haglund C, Hansson L, Klapdor R, Lamerz R, Nilsson O, Sturgeon C, Topolcan O. Clinical utility of biochemical markers in colorectal cancer:

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**Section 3**

**Surgery for colorectal cancer**

**Surgery for colorectal cancer**

**Chapter 5**

**Laparoscopy in the Management of Colorectal Cancer**

Since the introduction of laparoscopic surgery, minimally invasive techniques have been widely used for benign and malignant diseases. [1, 2] Although many surgeons perform laparoscopic colectomy for benign diseases, its application for colorectal malignancy had slow progress because of oncological considerations. [3] Over time, many randomized controlled trials have been published comparing open to laparoscopic surgery for colorectal cancer, which show that in experienced hands, competent oncology resections can be performed the results are equivalent to open surgery [4-7]. However, the results of the minimally invasive surgery for rectal cancer have not been thoroughly investigated and large multicenter randomized

Large number of randomized controlled trials comparing laparoscopic to open surgery for colon cancer have established better short-term results - less pain, shorter length of stay, faster return of bowel function and equivalent oncological outcomes [2-5]. Laparoscopic rectal surgery is still developing with promising short-term benefit, although depending on the skills and techniques of the surgeon [6]. Surgery of rectal cancer requires more technical skills (total mesorectal excision, low pelvic anastomosis), many fear that the oncological principles could be compromised during laparoscopic resection. In addition to oncological concerns, the widespread of laparoscopic surgery for colorectal cancer is impeded by the significant learning

Hand-assisted techniques introduced in the 1990s were an attempt to overcome some of these limitations and provide an overlap between open and laparoscopic techniques and the transition from open to minimally invasive surgery for many surgeons [1, 8]. Acceptance of minimally invasive procedures by patients and surgeons led to the developent of new technologies to ease the laparoscopic approach. The introduction of single incision laparo‐

> © 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.

Anton Tonev, Nikola Kolev, Valentin Ignatov, Vasil Bojkov, Tanya Kirilova and Krassimir Ivanov

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56913

**1. Introduction**

trials are underway.

curve.

## **Laparoscopy in the Management of Colorectal Cancer**

Anton Tonev, Nikola Kolev, Valentin Ignatov, Vasil Bojkov, Tanya Kirilova and Krassimir Ivanov

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56913

## **1. Introduction**

Since the introduction of laparoscopic surgery, minimally invasive techniques have been widely used for benign and malignant diseases. [1, 2] Although many surgeons perform laparoscopic colectomy for benign diseases, its application for colorectal malignancy had slow progress because of oncological considerations. [3] Over time, many randomized controlled trials have been published comparing open to laparoscopic surgery for colorectal cancer, which show that in experienced hands, competent oncology resections can be performed the results are equivalent to open surgery [4-7]. However, the results of the minimally invasive surgery for rectal cancer have not been thoroughly investigated and large multicenter randomized trials are underway.

Large number of randomized controlled trials comparing laparoscopic to open surgery for colon cancer have established better short-term results - less pain, shorter length of stay, faster return of bowel function and equivalent oncological outcomes [2-5]. Laparoscopic rectal surgery is still developing with promising short-term benefit, although depending on the skills and techniques of the surgeon [6]. Surgery of rectal cancer requires more technical skills (total mesorectal excision, low pelvic anastomosis), many fear that the oncological principles could be compromised during laparoscopic resection. In addition to oncological concerns, the widespread of laparoscopic surgery for colorectal cancer is impeded by the significant learning curve.

Hand-assisted techniques introduced in the 1990s were an attempt to overcome some of these limitations and provide an overlap between open and laparoscopic techniques and the transition from open to minimally invasive surgery for many surgeons [1, 8]. Acceptance of minimally invasive procedures by patients and surgeons led to the developent of new technologies to ease the laparoscopic approach. The introduction of single incision laparo‐

© 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.

scopic surgery (SILS) devices has allowed fewer cuts. [9] The clinical application of endoscopic natural orifice transluminal surgery (NOTES) in colorectal disease is not yet fully accepted, but it was possible great advances in instrumentation and improving techniques for specimen extraction after laparoscopic colectomy [12].

Regarding oncological radicality, there are significant differences in the number of lymph nodes removed. An average of 19 lymph nodes from the intracorporeal group and 14 lymph nodes from the extracorporeal group are reported to be removed. In the literature, some authors have reported no differences in safety, whereas others noted that the only advantage was a smaller incision. On the other hand, other studies affirmed the safety of intracorporeal anastomosis, with the same complication rate as for extracorporeal anastomosis. Because intracorporeal anastomosis is considered more difficult, only a few surgeons have used this kind of technique; however less mobilization is required, and less tension is applied to the bowel and mesentery because the bowel does not need to reach the anterior abdominal wall for externalization. [11] Furthermore, the excessive tension on the mesentery during the mobilization is associated with an increased risk of mesenteric or portal vein thrombosis. Concerning surgical times, there is not a significant difference in surgical time between the two groups. Patients in the intracorporeal group had a shorter hospitalization duration. In some cases, the hospitalization duration was longer possibly because of age (43.2% of patients in the intracorporeal group and 33.4% in the extracorporeal group were over 80 years old). Our results showed a significantly shorter average hospitalization stay in the intracorporeal group. These data agree with a recent Spanish study, although this difference was not significant (*P* = 0.5424) because hospitalization duration is influenced by many patient factors. On the other hand, we found that 71.4% of patients in the intracorporeal group went home within 7 d, and 54.7% of patients in the extracorporeal group went home within this period. [20, 21] Patients in the intracorporeal group and extracorporeal group went home within 7 d. Concerning the recovery of intestinal function, our results found significantly shorter average times for resumption of gas evacuation after 3 d in the intracorporeal group compared to after 3.8 d in the extracorporeal group. Bowel movements occurred after an average of 4.9 d in the intracorporeal group. In the intracorporeal group, the nasogastric tube was removed after 1.8 d, whereas it was removed after 3 d in the extracorporeal group. This difference can be explained by an increased percentage of paralytic ileus in the second group, which is due to the traction of the right colon and terminal ileum through the mini-incision on the pancreas and duodenum. This approach allowed a more rapid recovery of liquid and solid nutrition consumption. [25-27] There are met some major complications, which included severe anemia, occlusion, anastomotic dehisces, and enterocutaneous fistulae. There were no significant

Laparoscopy in the Management of Colorectal Cancer

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103

In conclusion, our study clearly shows that laparoscopic right colectomy with intracorporeal anastomosis improves patient outcome. Intracorporeal anastomosis resulted in faster recovery of nutrition consumption, faster recovery of intestinal function, and shorter hospitalization duration. The higher number of lymph nodes removed seems to be related to vascular division as the first surgical step as a rule. This confirms that a mini invasive approach improves patient

The early trials of laparoscopic colectomy have established high rate of tumor recurrence near the port wounds, which was considered a serious drawback of the new approach. The etiology

differences between the two groups.

**3. Port site metastasis**

outcome.

## **2. Systemic benefits**

Basic science studies have demonstrated the better preservation of oncological and immuno‐ logical functions after laparoscopic surgery before trials on humans [7-9], thus giving hope for better long-term oncologic outcome. Tumor cells are found in systemic blood circulation and in the peritoneal fluid immediately after surgery and if they survive may avoid the immuno‐ logical defense of the organism. The surgical trauma causes immunological alterations and the organism might be vulnerable during the postoperative period [7-9]. Laparoscopic surgery causes lesser trauma and therefore less effect on the immune system, decreases the prolifera‐ tion stimuli for cancer cells and neoangiogenesis [7-9, 11]. The changes can last shortly after the operation, but some are observed after months or longer [11]. These potential advantages do not provide better long-term outcomes in human trials, although some report better oncological results after laparoscopic surgery in terms of longer cancer-related survival and less tumor recurrences [10-14].

The rate of conversion to open surgery is still very high, as demonstrated by three multicenter prospective trials - the NCI Clinical Outcomes of Surgical Therapies (COST; 21%), Colon Cancer Laparoscopic or Open Resection (COLOR; 17%), and the Conventional versus Lapa‐ roscopic-Assisted Surgery in Colorectal Cancer (CLASICC; 29%) [15, 16]. This could be due to more precautious behavior of the surgeons and their inexperience.

A meta-analysis from 2006 demonstrated intriguing results. It includes 1134 patients after colectomy in two periods – 1996-2000 and 2000-2004. Laparoscopic colectomy was introduced as an option only in the second period. The authors found that 3-year overall survival decreased in the latter, while the overall survival of patients after open colectomy remained the same over the two periods. [17]

Intracorporeal anastomosis for right laparoscopic colectomy improved patient outcome compared with patients who underwent extracorporeal anastomosis. There is found faster recovery of nutrition, faster recovery of intestinal function, and shorter hospitalization. However, there was no difference in average surgery time between the two groups.

According to the differences in age, gender, BMI, ASA class, or abdominal surgical history, in laparoscopic colectomy with extracorporeal anastomosis (laparoscopic-assisted colectomy), the bowel is externalized through a lateral mini-incision. With this approach, bowel mobili‐ zation and ligation of vessels is usually laparoscopic, whereas resection of the specimen and creation of the anastomosis is extracorporeal. On the other hand, in laparoscopic right colectomy with intracorporeal anastomosis (totally laparoscopic colectomy), bowel mobiliza‐ tion, ligation of vessels, resection of the specimen, and creation of the anastomosis are totally intracorporeal.

Regarding oncological radicality, there are significant differences in the number of lymph nodes removed. An average of 19 lymph nodes from the intracorporeal group and 14 lymph nodes from the extracorporeal group are reported to be removed. In the literature, some authors have reported no differences in safety, whereas others noted that the only advantage was a smaller incision. On the other hand, other studies affirmed the safety of intracorporeal anastomosis, with the same complication rate as for extracorporeal anastomosis. Because intracorporeal anastomosis is considered more difficult, only a few surgeons have used this kind of technique; however less mobilization is required, and less tension is applied to the bowel and mesentery because the bowel does not need to reach the anterior abdominal wall for externalization. [11] Furthermore, the excessive tension on the mesentery during the mobilization is associated with an increased risk of mesenteric or portal vein thrombosis. Concerning surgical times, there is not a significant difference in surgical time between the two groups. Patients in the intracorporeal group had a shorter hospitalization duration. In some cases, the hospitalization duration was longer possibly because of age (43.2% of patients in the intracorporeal group and 33.4% in the extracorporeal group were over 80 years old). Our results showed a significantly shorter average hospitalization stay in the intracorporeal group. These data agree with a recent Spanish study, although this difference was not significant (*P* = 0.5424) because hospitalization duration is influenced by many patient factors. On the other hand, we found that 71.4% of patients in the intracorporeal group went home within 7 d, and 54.7% of patients in the extracorporeal group went home within this period. [20, 21] Patients in the intracorporeal group and extracorporeal group went home within 7 d. Concerning the recovery of intestinal function, our results found significantly shorter average times for resumption of gas evacuation after 3 d in the intracorporeal group compared to after 3.8 d in the extracorporeal group. Bowel movements occurred after an average of 4.9 d in the intracorporeal group. In the intracorporeal group, the nasogastric tube was removed after 1.8 d, whereas it was removed after 3 d in the extracorporeal group. This difference can be explained by an increased percentage of paralytic ileus in the second group, which is due to the traction of the right colon and terminal ileum through the mini-incision on the pancreas and duodenum. This approach allowed a more rapid recovery of liquid and solid nutrition consumption. [25-27] There are met some major complications, which included severe anemia, occlusion, anastomotic dehisces, and enterocutaneous fistulae. There were no significant differences between the two groups.

In conclusion, our study clearly shows that laparoscopic right colectomy with intracorporeal anastomosis improves patient outcome. Intracorporeal anastomosis resulted in faster recovery of nutrition consumption, faster recovery of intestinal function, and shorter hospitalization duration. The higher number of lymph nodes removed seems to be related to vascular division as the first surgical step as a rule. This confirms that a mini invasive approach improves patient outcome.

#### **3. Port site metastasis**

scopic surgery (SILS) devices has allowed fewer cuts. [9] The clinical application of endoscopic natural orifice transluminal surgery (NOTES) in colorectal disease is not yet fully accepted, but it was possible great advances in instrumentation and improving techniques for specimen

Basic science studies have demonstrated the better preservation of oncological and immuno‐ logical functions after laparoscopic surgery before trials on humans [7-9], thus giving hope for better long-term oncologic outcome. Tumor cells are found in systemic blood circulation and in the peritoneal fluid immediately after surgery and if they survive may avoid the immuno‐ logical defense of the organism. The surgical trauma causes immunological alterations and the organism might be vulnerable during the postoperative period [7-9]. Laparoscopic surgery causes lesser trauma and therefore less effect on the immune system, decreases the prolifera‐ tion stimuli for cancer cells and neoangiogenesis [7-9, 11]. The changes can last shortly after the operation, but some are observed after months or longer [11]. These potential advantages do not provide better long-term outcomes in human trials, although some report better oncological results after laparoscopic surgery in terms of longer cancer-related survival and

The rate of conversion to open surgery is still very high, as demonstrated by three multicenter prospective trials - the NCI Clinical Outcomes of Surgical Therapies (COST; 21%), Colon Cancer Laparoscopic or Open Resection (COLOR; 17%), and the Conventional versus Lapa‐ roscopic-Assisted Surgery in Colorectal Cancer (CLASICC; 29%) [15, 16]. This could be due to

A meta-analysis from 2006 demonstrated intriguing results. It includes 1134 patients after colectomy in two periods – 1996-2000 and 2000-2004. Laparoscopic colectomy was introduced as an option only in the second period. The authors found that 3-year overall survival decreased in the latter, while the overall survival of patients after open colectomy remained

Intracorporeal anastomosis for right laparoscopic colectomy improved patient outcome compared with patients who underwent extracorporeal anastomosis. There is found faster recovery of nutrition, faster recovery of intestinal function, and shorter hospitalization.

According to the differences in age, gender, BMI, ASA class, or abdominal surgical history, in laparoscopic colectomy with extracorporeal anastomosis (laparoscopic-assisted colectomy), the bowel is externalized through a lateral mini-incision. With this approach, bowel mobili‐ zation and ligation of vessels is usually laparoscopic, whereas resection of the specimen and creation of the anastomosis is extracorporeal. On the other hand, in laparoscopic right colectomy with intracorporeal anastomosis (totally laparoscopic colectomy), bowel mobiliza‐ tion, ligation of vessels, resection of the specimen, and creation of the anastomosis are totally

However, there was no difference in average surgery time between the two groups.

more precautious behavior of the surgeons and their inexperience.

extraction after laparoscopic colectomy [12].

102 Colorectal Cancer - Surgery, Diagnostics and Treatment

**2. Systemic benefits**

less tumor recurrences [10-14].

the same over the two periods. [17]

intracorporeal.

The early trials of laparoscopic colectomy have established high rate of tumor recurrence near the port wounds, which was considered a serious drawback of the new approach. The etiology is unclear, although some authors suggest poor surgical technique and tumor biology as a probable cause. The reported rate in the early trials reached 21%. Recent trials (Hughes et al., 1603 patients, [15] found the rate to be 0.68%. Fleshman et al. [5] reported results based on the NCI COST trial, which demonstrated comparable rates for open and laparoscopic surgery after 5- and 8-year follow up (0.5% and 0.9%, respectively). The Barcelona trials had similar outcome after a median follow-up of 95 months [7]. The European randomized controlled study, the Colon Cancer Laparoscopic or Open Resection (COLOR) trial (2009) established after 53-month median follow-up that the port site metastasis rate was 0.4% after open (n=542) and 1.3% after laparoscopic colectomy (n=534). [19] The location of the recurrences was near the extraction port (n=2) and near the trocar sites (n=5) [5]. Recent studies do not report such high recurrence rates.

opportunity to individualise peri-operative fluid administration. OD provides a real time representation of haemodynamic function, and has been shown to be comparable with other methods for estimating cardiac output such as LIDCO. A number of studies have shown that goal-directed fluids reduce morbidity, critical care admissions, and hospital stay [62]. It is not clear however whether these benefits are still significant within an enhanced recovery protocol. Other goal-directed techniques employ central venous oxygen saturation (ScvO2) as a surro‐ gate for mixed venous oxygen saturation. ScvO2 is related to tissue oxygenation and so can be used to titrate oxygen and fluid therapy, particularly in the immediate postoperative period. This approach requires central venous access which is not always available as some groups have developed a less invasive approach to monitoring. While a number of different fluid

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Epidural analgesia was considered central to early ERAS protocols, since it reduces the endocrine-mediated stress response [53, 54], and improves postoperative intestinal function [55]. Epidural analgesia also provides superior pain control to systemic opiates, particularly in the first 24-36 h after surgery [56]. Data on the effect of epidural analgesia come predomi‐ nantly from studies in open surgery while the benefits in laparoscopic surgery are less clear. Levy *et al* [65, 66] performed a meta-analysis to address this question but concluded that there was a paucity of quality data. The authors subsequently performed a study in which patients were randomised to receive epidural, spinal or patient-controlled opiate analgesia following elective laparoscopic colorectal resection. They demonstrated a significantly longer hospital stay, time to return of bowel function and duration of nausea in the epidural group. Intrathecal morphine has been proposed as an alternative [67]. A meta-analysis provides encour‐ aging results in patients undergoing abdominal surgery; reduced post-operative pain in the first 48 h and significantly reduced opiate consumption compared with systemic opiates [68]. Transversus abdominus plane blocks have also been gaining in popularity although compa‐ rative data is still lacking [69]. Epidurals can cause vasodilatation and hypotension [70], resulting in excess fluid challenges, third space shift and fluid overload. As studies emerge demonstrating benefits of alternative analgesic techniques, it does raise the question: Should epidural analgesia be the standard technique for all colorectal resections? Perhaps a more individualised approach dependent on the procedure, use of laparoscopy and placement of incisions should be considered. In this way more patients may be able to avoid potential complications while maintaining adequate analgesia and facilitating early mobilisation.

protocols have been proposed, the optimal approach is still unclear.

**7. Laparoscopic and open surgery in enhanced recovery**

The adoption of laparoscopic techniques within colorectal surgery came at a similar time to the introduction of "fast-track" surgery. Early studies examining the effect of laparoscopic surgery showed clear superiority in short term outcomes when compared with open surgery

**6. Evolving postoperative analgesia**

Proper training and the use of safe oncologic techniques are essential in the prevention of port site metastases. Such safe techniques are the routing use of wound protectors, less instrument exchange, avoidance of direct trauma to the tumor, avoidance of inadvertent desufflation.

## **4. Enhanced recovery after surgery**

The approach employs a multimodal perioperative care pathway with the aim of attenuating the stress response to surgery and accelerating recovery [21]. Implementation of enhanced recovery protocols has led to improved outcomes across a range of different specialties including reductions in postoperative morbidity and hospital stay [61-65]. The fundamental premise of ERAS is the incorporation of evidence-based practice. It would seem to follow therefore that the evolution of enhanced recovery guidelines should be dynamic, allowing modifications of certain aspects of the program as new data becomes available. Some authors have advocated a rigid adherence to the ERAS protocol, citing study data that demonstrates a proportional relationship between deviation from the protocol and increased morbidity [61]. However, as evidence for components of the ERAS protocol change, it may be that a more flexible and individualised approach should be considered.

## **5. Perioperative fluid administration**

Traditionally, patients undergoing major colorectal surgery have received liberal volumes of intravenous fluids [49]. Excess intravenous fluid during and after surgery has been associated with delayed gut function and increased complication rates [50, 51]. Fluid restriction has been proposed as a possible method of improving recovery and reducing postoperative complica‐ tions. Brandstrup *et al* [58] found that randomising patients undergoing elective colorectal surgery resection to a restricted fluid protocol reduced cardiopulmonary and wound morbid‐ ity. MacKay *et al* [59] found no difference in recovery of gastrointestinal function or time to discharge with postoperative fluid restriction while using a conservative intra-operative protocol. Goal directed fluid therapy *via* oesophageal Doppler (OD) monitoring offers an opportunity to individualise peri-operative fluid administration. OD provides a real time representation of haemodynamic function, and has been shown to be comparable with other methods for estimating cardiac output such as LIDCO. A number of studies have shown that goal-directed fluids reduce morbidity, critical care admissions, and hospital stay [62]. It is not clear however whether these benefits are still significant within an enhanced recovery protocol. Other goal-directed techniques employ central venous oxygen saturation (ScvO2) as a surro‐ gate for mixed venous oxygen saturation. ScvO2 is related to tissue oxygenation and so can be used to titrate oxygen and fluid therapy, particularly in the immediate postoperative period. This approach requires central venous access which is not always available as some groups have developed a less invasive approach to monitoring. While a number of different fluid protocols have been proposed, the optimal approach is still unclear.

## **6. Evolving postoperative analgesia**

is unclear, although some authors suggest poor surgical technique and tumor biology as a probable cause. The reported rate in the early trials reached 21%. Recent trials (Hughes et al., 1603 patients, [15] found the rate to be 0.68%. Fleshman et al. [5] reported results based on the NCI COST trial, which demonstrated comparable rates for open and laparoscopic surgery after 5- and 8-year follow up (0.5% and 0.9%, respectively). The Barcelona trials had similar outcome after a median follow-up of 95 months [7]. The European randomized controlled study, the Colon Cancer Laparoscopic or Open Resection (COLOR) trial (2009) established after 53-month median follow-up that the port site metastasis rate was 0.4% after open (n=542) and 1.3% after laparoscopic colectomy (n=534). [19] The location of the recurrences was near the extraction port (n=2) and near the trocar sites (n=5) [5]. Recent studies do not report such high recurrence

Proper training and the use of safe oncologic techniques are essential in the prevention of port site metastases. Such safe techniques are the routing use of wound protectors, less instrument exchange, avoidance of direct trauma to the tumor, avoidance of inadvertent desufflation.

The approach employs a multimodal perioperative care pathway with the aim of attenuating the stress response to surgery and accelerating recovery [21]. Implementation of enhanced recovery protocols has led to improved outcomes across a range of different specialties including reductions in postoperative morbidity and hospital stay [61-65]. The fundamental premise of ERAS is the incorporation of evidence-based practice. It would seem to follow therefore that the evolution of enhanced recovery guidelines should be dynamic, allowing modifications of certain aspects of the program as new data becomes available. Some authors have advocated a rigid adherence to the ERAS protocol, citing study data that demonstrates a proportional relationship between deviation from the protocol and increased morbidity [61]. However, as evidence for components of the ERAS protocol change, it may be that a more

Traditionally, patients undergoing major colorectal surgery have received liberal volumes of intravenous fluids [49]. Excess intravenous fluid during and after surgery has been associated with delayed gut function and increased complication rates [50, 51]. Fluid restriction has been proposed as a possible method of improving recovery and reducing postoperative complica‐ tions. Brandstrup *et al* [58] found that randomising patients undergoing elective colorectal surgery resection to a restricted fluid protocol reduced cardiopulmonary and wound morbid‐ ity. MacKay *et al* [59] found no difference in recovery of gastrointestinal function or time to discharge with postoperative fluid restriction while using a conservative intra-operative protocol. Goal directed fluid therapy *via* oesophageal Doppler (OD) monitoring offers an

rates.

**4. Enhanced recovery after surgery**

104 Colorectal Cancer - Surgery, Diagnostics and Treatment

flexible and individualised approach should be considered.

**5. Perioperative fluid administration**

Epidural analgesia was considered central to early ERAS protocols, since it reduces the endocrine-mediated stress response [53, 54], and improves postoperative intestinal function [55]. Epidural analgesia also provides superior pain control to systemic opiates, particularly in the first 24-36 h after surgery [56]. Data on the effect of epidural analgesia come predomi‐ nantly from studies in open surgery while the benefits in laparoscopic surgery are less clear. Levy *et al* [65, 66] performed a meta-analysis to address this question but concluded that there was a paucity of quality data. The authors subsequently performed a study in which patients were randomised to receive epidural, spinal or patient-controlled opiate analgesia following elective laparoscopic colorectal resection. They demonstrated a significantly longer hospital stay, time to return of bowel function and duration of nausea in the epidural group. Intrathecal morphine has been proposed as an alternative [67]. A meta-analysis provides encour‐ aging results in patients undergoing abdominal surgery; reduced post-operative pain in the first 48 h and significantly reduced opiate consumption compared with systemic opiates [68]. Transversus abdominus plane blocks have also been gaining in popularity although compa‐ rative data is still lacking [69]. Epidurals can cause vasodilatation and hypotension [70], resulting in excess fluid challenges, third space shift and fluid overload. As studies emerge demonstrating benefits of alternative analgesic techniques, it does raise the question: Should epidural analgesia be the standard technique for all colorectal resections? Perhaps a more individualised approach dependent on the procedure, use of laparoscopy and placement of incisions should be considered. In this way more patients may be able to avoid potential complications while maintaining adequate analgesia and facilitating early mobilisation.

## **7. Laparoscopic and open surgery in enhanced recovery**

The adoption of laparoscopic techniques within colorectal surgery came at a similar time to the introduction of "fast-track" surgery. Early studies examining the effect of laparoscopic surgery showed clear superiority in short term outcomes when compared with open surgery using traditional recovery technique [63, 64]. Patients undergoing laparoscopic surgery have reduced in-patient stays, less morbidity and improved postoperative pain [65, 66]. What is less clear is how much of the benefit is attributable to laparoscopy and how much is an effect of differing perioperative care pathways. Since these early trials there have been a number of small trials comparing laparoscopic and open colorectal surgery within an enhanced recovery setting with conflicting results [55-61]. Most recently a four-armed randomised study of patients undergoing either open or laparoscopic surgery, in an enhanced recovery or standard recovery programme was performed. They demonstrated a significantly faster recovery time following colonic surgery in those patients undergoing laparoscopic procedures within an ERAS programme. What is clear is that there are still a number of areas within the enhanced recovery protocol where the evidence-base continues to change. The relative contributions of different facets of the protocol also remain to be determined. While this is the case we should accept a flexible approach to facilitate the adoption of techniques supported by randomised data. There may also be scope for a degree of individualisation to reflect the wide range of patients and procedures to which enhanced recovery is now being applied. [70]

In the early 1990s, several multicenter prospective randomized controlled trials comparing laparoscopic and open surgery for colorectal cancer were initiated. Ultimately, seven largescale trials compared laparoscopic and open colectomy for colon carcinoma and examined short-term and long-term outcomes. These trials included the Clinical Outcomes of Surgical Therapies (COST) trial funded by the National Cancer Institute in the United States, the Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC) trial in the United Kingdom, the Colon Cancer Laparoscopic or Open Resection (COLOR), a multi‐ center European trial, the Barcelona trial, and several others [20–26]. The main focus of these trials was oncologic outcomes, but short-term outcomes, quality of life, and safety were also evaluated. The CLASICC trial was the only large trial that also evaluated MIS in rectal cancer. Though modest in early studies, the short-term patient-related advantages of laparoscopic surgery have now been confirmed and are significant over the open approach. The Minimally Invasive Colorectal Resection Outcomes (MICRO) review identified 22 randomized controlled trials and 66 cohort series for benign and malignant colorectal disease [27]. Laparoscopic colectomy results in significantly lower pain scores and analgesia requirements, estimated blood loss, return of bowel function, and length of stay. Numerous other trials, including the COST, COLOR, and CLASICC trials, examining short-term outcomes following laparoscopic colectomy for colorectal cancer have confirmed these findings [20–26, 28]. Several studies have also identified a decreased rate of postoperative morbidity including fewer wound infections [21, 23, 27, 29]; this was recently reinforced by a large trial from the National Surgical Quality Improvement Program (NSQIP) database of over 10, 000 patients identifying decreased incidence of wound infection following laparoscopic colectomy (9.5% versus 16.1%, *P* < 0.001) [30]. Quality of life has been assessed in several trials and results varied from no difference to

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favoring improved quality of life in laparoscopic colectomy [31].

The initially cited oncologic concerns of laparoscopic colectomy for colorectal cancer were later dispelled when surgeons trained in appropriate laparoscopic oncologic resection performed operations in the trial setting. Major trials, including the COST, CLASICC, and COLOR trials, examined tumor specimens and reported long-term data on recurrence and survival. The surgical specimens were evaluated, and parameters such as lymph node yield, circumferential resection margins, and longitudinal margins were quantified. No trial identified statistically significant differences in lymph node yield [20–26] or resection margins [20, 22, 26]. This initial evidence allayed some concerns regarding oncologic resections, but the long-term measures for recurrence and survival were still unknown. Trial data matured, and more evidence accumulated confirming similar recurrence patterns and rates between laparoscopic and open colectomy. Local recurrence, distant recurrence, and wound or port site metastases were the same between groups [4, 5, 7, 24, 32–34]. Disease-free and overall survival in long-term followup (up to 7 years) is equivalent [4, 5, 7, 32–34]. The concern that conversion from laparoscopic to open surgery in patients with colon cancer may lead to worse oncologic outcomes was not seen when 5-year COST trial data showed no statistical difference in these two groups.

Despite evidence demonstrating improved short-term outcomes of laparoscopic colectomy and oncologic equivalence, widespread implementation of this technique was slow. The lack of formalized training, outside single-day laparoscopic training courses, and the significant

#### **8. Laparoscopic colectomy**

After the initial description in 1991, several reports of laparoscopic colectomy (LC) for colorectal cancer were described. Significant concerns regarding this approach surfaced when minimally invasive techniques applied to colorectal malignancy lead to increased surgical complications and worse cancer outcomes compared to conventional open approaches. An early report, using minimally invasive techniques for benign colorectal disease, showed a significantly high rate of serious complications (18%), including inadvertent enterotomies, intraoperative hemorrhage, anastomotic leaks, and pelvic abscesses. When LC was used to treat colorectal cancer, several papers noted early wound or trocar site recurrences, including one case series documenting a 21% rate. With a less than 1 percent wound implantation rate for open surgery, serious concerns were raised as to the possibility that poor oncologic results were due to a combination of poor technique and abnormal distribution of malignant cells secondary to pneumoperitoneum. Further concerns that laparoscopic techniques may be problematic to cancer patients arose when some studies demonstrated statistically significant worse cancer-specific survival in patients who had conversion from laparoscopic to open surgery. Moloo et al. described decreased survival at 2 years of 76% from 87% for all stages (*P* = 0.02) of colorectal cancer collected from a prospective database of 377 consecutive laparoscopic patients. In the same cohort, at 5 year followup, there was a trend toward decreased overall survival in converted patients (61.9% versus 69.7%, *P* = 0.077). Chan et al. showed an increased local recurrence rate at 3 year followup of 9.8% in the laparoscopically converted group as compared to 2.8% in open patients (*P* = 0.03). The oncological concerns raised in early reports provided a compelling argument to study the question of oncologic equivalence between the open and laparoscopic approach to colorectal cancer in a controlled fashion.

In the early 1990s, several multicenter prospective randomized controlled trials comparing laparoscopic and open surgery for colorectal cancer were initiated. Ultimately, seven largescale trials compared laparoscopic and open colectomy for colon carcinoma and examined short-term and long-term outcomes. These trials included the Clinical Outcomes of Surgical Therapies (COST) trial funded by the National Cancer Institute in the United States, the Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC) trial in the United Kingdom, the Colon Cancer Laparoscopic or Open Resection (COLOR), a multi‐ center European trial, the Barcelona trial, and several others [20–26]. The main focus of these trials was oncologic outcomes, but short-term outcomes, quality of life, and safety were also evaluated. The CLASICC trial was the only large trial that also evaluated MIS in rectal cancer. Though modest in early studies, the short-term patient-related advantages of laparoscopic surgery have now been confirmed and are significant over the open approach. The Minimally Invasive Colorectal Resection Outcomes (MICRO) review identified 22 randomized controlled trials and 66 cohort series for benign and malignant colorectal disease [27]. Laparoscopic colectomy results in significantly lower pain scores and analgesia requirements, estimated blood loss, return of bowel function, and length of stay. Numerous other trials, including the COST, COLOR, and CLASICC trials, examining short-term outcomes following laparoscopic colectomy for colorectal cancer have confirmed these findings [20–26, 28]. Several studies have also identified a decreased rate of postoperative morbidity including fewer wound infections [21, 23, 27, 29]; this was recently reinforced by a large trial from the National Surgical Quality Improvement Program (NSQIP) database of over 10, 000 patients identifying decreased incidence of wound infection following laparoscopic colectomy (9.5% versus 16.1%, *P* < 0.001) [30]. Quality of life has been assessed in several trials and results varied from no difference to favoring improved quality of life in laparoscopic colectomy [31].

using traditional recovery technique [63, 64]. Patients undergoing laparoscopic surgery have reduced in-patient stays, less morbidity and improved postoperative pain [65, 66]. What is less clear is how much of the benefit is attributable to laparoscopy and how much is an effect of differing perioperative care pathways. Since these early trials there have been a number of small trials comparing laparoscopic and open colorectal surgery within an enhanced recovery setting with conflicting results [55-61]. Most recently a four-armed randomised study of patients undergoing either open or laparoscopic surgery, in an enhanced recovery or standard recovery programme was performed. They demonstrated a significantly faster recovery time following colonic surgery in those patients undergoing laparoscopic procedures within an ERAS programme. What is clear is that there are still a number of areas within the enhanced recovery protocol where the evidence-base continues to change. The relative contributions of different facets of the protocol also remain to be determined. While this is the case we should accept a flexible approach to facilitate the adoption of techniques supported by randomised data. There may also be scope for a degree of individualisation to reflect the wide range of

patients and procedures to which enhanced recovery is now being applied. [70]

After the initial description in 1991, several reports of laparoscopic colectomy (LC) for colorectal cancer were described. Significant concerns regarding this approach surfaced when minimally invasive techniques applied to colorectal malignancy lead to increased surgical complications and worse cancer outcomes compared to conventional open approaches. An early report, using minimally invasive techniques for benign colorectal disease, showed a significantly high rate of serious complications (18%), including inadvertent enterotomies, intraoperative hemorrhage, anastomotic leaks, and pelvic abscesses. When LC was used to treat colorectal cancer, several papers noted early wound or trocar site recurrences, including one case series documenting a 21% rate. With a less than 1 percent wound implantation rate for open surgery, serious concerns were raised as to the possibility that poor oncologic results were due to a combination of poor technique and abnormal distribution of malignant cells secondary to pneumoperitoneum. Further concerns that laparoscopic techniques may be problematic to cancer patients arose when some studies demonstrated statistically significant worse cancer-specific survival in patients who had conversion from laparoscopic to open surgery. Moloo et al. described decreased survival at 2 years of 76% from 87% for all stages (*P* = 0.02) of colorectal cancer collected from a prospective database of 377 consecutive laparoscopic patients. In the same cohort, at 5 year followup, there was a trend toward decreased overall survival in converted patients (61.9% versus 69.7%, *P* = 0.077). Chan et al. showed an increased local recurrence rate at 3 year followup of 9.8% in the laparoscopically converted group as compared to 2.8% in open patients (*P* = 0.03). The oncological concerns raised in early reports provided a compelling argument to study the question of oncologic equivalence between the open and laparoscopic approach to colorectal cancer in a controlled

**8. Laparoscopic colectomy**

106 Colorectal Cancer - Surgery, Diagnostics and Treatment

fashion.

The initially cited oncologic concerns of laparoscopic colectomy for colorectal cancer were later dispelled when surgeons trained in appropriate laparoscopic oncologic resection performed operations in the trial setting. Major trials, including the COST, CLASICC, and COLOR trials, examined tumor specimens and reported long-term data on recurrence and survival. The surgical specimens were evaluated, and parameters such as lymph node yield, circumferential resection margins, and longitudinal margins were quantified. No trial identified statistically significant differences in lymph node yield [20–26] or resection margins [20, 22, 26]. This initial evidence allayed some concerns regarding oncologic resections, but the long-term measures for recurrence and survival were still unknown. Trial data matured, and more evidence accumulated confirming similar recurrence patterns and rates between laparoscopic and open colectomy. Local recurrence, distant recurrence, and wound or port site metastases were the same between groups [4, 5, 7, 24, 32–34]. Disease-free and overall survival in long-term followup (up to 7 years) is equivalent [4, 5, 7, 32–34]. The concern that conversion from laparoscopic to open surgery in patients with colon cancer may lead to worse oncologic outcomes was not seen when 5-year COST trial data showed no statistical difference in these two groups.

Despite evidence demonstrating improved short-term outcomes of laparoscopic colectomy and oncologic equivalence, widespread implementation of this technique was slow. The lack of formalized training, outside single-day laparoscopic training courses, and the significant learning curve for straight laparoscopic techniques likely represented significant barriers to adoption. As hand-assisted laparoscopic surgery grew in popularity, a more widespread adaptation with fewer conversions to open surgery occurred in part due to a shorter learning curve with this technique. Three randomized controlled trials have been performed to compare a hand-assisted technique to a laparoscopic technique including patients with both benign and malignant disease, all demonstrating decreased rates of conversion to open surgery [35–37]. A recent meta-analysis compiling 13 studies demonstrated decreased operative times and decreased open conversion rates with a hand-assisted approach [38]. There were no differences in short-term clinical outcomes or oncologic resection results. A recent study by the Mayo Clinic prospectively analyzed the use of hand-assisted surgery in a minimally invasive colorectal practice and found that when applied to a center performing large volumes of laparoscopic surgery, hand-assisted techniques were responsible for more complex proce‐ dures to be done laparoscopically [39]. This technique is a minimally invasive approach that has been helpful for surgeons to transition from open to laparoscopic colectomy, especially if they have had little previous laparoscopic experience. Moreover, this technique has allowed a MIS approach in patients otherwise not previously considered candidates (obese, adhesions).

not show any statistical difference. The conclusion is that in a dedicated laparoscopic center, LAC may result in a long-term survival benefit compared with OC, particularly in advanced cases". This oncological advantage can be explained by a preserved cellular immunity,

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These results seem encouraging and lead the way for laparoscopic surgery, although in a 2007 study by Fleshman (5-year follow-up, COST trial) the data did not demonstrate significant difference in the 5-year overall survival, 5-year disease-free survival, and recurrence rates between the two groups. The pattern of recurrence is also similar. [5] In 2007 Bonjer et al. reported meta-analysis, based on 3-year follow-up data from Barcelona, COST, COLOR and CLASSIC trials. No significant difference in 3-year survival, 3-year disease free survival or tumor recurrence rates between study groups was observed. Analysis by stages did not show

The hand-assisted laparoscopic surgery is a potential way to decrease operative time and maintain the benefits of the minimally invasive approach. The type of laparoscopic surgery allows introducing a hand through special device in the abdominal cavity, while preserving pneumoperitoneum. This provides proprioception and tactile feedback and ability to perform manual dissection and retraction. A study by Marcell [8] reported the results after multicenter randomized trial. The hand assisted sigmoidectomy group had significantly shorter operative time by 30-minutes when compared with straight laparoscopic group. Both groups had similar short-term outcomes. There were no differences in time to bowel function, pain scores, narcotic use, or time to bowel function. Conversion to open surgery was also significantly less for the hand-assisted group. Incision length was significantly longer for the hand-assisted group, but the difference was small. The authors concluded that hand-assisted surgery results in signifi‐ cantly shorter operative time, while maintaining similar outcomes as straight laparoscopic surgery [17]. Hand-assisted surgery allows to perform more complex procedures and to

The use of laparoscopic approach in the treatment of rectal cancer has led to increase of surgical complications and worse cancer outcomes in comparison to the open surgery [6] strong statement to make, may be phrase it differently. Several papers reported increased rate of portsite recurrences, reaching up to 21% [3]. The same parameter for the open approach is 1%. Those results might be explained by poor surgical technique and abnormal distribution of cancer cell due to the pneumoperitoneum [7]. The cancer-specific survival was significantly

Based on the data of a prospective trial, including 377 laparoscopic patients [22] the survival decreased from 87% to 76% at 2 years for all stages of colorectal cancer. After a 5-year followup the overall survival decreased in converted patients. The local recurrence also proved to be higher: 9.8% and 2.8% for the laparoscopic and open groups, respectively. Several large trials were initiated in the 1990 (Clinical Outcomes of Surgical Therapies (COST) [21]in the

attenuated stress and inflammatory response. [7]

operate on patients with adhesion or obesity.

lower after conversion to open surgery [8, 9].

**9. Laparoscopy for rectal cancer**

any statistical difference in survival between both groups [16].

As surgeon experience increased and as more studies demonstrated that laparoscopic colec‐ tomy for benign and malignant disease is an acceptable alternative to open surgery, the overall ratio of laparoscopic to open colectomies in the United States has increased. A recent analysis from 2000 through 2004 demonstrated an increasing incidence of laparoscopic colectomy from 3% to 6.5% nationally with increased rates of laparoscopic approaches in urban centers and teaching hospitals [40]. A separate study and database of patients from 2004 through 2006 identified over 32, 000 patients, of which 34% underwent laparoscopic colectomy [41]. This trend toward increased laparoscopy has also been influenced by public knowledge and patient demand for this approach, as well as improved and formalized laparoscopic training in residency programs.

The short-term advantages of laparoscopic surgery over the open approach are confirmed. The minimally invasive approach is characterized by lower pain score and analgesia requirement, estimated blood loss; earlier return of bowel function and shorter length of stay (Minimally Invasive Colorectal Resection Outcomes (MICRO), [20]. The postoperative recovery of pulmonary function is quicker after laparoscopic colectomy. None of the randomized trials have observed significant increase in the anastomotic leakage rate [2-5]. Several studies demonstrated the decreased rate of postoperative morbidity and less wound infections [2-7]. Quality of life after laparoscopic surgery has been evaluated in several trials and the results varied from similar to better QoL than after open surgery [21].

In 2008 Lacy et al. reported the long-term outcomes of Barcelona trial (median follow-up 95 months). The overall survival rate was higher in the laparoscopic (64%) group when compared with the open group (51%) with no statistically significant difference (p<0.07). Laparoscopic group demonstrated higher cancer-related survival and lower cancer recurrence in (p<0.07 for both). The differences in survival and recurrences between the open and laparoscopic groups were observed for III stage tumors, with significantly better results in terms of overall-survival, cancer-related survival and chances of being free of recurrence. Results for stage I and II did not show any statistical difference. The conclusion is that in a dedicated laparoscopic center, LAC may result in a long-term survival benefit compared with OC, particularly in advanced cases". This oncological advantage can be explained by a preserved cellular immunity, attenuated stress and inflammatory response. [7]

These results seem encouraging and lead the way for laparoscopic surgery, although in a 2007 study by Fleshman (5-year follow-up, COST trial) the data did not demonstrate significant difference in the 5-year overall survival, 5-year disease-free survival, and recurrence rates between the two groups. The pattern of recurrence is also similar. [5] In 2007 Bonjer et al. reported meta-analysis, based on 3-year follow-up data from Barcelona, COST, COLOR and CLASSIC trials. No significant difference in 3-year survival, 3-year disease free survival or tumor recurrence rates between study groups was observed. Analysis by stages did not show any statistical difference in survival between both groups [16].

The hand-assisted laparoscopic surgery is a potential way to decrease operative time and maintain the benefits of the minimally invasive approach. The type of laparoscopic surgery allows introducing a hand through special device in the abdominal cavity, while preserving pneumoperitoneum. This provides proprioception and tactile feedback and ability to perform manual dissection and retraction. A study by Marcell [8] reported the results after multicenter randomized trial. The hand assisted sigmoidectomy group had significantly shorter operative time by 30-minutes when compared with straight laparoscopic group. Both groups had similar short-term outcomes. There were no differences in time to bowel function, pain scores, narcotic use, or time to bowel function. Conversion to open surgery was also significantly less for the hand-assisted group. Incision length was significantly longer for the hand-assisted group, but the difference was small. The authors concluded that hand-assisted surgery results in signifi‐ cantly shorter operative time, while maintaining similar outcomes as straight laparoscopic surgery [17]. Hand-assisted surgery allows to perform more complex procedures and to operate on patients with adhesion or obesity.

## **9. Laparoscopy for rectal cancer**

learning curve for straight laparoscopic techniques likely represented significant barriers to adoption. As hand-assisted laparoscopic surgery grew in popularity, a more widespread adaptation with fewer conversions to open surgery occurred in part due to a shorter learning curve with this technique. Three randomized controlled trials have been performed to compare a hand-assisted technique to a laparoscopic technique including patients with both benign and malignant disease, all demonstrating decreased rates of conversion to open surgery [35–37]. A recent meta-analysis compiling 13 studies demonstrated decreased operative times and decreased open conversion rates with a hand-assisted approach [38]. There were no differences in short-term clinical outcomes or oncologic resection results. A recent study by the Mayo Clinic prospectively analyzed the use of hand-assisted surgery in a minimally invasive colorectal practice and found that when applied to a center performing large volumes of laparoscopic surgery, hand-assisted techniques were responsible for more complex proce‐ dures to be done laparoscopically [39]. This technique is a minimally invasive approach that has been helpful for surgeons to transition from open to laparoscopic colectomy, especially if they have had little previous laparoscopic experience. Moreover, this technique has allowed a MIS approach in patients otherwise not previously considered candidates (obese, adhesions).

As surgeon experience increased and as more studies demonstrated that laparoscopic colec‐ tomy for benign and malignant disease is an acceptable alternative to open surgery, the overall ratio of laparoscopic to open colectomies in the United States has increased. A recent analysis from 2000 through 2004 demonstrated an increasing incidence of laparoscopic colectomy from 3% to 6.5% nationally with increased rates of laparoscopic approaches in urban centers and teaching hospitals [40]. A separate study and database of patients from 2004 through 2006 identified over 32, 000 patients, of which 34% underwent laparoscopic colectomy [41]. This trend toward increased laparoscopy has also been influenced by public knowledge and patient demand for this approach, as well as improved and formalized laparoscopic training in

The short-term advantages of laparoscopic surgery over the open approach are confirmed. The minimally invasive approach is characterized by lower pain score and analgesia requirement, estimated blood loss; earlier return of bowel function and shorter length of stay (Minimally Invasive Colorectal Resection Outcomes (MICRO), [20]. The postoperative recovery of pulmonary function is quicker after laparoscopic colectomy. None of the randomized trials have observed significant increase in the anastomotic leakage rate [2-5]. Several studies demonstrated the decreased rate of postoperative morbidity and less wound infections [2-7]. Quality of life after laparoscopic surgery has been evaluated in several trials and the results

In 2008 Lacy et al. reported the long-term outcomes of Barcelona trial (median follow-up 95 months). The overall survival rate was higher in the laparoscopic (64%) group when compared with the open group (51%) with no statistically significant difference (p<0.07). Laparoscopic group demonstrated higher cancer-related survival and lower cancer recurrence in (p<0.07 for both). The differences in survival and recurrences between the open and laparoscopic groups were observed for III stage tumors, with significantly better results in terms of overall-survival, cancer-related survival and chances of being free of recurrence. Results for stage I and II did

varied from similar to better QoL than after open surgery [21].

residency programs.

108 Colorectal Cancer - Surgery, Diagnostics and Treatment

The use of laparoscopic approach in the treatment of rectal cancer has led to increase of surgical complications and worse cancer outcomes in comparison to the open surgery [6] strong statement to make, may be phrase it differently. Several papers reported increased rate of portsite recurrences, reaching up to 21% [3]. The same parameter for the open approach is 1%. Those results might be explained by poor surgical technique and abnormal distribution of cancer cell due to the pneumoperitoneum [7]. The cancer-specific survival was significantly lower after conversion to open surgery [8, 9].

Based on the data of a prospective trial, including 377 laparoscopic patients [22] the survival decreased from 87% to 76% at 2 years for all stages of colorectal cancer. After a 5-year followup the overall survival decreased in converted patients. The local recurrence also proved to be higher: 9.8% and 2.8% for the laparoscopic and open groups, respectively. Several large trials were initiated in the 1990 (Clinical Outcomes of Surgical Therapies (COST) [21]in the

The use of laparoscopic stapler requires multiple firings to complete distal rectal resection. In the case of low rectal anastomoses, this increases the anastomotic leakage rate (17% below 12cm from the anal verge [11], 20% below 15cm [23]. The leakage rate after open total meso‐ rectal dissection varies from 4% to 11% [25, 26]. Future improvement of the stapler technology

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The proven benefits of laparoscopy noted in colon cancer surgery including decreased intraoperative blood loss, smaller length of incision, less postoperative pain, faster recovery of intestinal function, and shorter length of hospital stay likely also apply to rectal cancer surgery [37]. In RCTs the mean operative time for open surgical resection of rectal cancer ranged from 106 to 284 min compared to 120 to 245 min for laparoscopic resection. As expected, duration of operation was significantly longer in the laparoscopic group compared to the open group in 6 of the 8 RCTs [7, 22, 31, 38-40]. Similar results were reported in RCTs of open *vs* laparoscopic resection for colon cancer. Zhou *et al* [24] reported both shorter open and laparoscopic operative times compared to other trials with no significant difference between the two operative approaches (120 min *vs* 106 min for laparoscopic *vs* open resection respec‐ tively, *P*= 0.051). However, no details were provided on tumor stage, conversion rate, or whether the analysis was performed on an intent-to-treat basis. Araujo *et al* [25] was the only RCT to demonstrate significantly shorter operative times with laparoscopic compared to open resection (228 min *vs* 284 min respectively, *P* = 0.04). However, they attributed these results to fact that the surgical team performing laparoscopic APR was the same whereas open APR was often performed by different surgical teams. In addition, extraction of the specimen from the

**Figure 2.** Lymph node dissection in laparoscopic rectal cancer resection

is required.

**Figure 1.** Laparoscopic resection of rectal cancer –anterior mobilization of the rectum

USA, the Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLA‐ SICC) [6] in the United Kingdom, Colon Cancer Laparoscopic or Open Resection (COLOR) in Europe and the Barcelona trial) [15]. Those trials evaluated laparoscopic and open colectomy for colon carcinoma and examined short-term and long-term outcomes, as well as short-term outcomes, quality of life and safety. Only the CLASSIC trials evaluated minimally invasive surgery for rectal cancer.

The potential benefits of laparoscopic rectal surgery are known and were proven by metaanalysis of studies of non-randomized trials – shorter time of bowel function restoration, shorter length of stay [22]. A characteristic advantage of the laparoscopic surgery is that it provides unobstructed view to the entire surgical team and magnified view of the operating field, thus allowing more accurate dissection. The pneumoperitoneum helps to open the planes of dissection of the mesorectum. The limitations of the laparoscopic rectal surgery are the unsure data on oncological safety [2-5], the concerns about inadequate oncological distant dissection, anastomotic leakage, technical challenges [23, 24].

Significant difficulty poses the obtaining of adequate exposure of the rectum. The narrow pelvis in some patients may cause clashing of the instruments and poor dissection. An experience assistant is required in such cases. The CLASSIC trial reported increased rate of positive circumferential margin after laparoscopic rectal surgery (12%) in comparison to the open group (6%). The distant margin of the tumor is difficult to be identified, as it cannot be palpated. This may cause inadequate distal resection.

The use of laparoscopic stapler requires multiple firings to complete distal rectal resection. In the case of low rectal anastomoses, this increases the anastomotic leakage rate (17% below 12cm from the anal verge [11], 20% below 15cm [23]. The leakage rate after open total meso‐ rectal dissection varies from 4% to 11% [25, 26]. Future improvement of the stapler technology is required.

**Figure 2.** Lymph node dissection in laparoscopic rectal cancer resection

USA, the Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLA‐ SICC) [6] in the United Kingdom, Colon Cancer Laparoscopic or Open Resection (COLOR) in Europe and the Barcelona trial) [15]. Those trials evaluated laparoscopic and open colectomy for colon carcinoma and examined short-term and long-term outcomes, as well as short-term outcomes, quality of life and safety. Only the CLASSIC trials evaluated minimally invasive

The potential benefits of laparoscopic rectal surgery are known and were proven by metaanalysis of studies of non-randomized trials – shorter time of bowel function restoration, shorter length of stay [22]. A characteristic advantage of the laparoscopic surgery is that it provides unobstructed view to the entire surgical team and magnified view of the operating field, thus allowing more accurate dissection. The pneumoperitoneum helps to open the planes of dissection of the mesorectum. The limitations of the laparoscopic rectal surgery are the unsure data on oncological safety [2-5], the concerns about inadequate oncological distant

Significant difficulty poses the obtaining of adequate exposure of the rectum. The narrow pelvis in some patients may cause clashing of the instruments and poor dissection. An experience assistant is required in such cases. The CLASSIC trial reported increased rate of positive circumferential margin after laparoscopic rectal surgery (12%) in comparison to the open group (6%). The distant margin of the tumor is difficult to be identified, as it cannot be

dissection, anastomotic leakage, technical challenges [23, 24].

**Figure 1.** Laparoscopic resection of rectal cancer –anterior mobilization of the rectum

palpated. This may cause inadequate distal resection.

surgery for rectal cancer.

110 Colorectal Cancer - Surgery, Diagnostics and Treatment

The proven benefits of laparoscopy noted in colon cancer surgery including decreased intraoperative blood loss, smaller length of incision, less postoperative pain, faster recovery of intestinal function, and shorter length of hospital stay likely also apply to rectal cancer surgery [37]. In RCTs the mean operative time for open surgical resection of rectal cancer ranged from 106 to 284 min compared to 120 to 245 min for laparoscopic resection. As expected, duration of operation was significantly longer in the laparoscopic group compared to the open group in 6 of the 8 RCTs [7, 22, 31, 38-40]. Similar results were reported in RCTs of open *vs* laparoscopic resection for colon cancer. Zhou *et al* [24] reported both shorter open and laparoscopic operative times compared to other trials with no significant difference between the two operative approaches (120 min *vs* 106 min for laparoscopic *vs* open resection respec‐ tively, *P*= 0.051). However, no details were provided on tumor stage, conversion rate, or whether the analysis was performed on an intent-to-treat basis. Araujo *et al* [25] was the only RCT to demonstrate significantly shorter operative times with laparoscopic compared to open resection (228 min *vs* 284 min respectively, *P* = 0.04). However, they attributed these results to fact that the surgical team performing laparoscopic APR was the same whereas open APR was often performed by different surgical teams. In addition, extraction of the specimen from the perineum likely decreased operative time because there was not an abdominal incision to close. Two meta-analyses included operative time as an outcome of interest. Aziz *et al* [17] included 22 studies comparing laparoscopic *vs* open rectal cancer resection in 2071 patients and found that operative time was significantly increased with the laparoscopic group as compared to the open group with a weighted mean difference (WMD) of 40.18 (95% CI, 26.46-56.13). Gao *et al* [26] performed a meta-analysis of short-term outcomes after laparoscopic resection for rectal cancer based on 11 studies and included 643 patients which reported no difference in operating time between open and laparoscopic approaches with a WMD of 1.59 [1.2-1.98]. Intraoperative blood loss was significantly less for the laparoscopic group compared to the open group in 4 of 6 RCTs and ranged from 20 mL to 321.7 mL and from 92 mL to 555.6 mL in the laparoscopic and open groups respectively [31, 35, 38, 40]. Araujo *et al* [25] did not specifically report on the amount of intraoperative blood loss but there was no statistically significant difference in the need for blood transfusions between the two groups which was attributed to the fact that in an APR the majority of blood loss occurs during the perineal portion of the case which is the same regardless of surgical access.

Conversion was also associated with worse oncologic outcomes in nonrandomized compara‐

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While the number of lymph nodes retrieved can vary based on age, gender, tumor site, use of pre-operative radiation, and tumor grade, the extent and quality of surgical resection can also have an impact on the number of nodes collected and is therefore often considered a surrogate marker of the oncologic completeness of the resection [37]. The American Joint Committee on Cancer recommends that at least 12 lymph nodes be examined in patients with rectal cancer to confirm the absence of nodal involvement by the tumor [34]. In addition, a number of studies have reported that the number of lymph nodes examined may be associated with patient outcome [25, 26]. Six of the 8 RCTs reported the mean number of lymph nodes retrieved with a range of 5.5 to 17 nodes in the laparoscopic group compared to 11.6 to 18 nodes in the open group [22, 31, 34]. In 4 of the 6 trials the number of lymph nodes isolated was not significantly different based on surgical approach. Araujo *et al* [25] reported a significantly lower yield of lymph nodes with laparoscopic rectal resection compared to open resection (5.5 *vs* 11.9 respectively, *P* = 0.04). They suggested that laparoscopy offered better dissection and accuracy due to better visualization and exposure of structures with less manipulation of the mesorec‐

tive and descriptive studies [46].

**Figure 3.** Total mesorectal excision after laparoscopic rectal resection

**10. Short-term oncologic outcomes**

A recent Cochrane review by Breukink *et al* [41] evaluating the safety and efficacy of elective laparoscopic TME for the resection of rectal cancer found that in the majority of studies blood loss was reduced with the laparoscopic approach although this did not translate to fewer blood transfusions. Length of incision was measured in 3 of 8 RCTs and ranged from an average of 5 cm to 10 cm with the laparoscopic approach compared to an average of 19.1 cm to 22 cm with the open approach [7, 38, 40]. Seven of the 8 trials reported a conversion rate which ranged from 0%-34% [7, 38-40]. Conversion to the open approach was commonly defined as length of incision greater than the size needed for tumor extraction or premature abdominal incision to allow improved mobilization. In the majority of studies conversion to open surgery was required because of local tumor invasion or difficult dissection in a narrow pelvis although bulky tumor, dilated small bowel, dense adhesions, bleeding, rectal perforation, difficulty mobilizing the splenic flexure, failure to identify or injury to the ureter, ischemia of the descending colon, and anastomotic failure were also cited. Breukink *et al* [41] reported that 36 of 48 studies assessed conversion and showed a highly variable rate ranging from 0% to 33%. However, they report that the lack of consensus in the definition made results difficult to interpret. In addition, surgeon experience and patient selection criteria were often not mentioned. Two trials reported particularly high rates of conversion. Ng *et al* [37] had a conversion rate of 30.3% but they did not routinely perform preoperative staging with computed tomography scans and therefore frequently converted after diagnostic laparoscopy. Twelve of the 23 patients randomized to laparoscopic surgery were converted to open due to local tumor invasion, bulky tumor, or dilated small bowel which may have been recognized by preoperative imaging. In the CLASICC trial the conversion rate for laparoscopic resection of rectal cancer was reported at 34% and attributed to excessive tumor fixation and uncertainty of tumor clearance [6]. Surgeon learning curve may account for this high rate of conversion as evidenced by the fact that the overall rate of conversion dropped by year of study from 38% in year one to 16% in year six. However, consistent with several non-randomized reports, in the CLASICC trial patients converted to open resection had a higher operative mortality compared to patients in the laparoscopic or open groups (9% *vs* 1% *vs* 5% respectively) [6]. Conversion was also associated with worse oncologic outcomes in nonrandomized compara‐ tive and descriptive studies [46].

**Figure 3.** Total mesorectal excision after laparoscopic rectal resection

## **10. Short-term oncologic outcomes**

perineum likely decreased operative time because there was not an abdominal incision to close. Two meta-analyses included operative time as an outcome of interest. Aziz *et al* [17] included 22 studies comparing laparoscopic *vs* open rectal cancer resection in 2071 patients and found that operative time was significantly increased with the laparoscopic group as compared to the open group with a weighted mean difference (WMD) of 40.18 (95% CI, 26.46-56.13). Gao *et al* [26] performed a meta-analysis of short-term outcomes after laparoscopic resection for rectal cancer based on 11 studies and included 643 patients which reported no difference in operating time between open and laparoscopic approaches with a WMD of 1.59 [1.2-1.98]. Intraoperative blood loss was significantly less for the laparoscopic group compared to the open group in 4 of 6 RCTs and ranged from 20 mL to 321.7 mL and from 92 mL to 555.6 mL in the laparoscopic and open groups respectively [31, 35, 38, 40]. Araujo *et al* [25] did not specifically report on the amount of intraoperative blood loss but there was no statistically significant difference in the need for blood transfusions between the two groups which was attributed to the fact that in an APR the majority of blood loss occurs during the perineal

A recent Cochrane review by Breukink *et al* [41] evaluating the safety and efficacy of elective laparoscopic TME for the resection of rectal cancer found that in the majority of studies blood loss was reduced with the laparoscopic approach although this did not translate to fewer blood transfusions. Length of incision was measured in 3 of 8 RCTs and ranged from an average of 5 cm to 10 cm with the laparoscopic approach compared to an average of 19.1 cm to 22 cm with the open approach [7, 38, 40]. Seven of the 8 trials reported a conversion rate which ranged from 0%-34% [7, 38-40]. Conversion to the open approach was commonly defined as length of incision greater than the size needed for tumor extraction or premature abdominal incision to allow improved mobilization. In the majority of studies conversion to open surgery was required because of local tumor invasion or difficult dissection in a narrow pelvis although bulky tumor, dilated small bowel, dense adhesions, bleeding, rectal perforation, difficulty mobilizing the splenic flexure, failure to identify or injury to the ureter, ischemia of the descending colon, and anastomotic failure were also cited. Breukink *et al* [41] reported that 36 of 48 studies assessed conversion and showed a highly variable rate ranging from 0% to 33%. However, they report that the lack of consensus in the definition made results difficult to interpret. In addition, surgeon experience and patient selection criteria were often not mentioned. Two trials reported particularly high rates of conversion. Ng *et al* [37] had a conversion rate of 30.3% but they did not routinely perform preoperative staging with computed tomography scans and therefore frequently converted after diagnostic laparoscopy. Twelve of the 23 patients randomized to laparoscopic surgery were converted to open due to local tumor invasion, bulky tumor, or dilated small bowel which may have been recognized by preoperative imaging. In the CLASICC trial the conversion rate for laparoscopic resection of rectal cancer was reported at 34% and attributed to excessive tumor fixation and uncertainty of tumor clearance [6]. Surgeon learning curve may account for this high rate of conversion as evidenced by the fact that the overall rate of conversion dropped by year of study from 38% in year one to 16% in year six. However, consistent with several non-randomized reports, in the CLASICC trial patients converted to open resection had a higher operative mortality compared to patients in the laparoscopic or open groups (9% *vs* 1% *vs* 5% respectively) [6].

portion of the case which is the same regardless of surgical access.

112 Colorectal Cancer - Surgery, Diagnostics and Treatment

While the number of lymph nodes retrieved can vary based on age, gender, tumor site, use of pre-operative radiation, and tumor grade, the extent and quality of surgical resection can also have an impact on the number of nodes collected and is therefore often considered a surrogate marker of the oncologic completeness of the resection [37]. The American Joint Committee on Cancer recommends that at least 12 lymph nodes be examined in patients with rectal cancer to confirm the absence of nodal involvement by the tumor [34]. In addition, a number of studies have reported that the number of lymph nodes examined may be associated with patient outcome [25, 26]. Six of the 8 RCTs reported the mean number of lymph nodes retrieved with a range of 5.5 to 17 nodes in the laparoscopic group compared to 11.6 to 18 nodes in the open group [22, 31, 34]. In 4 of the 6 trials the number of lymph nodes isolated was not significantly different based on surgical approach. Araujo *et al* [25] reported a significantly lower yield of lymph nodes with laparoscopic rectal resection compared to open resection (5.5 *vs* 11.9 respectively, *P* = 0.04). They suggested that laparoscopy offered better dissection and accuracy due to better visualization and exposure of structures with less manipulation of the mesorec‐ tum especially in a narrow pelvis. Four of the 8 RCTs reported the use of pre-operative chemoradiation. In these trials, the mean number of lymph nodes retrieved ranged from 5.5 to 17 nodes in the laparoscopic group and from 11.6 to 18 nodes in the open group [31, 34, 38, 40]. Some authors [37] found that in the 17 trials that reported the number of lymph nodes retrieved, the mean number of nodes was 10 for the laparoscopic group and 12 for the open group (*P* = 0.001) with the majority of trials reporting a median of 11 or fewer nodes obtained. In 9 of these 17 trials, both groups were treated with preoperative radiation therapy and reported a mean of 10 lymph nodes harvested in the laparoscopic group and 11 in the open group. One of the greatest concerns of laparoscopic TME is that obtaining a complete oncologic resection will be more difficult. Involvement of the circumferential or distal margin is one of the most important prognostic factors in rectal resection with TME and can lead to an increase in local recurrence and a reduction in survival. Radial margins of less than 2 mm are associated with a local recurrence rate of 16% compared to a significantly reduced local recurrence rate of 6% with margins greater than 2 mm [27]. Six of the 8 RCTs reported the involvement of the CRM and no difference was found by surgical approach [7, 31, 38-40, 45]. In the majority of trials the rate of CRM involvement was less than 5%. Patients with positive radial margins often had tumor invading the pelvic side wall or adjacent structure and were frequently converted from a laparoscopic to an open procedure [39]. In the CLASICC study, the only multicenter trial, a positive CRM was identified in 14 of 97 (14%) patients with open surgery and in 30 of 193 (16%) patients with laparoscopic rectal resection [6]. Of patients undergoing anterior resection, the CRM was positive in 16 of 129 (12%) individuals in the laparoscopic group and in 4 of 64 (6%) individuals in the open group. While there is a non-significant higher positivity of the CRM in the laparoscopic anterior resection group, this is once again likely due to the fact that the learning curve was not completed before the start of this study. Two RCTs reported on distal margin status and the incidence of distal margin positivity was not signif‐ icantly different between the two surgical approaches and in fact was 0% [3, 31]. All 3 metaanalyses and the Cochrane review by Breukink *et al*[41] found no difference in positive margins based on surgical access.

trials, the length of stay was not significantly different between surgical approaches, there was a trend toward decreased length of stay with laparoscopic rectal surgery. Breukink *et al* [41] found that laparoscopic TME resulted in earlier return of normal diet, less pain, less narcotic

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Rectal cancer surgery is associated with a high rate of morbidity and mortality. Post-operative mortality in RCTs ranged from 1%-4% and demonstrated no statistically significant difference based on surgical approach. The rate of post-operative complications ranged from 6% to 69% and with the exception of Zhou et al [24] did not differ significantly between laparoscopic and open groups. Wound infection and urinary tract infection accounted for the majority of perioperative complications in both groups. There was a higher incidence of wound infection with the open approach however this did not reach statistical significance. Breukink *et al* [41] found no difference in morbidity between the laparoscopic and open groups although there was a trend toward lower morbidity with laparoscopic TME. Aziz *et al* [17] found no difference in perioperative morbidity between the 2 groups while Gao *et al* [26] found that the overall morbidity rate of the laparoscopic group was significantly lower than that of the open group. Anastomotic leak is the most serious complication after sphincter sparing rectal cancer resection especially with neoadjuvant chemoradiation. In addition, development of an anastomotic leak is reported to be associated with decreased long-term survival and higher rates of local recurrence after curative resection for colorectal cancer [39-43]. Operative expertise and selective diversion in high risk patients has resulted in a anastomotic leak rate of 1%-17% in most published series studying laparoscopic resection for rectal cancer [29, 30]. Consistent with reports from non-randomized comparative trials, RCTs demonstrated no significant difference in the incidence of anastomotic leak between the laparoscopic and open technique for the resection of rectal cancer. While the incidence of perioperative morbidity was not different based on surgical access, fewer patients had long-term complications with laparoscopic rectal cancer resection compared to the open approach. Adhesion related bowel obstruction was the most common longterm morbidity. With a median follow-up of greater than 9 years, Ng *et al* [37] found that adhesion-related obstruction requiring hospitalization (18.9% *vs* 2.7%) and reoperation (6.8% *vs* 0%) was higher in the open group. They report a cumulative probability of adhesion-related bowel obstruction at 10 years of 20.5% in the open group and 3.9% in the laparoscopic group. [45] Data on long-term complications was not separated by site of disease but the overall occurrence of incisional hernia (7.9% *vs* 10.9%, *P* = 0.32) and reoperation for adhesions (1.1% *vs* 2.5%, *P* = 0.30) was not statistically difference between laparoscopic and open resection. Long-term studies need to be done to determine if laparoscopy decreases the incidence of intra-abdominal adhesion formation by reduced

surgical trauma, less tissue handling, and smaller incisions.

use and a shorter hospital stay.

**12. Complications**

#### **11. Postoperative course**

Less postoperative pain, faster recovery of intestinal function, and shorter length of stay are important benefits of laparoscopic colorectal surgery. Only 3 of 8 RCTs compared the exact amount of post-operative pain medication and 2 of these studies reported a significant reduction in analgesic use in the laparoscopic group [39, 40, 45]. Zhou et al [24] did not quantify the exact usage of pain medication, but found no significant difference in the number of days parental analgesics were necessary (4.1 *vs* 3.9 in the open and laparoscopic groups respective‐ ly). Resumption of bowel function was usually reported on post-operative days 3 to 5 and ability to tolerate a solid food diet was reported on post-operative days 3 to 6 [7, 31, 35, 39, 40, 45]. In the majority of RCTs earlier bowel movements and diet advancement was reported with the laparoscopic approach. The return of bowel function and reduction in wound pain was thought to contribute to earlier discharge after laparoscopic surgery. While in a majority of trials, the length of stay was not significantly different between surgical approaches, there was a trend toward decreased length of stay with laparoscopic rectal surgery. Breukink *et al* [41] found that laparoscopic TME resulted in earlier return of normal diet, less pain, less narcotic use and a shorter hospital stay.

## **12. Complications**

tum especially in a narrow pelvis. Four of the 8 RCTs reported the use of pre-operative chemoradiation. In these trials, the mean number of lymph nodes retrieved ranged from 5.5 to 17 nodes in the laparoscopic group and from 11.6 to 18 nodes in the open group [31, 34, 38, 40]. Some authors [37] found that in the 17 trials that reported the number of lymph nodes retrieved, the mean number of nodes was 10 for the laparoscopic group and 12 for the open group (*P* = 0.001) with the majority of trials reporting a median of 11 or fewer nodes obtained. In 9 of these 17 trials, both groups were treated with preoperative radiation therapy and reported a mean of 10 lymph nodes harvested in the laparoscopic group and 11 in the open group. One of the greatest concerns of laparoscopic TME is that obtaining a complete oncologic resection will be more difficult. Involvement of the circumferential or distal margin is one of the most important prognostic factors in rectal resection with TME and can lead to an increase in local recurrence and a reduction in survival. Radial margins of less than 2 mm are associated with a local recurrence rate of 16% compared to a significantly reduced local recurrence rate of 6% with margins greater than 2 mm [27]. Six of the 8 RCTs reported the involvement of the CRM and no difference was found by surgical approach [7, 31, 38-40, 45]. In the majority of trials the rate of CRM involvement was less than 5%. Patients with positive radial margins often had tumor invading the pelvic side wall or adjacent structure and were frequently converted from a laparoscopic to an open procedure [39]. In the CLASICC study, the only multicenter trial, a positive CRM was identified in 14 of 97 (14%) patients with open surgery and in 30 of 193 (16%) patients with laparoscopic rectal resection [6]. Of patients undergoing anterior resection, the CRM was positive in 16 of 129 (12%) individuals in the laparoscopic group and in 4 of 64 (6%) individuals in the open group. While there is a non-significant higher positivity of the CRM in the laparoscopic anterior resection group, this is once again likely due to the fact that the learning curve was not completed before the start of this study. Two RCTs reported on distal margin status and the incidence of distal margin positivity was not signif‐ icantly different between the two surgical approaches and in fact was 0% [3, 31]. All 3 metaanalyses and the Cochrane review by Breukink *et al*[41] found no difference in positive margins

Less postoperative pain, faster recovery of intestinal function, and shorter length of stay are important benefits of laparoscopic colorectal surgery. Only 3 of 8 RCTs compared the exact amount of post-operative pain medication and 2 of these studies reported a significant reduction in analgesic use in the laparoscopic group [39, 40, 45]. Zhou et al [24] did not quantify the exact usage of pain medication, but found no significant difference in the number of days parental analgesics were necessary (4.1 *vs* 3.9 in the open and laparoscopic groups respective‐ ly). Resumption of bowel function was usually reported on post-operative days 3 to 5 and ability to tolerate a solid food diet was reported on post-operative days 3 to 6 [7, 31, 35, 39, 40, 45]. In the majority of RCTs earlier bowel movements and diet advancement was reported with the laparoscopic approach. The return of bowel function and reduction in wound pain was thought to contribute to earlier discharge after laparoscopic surgery. While in a majority of

based on surgical access.

**11. Postoperative course**

114 Colorectal Cancer - Surgery, Diagnostics and Treatment

Rectal cancer surgery is associated with a high rate of morbidity and mortality. Post-operative mortality in RCTs ranged from 1%-4% and demonstrated no statistically significant difference based on surgical approach. The rate of post-operative complications ranged from 6% to 69% and with the exception of Zhou et al [24] did not differ significantly between laparoscopic and open groups. Wound infection and urinary tract infection accounted for the majority of perioperative complications in both groups. There was a higher incidence of wound infection with the open approach however this did not reach statistical significance. Breukink *et al* [41] found no difference in morbidity between the laparoscopic and open groups although there was a trend toward lower morbidity with laparoscopic TME. Aziz *et al* [17] found no difference in perioperative morbidity between the 2 groups while Gao *et al* [26] found that the overall morbidity rate of the laparoscopic group was significantly lower than that of the open group. Anastomotic leak is the most serious complication after sphincter sparing rectal cancer resection especially with neoadjuvant chemoradiation. In addition, development of an anastomotic leak is reported to be associated with decreased long-term survival and higher rates of local recurrence after curative resection for colorectal cancer [39-43]. Operative expertise and selective diversion in high risk patients has resulted in a anastomotic leak rate of 1%-17% in most published series studying laparoscopic resection for rectal cancer [29, 30]. Consistent with reports from non-randomized comparative trials, RCTs demonstrated no significant difference in the incidence of anastomotic leak between the laparoscopic and open technique for the resection of rectal cancer. While the incidence of perioperative morbidity was not different based on surgical access, fewer patients had long-term complications with laparoscopic rectal cancer resection compared to the open approach. Adhesion related bowel obstruction was the most common longterm morbidity. With a median follow-up of greater than 9 years, Ng *et al* [37] found that adhesion-related obstruction requiring hospitalization (18.9% *vs* 2.7%) and reoperation (6.8% *vs* 0%) was higher in the open group. They report a cumulative probability of adhesion-related bowel obstruction at 10 years of 20.5% in the open group and 3.9% in the laparoscopic group. [45] Data on long-term complications was not separated by site of disease but the overall occurrence of incisional hernia (7.9% *vs* 10.9%, *P* = 0.32) and reoperation for adhesions (1.1% *vs* 2.5%, *P* = 0.30) was not statistically difference between laparoscopic and open resection. Long-term studies need to be done to determine if laparoscopy decreases the incidence of intra-abdominal adhesion formation by reduced surgical trauma, less tissue handling, and smaller incisions.

#### **13. Long-term outcomes**

The initial reports of the long-term outcomes after laparoscopic surgery for rectal cancer were discouraging. Several randomized trials report of the rate of positive circumferential radial margin in the laparoscopic group in comparison to the open group (12-5.9% and 6-4.2%, respectively). The 3-year follow-up did not establish higher local recurrence rate – 7.0% and 7.8%, respectively. The local recurrence rate after laparoscopic and open abdomino-perineal resection were 15.1% and 21.1%, respectively. The overall disease-free survival rate was also similar after laparoscopic and open anterior resection 70.9% and 70.4% and APR – 49.8% and 46.9%. Other data demonstrated 5-year disease survival reaching 83.7% for laparoscopic and 80.4% for open surgery. According to a meta-analysis of 20 laparoscopic rectal cancer studies between 1993 and 2004, including over 2000 patients, there is no significant difference in the number of harvested lymph nodes [22]. Despite the encouraging results, the laparoscopic rectal surgery could be fully evaluated only after long-term results are available. The ongoing studies are the American College of Surgeons Oncology Group (ACOSOG) Z6051 trial from the U.S.; the COLOR II trial from Europe, Canada, and Asia; and the Japanese Japan Clinical Oncology Group (JCOG) 0040 trial.

survival. Overall survival was 72% for patients undergoing laparoscopic rectal cancer resection and 65% for open resection at an average of 4.4 years (P = 0.5). Subset analysis by [36] dem‐ onstrated no significant difference between laparoscopic and open rectal cancer resection in terms of local recurrence (laparoscopic 7.2% vs open 7.8%, P = 0.46), development of distant metastases (laparoscopic 13.5% vs open 9.1%, P = 0.60), or cancer-related mortality (laparo‐

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Some authors have introduced a new method of hybrid rectal surgery, aiming to combine the benefits of open and laparoscopic approach. The colonic mobilization is performed laparos‐ copically, while the rectal dissection is performed through a Pfannenstiel incision. A retro‐ spective review established significantly longer hospital stay after hybrid procedures than

Another method is the hand-assisted laparoscopic surgery. A special access device for the hand is introduced in the abdomen. Compared with fully open techniques this method provides shorter operative time. High ligation of vessels, splenic flexure takedown, and lateral mobili‐ zation may be accomplished in a shorter period time with a hand-assisted technique. In handassisted laparoscopic surgery, rectal exposure and dissection can be either performed directly through the incision using the open techniques or laparoscopically with manual assistance [28]. This method combines the excellent laparoscopic view and the dissection techniques in

By performing distal rectal division directly through the incision using the open surgical staplers, hand-assisted laparoscopic rectal surgery may result in a lower anastomotic leakage

After rigorous evaluation the laparoscopic surgery for colon cancer has become the gold standard.Laparoscopiccolonresectionforcancer,inexperiencedhands,canbeperformedsafely and reliably with many short-term benefits to the patients while resulting in at least equiva‐ lent long-term outcomes as open surgery, which is supported by level 1 data. In conclusion, RCTs have demonstrated that laparoscopy does not adversely affect cancer related survival in patients with adenocarcinoma of the colon. Concerns about the technical difficulty of TME may have contributed to the exclusion of rectal cancer patients from most of these large multicen‐ ter RCTs resulting in little data on oncologic outcomes with laparoscopic rectal cancer resec‐ tion. Laparoscopic rectal dissection is technically more demanding than open and constraints of a narrow pelvis may result in difficulty assessing and obtaining adequate surgical margins. However, there are several proposed benefits of laparoscopic rectal resection. A clear and magnified view of the pelvis provided by the improved optics of laparoscopy may aid sharp

scopic 9% vs open 10%, P = 0.16). While, this data is encouraging, it is no conclusive.

**14. Hybrid and hand-assisted laparoscopic rectal surgery**

after open procedures [27].

rate.

**15. Summary**

open surgery and provides tactile sensation.

A number of the clinical trials were performed to determine the safety and feasibility of the laparoscopic approach for rectal adenocarcinoma and therefore the data we have for long-term outcomes is limited [5]. Braga *et al [48]* found no difference in local recurrence (4.0% in the laparoscopic group vs 5.2% in the open group, P= 0.97), overall five-year survival, or disease free five-year survival based on surgical approach. With a median follow-up of 87.2 mo in the laparoscopic group and 90.1 mo in the open group, Ng et al [45] demonstrated that after curative resection, the probability of five-year survival was 75.2% vs 76.5% for laparoscopic vs open APR respectively (P = 0.20). In addition, stage-by-stage comparison for the two groups showed no statistical difference. There were no port site recurrences and overall recurrence rates were not significantly different between the two groups (laparoscopic 20% vs open 25%, P = 0.60). Despite the higher rate of circumferential margin positivity in patients undergoing laparoscopic anterior resection in the CLASICC trial, there was no difference in local recur‐ rence, three- year overall or three-year disease free survival between the two approaches (open OS 66.7% and laparoscopic OS 74.6%, P = 0.17; open DFS 70.4% and laparoscopic DFS 70.9%, P = 0.72; open LR 7.0% and laparoscopic LR 7.98%, P = 0.70) [6]. In addition, there was no significant difference in the rates of local recurrence, three-year overall survival, or three-year disease-free survival in patients undergoing laparoscopic vs open APR [12]. However, the sample size is small and therefore larger studies are needed for conclusive results. Ng et al [37] published results of a randomized trial of laparoscopic vs open anterior resection for upper rectal cancer with a median follow-up of 9 years. No difference in local recurrence, overall survival, or disease-free survival was reported. Although these studies suggest comparative oncologic outcomes between laparoscopic and open rectal cancer resection, they include small sample sizes and are almost all are single institution studies, highlighting the need for large, multi-center RCTs to provide confirmatory data. With a mean follow-up of 35 mo for both groups, overall local recurrence was not statistically different between the 2 groups (laparo‐ scopic 7% vs open 8%, P = NS). Eleven studies provided sufficient data to compare overall survival. Overall survival was 72% for patients undergoing laparoscopic rectal cancer resection and 65% for open resection at an average of 4.4 years (P = 0.5). Subset analysis by [36] dem‐ onstrated no significant difference between laparoscopic and open rectal cancer resection in terms of local recurrence (laparoscopic 7.2% vs open 7.8%, P = 0.46), development of distant metastases (laparoscopic 13.5% vs open 9.1%, P = 0.60), or cancer-related mortality (laparo‐ scopic 9% vs open 10%, P = 0.16). While, this data is encouraging, it is no conclusive.

## **14. Hybrid and hand-assisted laparoscopic rectal surgery**

Some authors have introduced a new method of hybrid rectal surgery, aiming to combine the benefits of open and laparoscopic approach. The colonic mobilization is performed laparos‐ copically, while the rectal dissection is performed through a Pfannenstiel incision. A retro‐ spective review established significantly longer hospital stay after hybrid procedures than after open procedures [27].

Another method is the hand-assisted laparoscopic surgery. A special access device for the hand is introduced in the abdomen. Compared with fully open techniques this method provides shorter operative time. High ligation of vessels, splenic flexure takedown, and lateral mobili‐ zation may be accomplished in a shorter period time with a hand-assisted technique. In handassisted laparoscopic surgery, rectal exposure and dissection can be either performed directly through the incision using the open techniques or laparoscopically with manual assistance [28]. This method combines the excellent laparoscopic view and the dissection techniques in open surgery and provides tactile sensation.

By performing distal rectal division directly through the incision using the open surgical staplers, hand-assisted laparoscopic rectal surgery may result in a lower anastomotic leakage rate.

## **15. Summary**

**13. Long-term outcomes**

116 Colorectal Cancer - Surgery, Diagnostics and Treatment

Group (JCOG) 0040 trial.

The initial reports of the long-term outcomes after laparoscopic surgery for rectal cancer were discouraging. Several randomized trials report of the rate of positive circumferential radial margin in the laparoscopic group in comparison to the open group (12-5.9% and 6-4.2%, respectively). The 3-year follow-up did not establish higher local recurrence rate – 7.0% and 7.8%, respectively. The local recurrence rate after laparoscopic and open abdomino-perineal resection were 15.1% and 21.1%, respectively. The overall disease-free survival rate was also similar after laparoscopic and open anterior resection 70.9% and 70.4% and APR – 49.8% and 46.9%. Other data demonstrated 5-year disease survival reaching 83.7% for laparoscopic and 80.4% for open surgery. According to a meta-analysis of 20 laparoscopic rectal cancer studies between 1993 and 2004, including over 2000 patients, there is no significant difference in the number of harvested lymph nodes [22]. Despite the encouraging results, the laparoscopic rectal surgery could be fully evaluated only after long-term results are available. The ongoing studies are the American College of Surgeons Oncology Group (ACOSOG) Z6051 trial from the U.S.; the COLOR II trial from Europe, Canada, and Asia; and the Japanese Japan Clinical Oncology

A number of the clinical trials were performed to determine the safety and feasibility of the laparoscopic approach for rectal adenocarcinoma and therefore the data we have for long-term outcomes is limited [5]. Braga *et al [48]* found no difference in local recurrence (4.0% in the laparoscopic group vs 5.2% in the open group, P= 0.97), overall five-year survival, or disease free five-year survival based on surgical approach. With a median follow-up of 87.2 mo in the laparoscopic group and 90.1 mo in the open group, Ng et al [45] demonstrated that after curative resection, the probability of five-year survival was 75.2% vs 76.5% for laparoscopic vs open APR respectively (P = 0.20). In addition, stage-by-stage comparison for the two groups showed no statistical difference. There were no port site recurrences and overall recurrence rates were not significantly different between the two groups (laparoscopic 20% vs open 25%, P = 0.60). Despite the higher rate of circumferential margin positivity in patients undergoing laparoscopic anterior resection in the CLASICC trial, there was no difference in local recur‐ rence, three- year overall or three-year disease free survival between the two approaches (open OS 66.7% and laparoscopic OS 74.6%, P = 0.17; open DFS 70.4% and laparoscopic DFS 70.9%, P = 0.72; open LR 7.0% and laparoscopic LR 7.98%, P = 0.70) [6]. In addition, there was no significant difference in the rates of local recurrence, three-year overall survival, or three-year disease-free survival in patients undergoing laparoscopic vs open APR [12]. However, the sample size is small and therefore larger studies are needed for conclusive results. Ng et al [37] published results of a randomized trial of laparoscopic vs open anterior resection for upper rectal cancer with a median follow-up of 9 years. No difference in local recurrence, overall survival, or disease-free survival was reported. Although these studies suggest comparative oncologic outcomes between laparoscopic and open rectal cancer resection, they include small sample sizes and are almost all are single institution studies, highlighting the need for large, multi-center RCTs to provide confirmatory data. With a mean follow-up of 35 mo for both groups, overall local recurrence was not statistically different between the 2 groups (laparo‐ scopic 7% vs open 8%, P = NS). Eleven studies provided sufficient data to compare overall

After rigorous evaluation the laparoscopic surgery for colon cancer has become the gold standard.Laparoscopiccolonresectionforcancer,inexperiencedhands,canbeperformedsafely and reliably with many short-term benefits to the patients while resulting in at least equiva‐ lent long-term outcomes as open surgery, which is supported by level 1 data. In conclusion, RCTs have demonstrated that laparoscopy does not adversely affect cancer related survival in patients with adenocarcinoma of the colon. Concerns about the technical difficulty of TME may have contributed to the exclusion of rectal cancer patients from most of these large multicen‐ ter RCTs resulting in little data on oncologic outcomes with laparoscopic rectal cancer resec‐ tion. Laparoscopic rectal dissection is technically more demanding than open and constraints of a narrow pelvis may result in difficulty assessing and obtaining adequate surgical margins. However, there are several proposed benefits of laparoscopic rectal resection. A clear and magnified view of the pelvis provided by the improved optics of laparoscopy may aid sharp

dissectionforTMEandassistinidentificationofvitalpelvic structures includingtheureters and autonomicnerves.Inaddition,pneumoperitoneummayseparatetheparietalandvisceralfascia of the mesorectum facilitating dissection in this plane. Laparoscopic rectal cancer resection has a steep learning curve but increased experience with both open and laparoscopic TME will lead to shorter operating times and decreased morbidity. Current data suggests that laparoscopic rectalcancerresectionmaybenefitpatientsbecauseofreducedbloodloss,earlierreturnofbowel function, and shorter hospital length of stay. Concerns that laparoscopic rectal cancer surgery may compromise short-term oncologic outcomes including number of lymph nodes harvest‐ edandCRMpositivitydonot appeartobe supportedbythe available literature.However,there is a paucity of data concerning long-term oncologic outcomes and complications with laparo‐ scopic rectal cancer surgery. There are two large, multicenter RCTs that are currently being conducted:theCOLORIItrialinEurope andtheACOSOG-Z6051 trialintheUnitedStates.Both of these studies are comparing the laparoscopic and open approach for treatment of resectable rectal cancer. Results from these trials will provide information on the long-term outcomes of laparoscopic rectal cancerresectionandare eagerly awaited.Inview ofthe lack oflevel onedata on oncologic outcomes, laparoscopic TME for locally advanced, curable rectal cancer should only be performed within the confines of a RCT.

[2] Jacobs M., J. C. Verdeja, and H. S. Goldstein, "Minimally invasive colon resection (laparoscopic colectomy), " Surgical Laparoscopy & Endoscopy, vol. 1, no. 3, pp.

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[3] Berends F. J., G. Kazemier, H. J. Bonjer, and J. F. Lange, "Subcutaneous metastases

[4] Buunen M. et al., "Survival after laparoscopic surgery versus open surgery for colon cancer, long-term outcome of a randomized clinical trial, " The Lancet Oncology, vol.

[5] Fleshman J., D. J. Sargent, E. Green et al., "Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial, "

[6] Jayne D. G., P. J. Guillou, H. Thorpe et al., "Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC trial

[7] Lacy M., S. Delgado, A. Castells et al., "The long-term results of a randomized clini‐ cal trial of laparoscopy-assisted versus open surgery for colon cancer, " Annals of

[8] Cima R. R., J. Pattana-arun, D. W. Larson, E. J. Dozois, B. G. Wolff, and J. H. Pember‐ ton, "Experience with 969 minimal access colectomies: the role of hand-assisted lapa‐ roscopy in expanding minimally invasive surgery for complex colectomies, " Journal

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Other potential, but less conclusively demonstrated benefits include better preservation of cellmediated immune function and reduced tumor cell proliferation. Although a similar level of evidence does not yet exist for the laparoscopic rectal surgery for cancer, the evidence to date suggests that it is likely that the ongoing large randomized trials will demonstrate clinical benefits of laparoscopic rectal cancer surgery. New devices for minimizing of the abdominal trauma are being developed. The steep learning curve, cost and difficult training are still hindrance to the wide use of laparoscopic colon surgery.

## **Author details**

Anton Tonev1 , Nikola Kolev1 , Valentin Ignatov1 , Vasil Bojkov3 , Tanya Kirilova2 and Krassimir Ivanov1

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


## **References**

[1] Reynolds Jr., W. "The first laparoscopic cholecystectomy, " Journal of the Society of Laparoendoscopic Surgeons, vol. 5, no. 1, pp. 89–94, 2001.

[2] Jacobs M., J. C. Verdeja, and H. S. Goldstein, "Minimally invasive colon resection (laparoscopic colectomy), " Surgical Laparoscopy & Endoscopy, vol. 1, no. 3, pp. 144–150, 1991.

dissectionforTMEandassistinidentificationofvitalpelvic structures includingtheureters and autonomicnerves.Inaddition,pneumoperitoneummayseparatetheparietalandvisceralfascia of the mesorectum facilitating dissection in this plane. Laparoscopic rectal cancer resection has a steep learning curve but increased experience with both open and laparoscopic TME will lead to shorter operating times and decreased morbidity. Current data suggests that laparoscopic rectalcancerresectionmaybenefitpatientsbecauseofreducedbloodloss,earlierreturnofbowel function, and shorter hospital length of stay. Concerns that laparoscopic rectal cancer surgery may compromise short-term oncologic outcomes including number of lymph nodes harvest‐ edandCRMpositivitydonot appeartobe supportedbythe available literature.However,there is a paucity of data concerning long-term oncologic outcomes and complications with laparo‐ scopic rectal cancer surgery. There are two large, multicenter RCTs that are currently being conducted:theCOLORIItrialinEurope andtheACOSOG-Z6051 trialintheUnitedStates.Both of these studies are comparing the laparoscopic and open approach for treatment of resectable rectal cancer. Results from these trials will provide information on the long-term outcomes of laparoscopic rectal cancerresectionandare eagerly awaited.Inview ofthe lack oflevel onedata on oncologic outcomes, laparoscopic TME for locally advanced, curable rectal cancer should

Other potential, but less conclusively demonstrated benefits include better preservation of cellmediated immune function and reduced tumor cell proliferation. Although a similar level of evidence does not yet exist for the laparoscopic rectal surgery for cancer, the evidence to date suggests that it is likely that the ongoing large randomized trials will demonstrate clinical benefits of laparoscopic rectal cancer surgery. New devices for minimizing of the abdominal trauma are being developed. The steep learning curve, cost and difficult training are still

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

[1] Reynolds Jr., W. "The first laparoscopic cholecystectomy, " Journal of the Society of

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

, Vasil Bojkov3

, Tanya Kirilova2

and

only be performed within the confines of a RCT.

118 Colorectal Cancer - Surgery, Diagnostics and Treatment

, Nikola Kolev1

**Author details**

Krassimir Ivanov1

Anton Tonev1

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Bulgaria

hindrance to the wide use of laparoscopic colon surgery.

, Valentin Ignatov1

3 Department of Surgery, University Hospital "St. Marina", Varna, Bulgaria

Laparoendoscopic Surgeons, vol. 5, no. 1, pp. 89–94, 2001.


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[59] MacKay G, Fearon K, McConnachie A, Serpell MG, Molloy RG, O'Dwyer PJ. Randomized clinical trial of the effect of postoperative intravenous fluid restriction

[60] Conway DH, Mayall R, Abdul-Latif MS, Gilligan S, Tackaberry C. Randomised con‐ trolled trial investigating the influence of intravenous fluid titration using oesopha‐

[61] Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in post‐

[62] Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perio‐ perative outcome: a randomized, controlled Veterans Affairs cooperative study. Ann

[63] Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and mor‐

geal Doppler monitoring during bowel surgery. Anaesthesia 2002; 57:845-849

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[51] Spanjersberg WR, Reurings J, Keus F, van Laarhoven CJ. Fast track surgery versus conventional recovery strategies for colorectal surgery. Cochrane Database Syst Rev 2011; (2): CD007635

tal cancer surgery: a preliminary report. J Am Coll Surg 1998; 187: 46-54; discussion

[40] Kemp JA, Finlayson SR. Outcomes of laparoscopic and open colectomy: a national

[41] Breukink S, Pierie J, Wiggers T. Laparoscopic versus open total mesorectal excision

[42] Kim SH, Park IJ, Joh YG, Hahn KY. Laparoscopic resection for rectal cancer: a pro‐ spective analysis of thirty-month follow-up outcomes in 312 patients. Surg Endosc

[43] Laurent C, Leblanc F, Gineste C, Saric J, Rullier E. Laparoscopic approach in surgical

[44] Quirke P, Steele R, Monson J, Grieve R, Khanna S, Couture J, O'Callaghan C, Myint AS, Bessell E, Thompson LC, Parmar M, Stephens RJ, Sebag-Montefiore D. Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16

[45] Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the mod‐

[46] Rullier A, Gourgou-Bourgade S, Jarlier M, Bibeau F, Chassagne-Clément C, Henne‐ quin C, Tisseau L, Leroux A, Ettore F, Peoc'h M, Diebold MA, Robin YM, Kleinclaus I, Mineur L, Petitjean C, Mosnier JF, Soubeyran I, Padilla N, Lemaistre AI, Bérille J, Denis B, Conroy T, Gérard JP. Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: The French randomised trial AC‐

[47] Marijnen CA, Nagtegaal ID, Kapiteijn E, Kranenbarg EK, Noordijk EM, van Krieken JH, van de Velde CJ, Leer JW. Radiotherapy does not compensate for positive resec‐ tion margins in rectal cancer patients: report of a multicenter randomized trial. Int J

[48] Braga M, Frasson M, Vignali A, Zuliani W, Capretti G, Di Carlo V Laparoscopic re‐ section in rectal cancer patients: outcome and cost-benefit analysis. Dis Colon Rec‐

[49] Kehlet H. Multimodal approach to control postoperative pathophysiology and reha‐

[50] Lassen K, Soop M, Nygren J, Cox PB, Hendry PO, Spies C, von Meyenfeldt MF, Fear‐ on KC, Revhaug A, Norderval S, Ljungqvist O, Lobo DN, Dejong CH. Consensus re‐ view of optimal perioperative care in colorectal surgery: Enhanced Recovery After

Surgery (ERAS) Group recommendations. Arch Surg 2009; 144: 961-969

population-based comparison. Surg Innov 2008; 15: 277-283

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randomised clinical trial. Lancet 2009; 373: 821-828

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bilitation. Br J Anaesth 1997; 78: 606-617

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54-55

2006; 20: 1197-1202

122 Colorectal Cancer - Surgery, Diagnostics and Treatment


bidity with epidural or spinal anaesthesia: results from overview of randomized tri‐ als. BMJ 2000; 321: 1493

**Chapter 6**

**Single-Incision Laparoscopic Colectomy: A New Era in**

The laparoscopic technique has been enthusiastically applied to the resection of colorectal cancer for more than 15 years [1]. There is evidence that laparoscopy for colorectal cancer offers the opportunity for a meticulous dissection of the mesocolon and mesorectum under direct vision while facilitating a true no-touch technique [2]. Additional benefits, such as less postoperative pain, reduced need for postoperative analgesia, less ileus, shorter hospital stay,

During recent years, great effort has been made to minimize parietal trauma for cosmetic reasons and to further reduce surgery-related pain and morbidity. New techniques, such as natural orifice transluminal endoscopic surgery (NOTES) [5] have been developed in order to reach the goal of "scarless" surgery. Although NOTES actually allows for no scarring of the body surface, it has several disadvantages and limitations with the currently available instruments, including limited access, less familiar working angles and operative approaches. Furthermore, it is associated with possible complications caused by opening of the stomach, colon or vagina, and may not be fully suitable or safe for advanced procedures, such as

Single incision laparoscopic surgery (SILS) is currently regarded as the next major advance in minimally invasive surgical approaches to colorectal disease that is more feasible for general‐ ized use [7-10]. SILS reduces the invasiveness of laparoscopic conventional surgery (LCS) by decreasing the number of incisions and ports through the abdominal wall. This theoretically could provide important clinical advantages, including less postoperative pain, reduction of port-site associated morbidity (such as wound infection, bleeding, visceral injury and port site herniation), quicker recovery and shorter hospital stay. The small incision through the abdominal wall allows for "scarless" surgery as the wound is usually hidden within 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.

**the Treatment of Colorectal Cancer?**

Fabio Cianchi, Fabio Staderini and Benedetta Badii

less blood loss, and better cosmesis are also well documented [3,4].

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56871

**1. Introduction**

colectomies [6].


## **Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer?**

Fabio Cianchi, Fabio Staderini and Benedetta Badii

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56871

## **1. Introduction**

bidity with epidural or spinal anaesthesia: results from overview of randomized tri‐

[64] Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS. Efficacy of postoperative patient-controlled and continuous infusion epidural an‐ algesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis.

[65] Levy BF, Tilney HS, Dowson HM, Rockall TA. A systematic review of postoperative analgesia following laparoscopic colorectal surgery. Colorectal Dis 2010; 12: 5-15 [66] Levy BF, Scott MJ, Fawcett W, Fry C, Rockall TA. Randomized clinical trial of epidur‐ al, spinal or patient-controlled analgesia for patients undergoing laparoscopic color‐

[67] Virlos I, Clements D, Beynon J, Ratnalikar V, Khot U. Shortterm outcomes with intra‐ thecal versus epidural analgesia in laparoscopic colorectal surgery. Br J Surg 2010; 97:

[68] Meylan N, Elia N, Lysakowski C, Tramèr MR. Benefit and risk of intrathecal mor‐ phine without local anaesthetic in patients undergoing major surgery: meta-analysis

[69] Charlton S, Cyna AM, Middleton P, Griffiths JD. Perioperative transversus abdomi‐ nis plane (TAP) blocks for analgesia after abdominal surgery. Cochrane Database

[70] Marret E, Remy C, Bonnet F. Meta-analysis of epidural analgesia versus parenteral

opioid analgesia after colorectal surgery. Br J Surg 2007; 94: 665-673

Anesthesiology 2005; 103: 1079-1088; quiz 1109-1110

of randomized trials. Br J Anaesth 2009; 102: 156-167

ectal surgery. Br J Surg 2011; 98: 1068-1078

Syst Rev 2010; (12):CD007705

als. BMJ 2000; 321: 1493

124 Colorectal Cancer - Surgery, Diagnostics and Treatment

1401-1406

The laparoscopic technique has been enthusiastically applied to the resection of colorectal cancer for more than 15 years [1]. There is evidence that laparoscopy for colorectal cancer offers the opportunity for a meticulous dissection of the mesocolon and mesorectum under direct vision while facilitating a true no-touch technique [2]. Additional benefits, such as less postoperative pain, reduced need for postoperative analgesia, less ileus, shorter hospital stay, less blood loss, and better cosmesis are also well documented [3,4].

During recent years, great effort has been made to minimize parietal trauma for cosmetic reasons and to further reduce surgery-related pain and morbidity. New techniques, such as natural orifice transluminal endoscopic surgery (NOTES) [5] have been developed in order to reach the goal of "scarless" surgery. Although NOTES actually allows for no scarring of the body surface, it has several disadvantages and limitations with the currently available instruments, including limited access, less familiar working angles and operative approaches. Furthermore, it is associated with possible complications caused by opening of the stomach, colon or vagina, and may not be fully suitable or safe for advanced procedures, such as colectomies [6].

Single incision laparoscopic surgery (SILS) is currently regarded as the next major advance in minimally invasive surgical approaches to colorectal disease that is more feasible for general‐ ized use [7-10]. SILS reduces the invasiveness of laparoscopic conventional surgery (LCS) by decreasing the number of incisions and ports through the abdominal wall. This theoretically could provide important clinical advantages, including less postoperative pain, reduction of port-site associated morbidity (such as wound infection, bleeding, visceral injury and port site herniation), quicker recovery and shorter hospital stay. The small incision through the abdominal wall allows for "scarless" surgery as the wound is usually hidden within 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.

umbilicus, thus providing potentially better cosmesis. Moreover, SILS permits surgeons to use familiar standard laparoscopic instruments but also perform complex procedures, such as colorectal operations, which require extraction of large surgical specimens or intestinal anastomosis.

## **2. Technical aspects of SILS**

SILS was first reported in 1992 by gynecologists who performed single-incision hysterectomy [11]. The performance of the first transumbilical cholecystectomy was published in 1999 [12] and the first single-incision appendectomy was reported in 1998 [13]. The use of SILS in colorectal surgery was first reported in 2008 by Remzi and co-workers [8] and Bucher and colleagues [14].

Since these first reports, it has been evident that SILS raises a number of specific new challenges compared with LCS. The skills required for SILS are different from those needed in conven‐ tional multiport laparoscopy, even for experienced laparoscopic surgeons [15]. The handling of straight instruments in parallel with the laparoscope through a small single incision decreases the freedom of movement for the surgeon, and complicates the holding of the laparoscope for the assistant and instruments for the surgeon. The most outstanding technical challenges involved in SILS are the following:


articulating or curved instruments and flexible scopes, have been introduced to recreate

**Figure 1.** Single port systems: (a) Uni-x (Pnavel Systems, Morganville, New Jersey, USA); (b) X-Cone (Karl Storz, Tuttlin‐ gen, Germany); (c) Endo-Cone (Karl Storz, Tuttlingen, Germany); (d) SILS Port (Covidien, Norwalk, Connecticut, USA);

Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer?

http://dx.doi.org/10.5772/56871

127

**Figure 2.** Articulating and curved instruments for SILS: (a) SILS Hand Instrument (Covidien, Norwalk, Connecticut, USA); (b) The Cuschieri Coaxial Deviating Instruments (Karl Storz, Tuttlingen, Germany); (c) Cambridge Endo Instru‐

ments (Cambridge Endoscopic Devices, Framingham, Massachusetts, USA).

(e) Olympus TriPort + (Advanced Surgical Concepts, Bray, Ireland.

triangulation (Figure 2).


New operative hardware is being developed to facilitate the technique [16]. Many of the big healthcare manufacturers have developed multilumen access devices to allow for the insertion of several instruments through a single large fascial incision (Figure 1).

Initially, these devices offered three openings with limited gas inflow and outflow, but we are now seeing revision of the devices, incorporating more access ports so standard laparoscopic dissection techniques can be utilized. Newly designed equipment, such as

Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer? http://dx.doi.org/10.5772/56871 127

umbilicus, thus providing potentially better cosmesis. Moreover, SILS permits surgeons to use familiar standard laparoscopic instruments but also perform complex procedures, such as colorectal operations, which require extraction of large surgical specimens or intestinal

SILS was first reported in 1992 by gynecologists who performed single-incision hysterectomy [11]. The performance of the first transumbilical cholecystectomy was published in 1999 [12] and the first single-incision appendectomy was reported in 1998 [13]. The use of SILS in colorectal surgery was first reported in 2008 by Remzi and co-workers [8] and Bucher and

Since these first reports, it has been evident that SILS raises a number of specific new challenges compared with LCS. The skills required for SILS are different from those needed in conven‐ tional multiport laparoscopy, even for experienced laparoscopic surgeons [15]. The handling of straight instruments in parallel with the laparoscope through a small single incision decreases the freedom of movement for the surgeon, and complicates the holding of the laparoscope for the assistant and instruments for the surgeon. The most outstanding technical

**1.** Loss of triangulation with straight instruments: the loss of this dogmatic principle of laparoscopic surgery often imposes the need to operate with crossed hands and does not allow an ergonomically favorable position for the surgeon and assistants. The inherent technical challenge is that the visual axis becomes more axial or in-line, so a movement of the camera often results in a inadvertent movement of an adjacent instrument, thus

**2.** Restricted number of working instruments and thus difficulty of achieving correct

**3.** Restricted external working space: the multiple instruments and laparoscopes required for a procedure are competing for the same space at the fulcrum of the entry port, causing external hand collisions and difficulty with instrument tip manipulation internally.

New operative hardware is being developed to facilitate the technique [16]. Many of the big healthcare manufacturers have developed multilumen access devices to allow for the insertion

Initially, these devices offered three openings with limited gas inflow and outflow, but we are now seeing revision of the devices, incorporating more access ports so standard laparoscopic dissection techniques can be utilized. Newly designed equipment, such as

increasing the difficulty of performing even relatively simple tasks.

of several instruments through a single large fascial incision (Figure 1).

anastomosis.

colleagues [14].

**2. Technical aspects of SILS**

126 Colorectal Cancer - Surgery, Diagnostics and Treatment

challenges involved in SILS are the following:

exposure and the necessary traction to tissues.

**4.** Difficulty in maintaining pneumoperitoneum.

**5.** Requirement of training and adjustment.

**Figure 1.** Single port systems: (a) Uni-x (Pnavel Systems, Morganville, New Jersey, USA); (b) X-Cone (Karl Storz, Tuttlin‐ gen, Germany); (c) Endo-Cone (Karl Storz, Tuttlingen, Germany); (d) SILS Port (Covidien, Norwalk, Connecticut, USA); (e) Olympus TriPort + (Advanced Surgical Concepts, Bray, Ireland.

articulating or curved instruments and flexible scopes, have been introduced to recreate triangulation (Figure 2).

**Figure 2.** Articulating and curved instruments for SILS: (a) SILS Hand Instrument (Covidien, Norwalk, Connecticut, USA); (b) The Cuschieri Coaxial Deviating Instruments (Karl Storz, Tuttlingen, Germany); (c) Cambridge Endo Instru‐ ments (Cambridge Endoscopic Devices, Framingham, Massachusetts, USA).

Moreover, the introduction of an extra-long, 5 mm laparoscope allows placement of the camera on a different plane from the other instruments and help in moving the operator's hand further apart to avoid handle collision (Figure 3) [17]. All these devices have made single site surgery easier and more efficient.

type of surgery had a low BMI. Makino et al. [18] have reviewed 23 studies with a total of 378

patients. Similar results have been found by Fung et al. [19] in their recent review. These authors have analyzed 38 colonic SILS articles containing 565 patients and the median BMI

preoperative abdominal computed tomography to predict accurately the pattern of visceral fat, allowing better selection of patients for SILS colectomy and reducing the number of

The other factor that has markedly influenced the currently available data on SILS for colorectal cancer is the type of surgical procedure. Makino et al. [18] have reported that 279 (73.8%) of the 378 procedures analyzed in their review were right hemicolectomy, followed by sigmoi‐ dectomy (n = 27), performed essentially for diverticular disease, and anterior resection of the rectum (n = 20). Moreover, a high number of published studies have specifically limited the analysis of safety, feasibility and short-term results to only single-port right hemicolectomy [14,25,32-38,42,45-48], thus demonstrating that this type of procedure is the least complex to perform with the single-port technique at the beginning of the experience. Actually, right hemicolectomy involves surgery only in one/two quadrants while left procedures require operating in a multitude of different and opposite abdominal quadrants, from the hypochon‐ drium for splenic flexure mobilization to the pelvis for a total mesorectal excision (TME). Moreover, in right hemicolectomy the surgeon has the possibility of creating an extracorporeal intestinal anastomosis through umbilical access while in left colectomies and anterior resection of the rectum the anastomosis is intracorporeal, thus augmenting the complexity of the

These considerations clearly show that there is an inevitable case-selection bias in assessing the outcomes of colo-rectal SILS from published studies. Although randomized controlled trials comparing single-port and multi-port right hemicolectomy have not been reported yet, the most significant data available to date relate to this type of procedure. In 2012, the two largest experiences with single-port right hemicolectomies in a single institution have been reported. Waters et al. [49] analyzed the short-term outcomes with single-incision right hemicolectomy in 100 patients. Operative indications were oncological in 92 patients, 57 for adenocarcinoma and 35 for polyps not suitable for endoscopic removal. Morbidity (13%) and mortality (1%) rates were acceptable as well as operative time (median value, 105 minutes) and conversion rate to multiport or open procedures (2% and 4%, respectively). Most impor‐ tantly, there was no compromise of oncological adequacy with no positive tumor margins and a mean number of 18 lymph nodes retrieved and examined in the surgical specimens. Interestingly, patients with a wide range of BMI measurements were offered single-incision right hemicolectomy, with the largest approaching superobesity at a BMI of 46 kg/m2

mean patient BMI of 28. Unfortunately, no results regarding postoperative pain, cosmetic results or direct comparison with the multi-port laparoscopic approach were reported.

Chew et al. [50] have reported the short outcomes of single-incision laparoscopic hemicolec‐ tomy in 40 consecutive patients. These results were compared with those of 104 conventional laparoscopic hemicolectomies. Indications for surgery were oncological in the majority of

. On the basis of these findings, some studies have suggested the use of

Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer?

in these

129

http://dx.doi.org/10.5772/56871

and a

patients undergoing single-port colectomy. The mean value of BMI was 25.5 kg/m2

was 25.8 kg/m2

conversions [44].

procedure.

**Figure 3.** Extra-long, 5 mm, 30° laparoscope (Karl Storz, Tuttlingen, Germany).

## **3. Feasibility and safety of single-incision colectomy**

All the challenges encountered with single-port surgery are magnified with colorectal procedures. Unlike laparoscopic cholecystectomy or appendicectomy, which involve surgery in only one abdominal quadrant, single-incision laparoscopic colectomy often requires operating in different abdominal quadrants. In addition, the need for adequate oncological margins and the creation of a tension-free anastomosis are essential. Although the use of this new approach for complex colorectal procedures might understandingly be viewed as difficult to implement, over the past few years there has been significant interest in SILS for colonic resections in both benign and malignant conditions. In fact, between 2008 and 2012, a nearly 7-fold increase occurred in the number of articles related to single-port colorectal surgery [18-20]. Unfortunately, the currently available literature relating to the technique includes mostly case reports or small case series describing the feasibility, safety and technical difficul‐ ties of different operations [21-42]. There are very few studies comparing SILS to LCS and there is a need for randomized controlled trials to definitively establish that SILS is no different from standard laparoscopic surgery in terms of completion rates, complications and oncological adequacy but with the advantage of being more cosmetic with subsequently reduced mor‐ bidities including pain [43]. The studies published to date have a number of other flaws limiting their impact. These include low sample size, selection bias and difficulty in blinding the patients enrolled. The vast majority of studies involve a very carefully selected SILS cohort of uncomplicated cases, which significantly limits their generalization.

The most significant datum emerging from the literature is that colonic SILS has been offered to date to a highly selected group of patients [18,19]. This selection is based on two main parameters: body mass index (BMI) that is an indirect measure of visceral fat, and tumor site, that is directly linked to the type of surgical procedure.

It is well known that visceral fat is one the most critical factors in the identification of the correct surgical plane in laparoscopic surgery [44]. This concept is obviously amplified in SILS and visceral obesity is reported as the primary cause of conversion to multiport laparoscopy in most studies [45]. Therefore it is understandable that most patients who are candidates for this type of surgery had a low BMI. Makino et al. [18] have reviewed 23 studies with a total of 378 patients undergoing single-port colectomy. The mean value of BMI was 25.5 kg/m2 in these patients. Similar results have been found by Fung et al. [19] in their recent review. These authors have analyzed 38 colonic SILS articles containing 565 patients and the median BMI was 25.8 kg/m2 . On the basis of these findings, some studies have suggested the use of preoperative abdominal computed tomography to predict accurately the pattern of visceral fat, allowing better selection of patients for SILS colectomy and reducing the number of conversions [44].

Moreover, the introduction of an extra-long, 5 mm laparoscope allows placement of the camera on a different plane from the other instruments and help in moving the operator's hand further apart to avoid handle collision (Figure 3) [17]. All these devices have made single site surgery

All the challenges encountered with single-port surgery are magnified with colorectal procedures. Unlike laparoscopic cholecystectomy or appendicectomy, which involve surgery in only one abdominal quadrant, single-incision laparoscopic colectomy often requires operating in different abdominal quadrants. In addition, the need for adequate oncological margins and the creation of a tension-free anastomosis are essential. Although the use of this new approach for complex colorectal procedures might understandingly be viewed as difficult to implement, over the past few years there has been significant interest in SILS for colonic resections in both benign and malignant conditions. In fact, between 2008 and 2012, a nearly 7-fold increase occurred in the number of articles related to single-port colorectal surgery [18-20]. Unfortunately, the currently available literature relating to the technique includes mostly case reports or small case series describing the feasibility, safety and technical difficul‐ ties of different operations [21-42]. There are very few studies comparing SILS to LCS and there is a need for randomized controlled trials to definitively establish that SILS is no different from standard laparoscopic surgery in terms of completion rates, complications and oncological adequacy but with the advantage of being more cosmetic with subsequently reduced mor‐ bidities including pain [43]. The studies published to date have a number of other flaws limiting their impact. These include low sample size, selection bias and difficulty in blinding the patients enrolled. The vast majority of studies involve a very carefully selected SILS cohort of

The most significant datum emerging from the literature is that colonic SILS has been offered to date to a highly selected group of patients [18,19]. This selection is based on two main parameters: body mass index (BMI) that is an indirect measure of visceral fat, and tumor site,

It is well known that visceral fat is one the most critical factors in the identification of the correct surgical plane in laparoscopic surgery [44]. This concept is obviously amplified in SILS and visceral obesity is reported as the primary cause of conversion to multiport laparoscopy in most studies [45]. Therefore it is understandable that most patients who are candidates for this

**Figure 3.** Extra-long, 5 mm, 30° laparoscope (Karl Storz, Tuttlingen, Germany).

**3. Feasibility and safety of single-incision colectomy**

uncomplicated cases, which significantly limits their generalization.

that is directly linked to the type of surgical procedure.

easier and more efficient.

128 Colorectal Cancer - Surgery, Diagnostics and Treatment

The other factor that has markedly influenced the currently available data on SILS for colorectal cancer is the type of surgical procedure. Makino et al. [18] have reported that 279 (73.8%) of the 378 procedures analyzed in their review were right hemicolectomy, followed by sigmoi‐ dectomy (n = 27), performed essentially for diverticular disease, and anterior resection of the rectum (n = 20). Moreover, a high number of published studies have specifically limited the analysis of safety, feasibility and short-term results to only single-port right hemicolectomy [14,25,32-38,42,45-48], thus demonstrating that this type of procedure is the least complex to perform with the single-port technique at the beginning of the experience. Actually, right hemicolectomy involves surgery only in one/two quadrants while left procedures require operating in a multitude of different and opposite abdominal quadrants, from the hypochon‐ drium for splenic flexure mobilization to the pelvis for a total mesorectal excision (TME). Moreover, in right hemicolectomy the surgeon has the possibility of creating an extracorporeal intestinal anastomosis through umbilical access while in left colectomies and anterior resection of the rectum the anastomosis is intracorporeal, thus augmenting the complexity of the procedure.

These considerations clearly show that there is an inevitable case-selection bias in assessing the outcomes of colo-rectal SILS from published studies. Although randomized controlled trials comparing single-port and multi-port right hemicolectomy have not been reported yet, the most significant data available to date relate to this type of procedure. In 2012, the two largest experiences with single-port right hemicolectomies in a single institution have been reported. Waters et al. [49] analyzed the short-term outcomes with single-incision right hemicolectomy in 100 patients. Operative indications were oncological in 92 patients, 57 for adenocarcinoma and 35 for polyps not suitable for endoscopic removal. Morbidity (13%) and mortality (1%) rates were acceptable as well as operative time (median value, 105 minutes) and conversion rate to multiport or open procedures (2% and 4%, respectively). Most impor‐ tantly, there was no compromise of oncological adequacy with no positive tumor margins and a mean number of 18 lymph nodes retrieved and examined in the surgical specimens. Interestingly, patients with a wide range of BMI measurements were offered single-incision right hemicolectomy, with the largest approaching superobesity at a BMI of 46 kg/m2 and a mean patient BMI of 28. Unfortunately, no results regarding postoperative pain, cosmetic results or direct comparison with the multi-port laparoscopic approach were reported.

Chew et al. [50] have reported the short outcomes of single-incision laparoscopic hemicolec‐ tomy in 40 consecutive patients. These results were compared with those of 104 conventional laparoscopic hemicolectomies. Indications for surgery were oncological in the majority of patients in the two groups. The authors found that single-incision right hemicolectomy is a feasible and safe procedure with equivalent outcomes in terms of operative time, oncological adequacy, postoperative morbidity, and conversions when compared with conventional laparoscopic right hemicolectomy. In particular, there were no differences in lymph node retrieval (median value of 18 and 19 lymph nodes for multi-port and single-port surgery, respectively) and resection margin clearance.

(n = 142) followed by colonic polyps (n = 4) and colonic cancer (n = 4). The mean operative time for left-sided procedures was 146 ± 48 min and in all cases standard straight, non-articulating laparoscopic instruments along with ultrasonic or radiofrequency dissector/sealer were used. It seems that the authors did not experience any particular technical problems in performing these types of procedures that do not actually need wide splenic flexure mobilization or mesorectal dissection. The fairly higher incidence of early postoperative complications (12.6%) than rates stated in the literature, was imputed to the high rate of severe, complicated diver‐

Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer?

http://dx.doi.org/10.5772/56871

131

The literature concerning subtotal colectomy or proctocolectomy (with or without ileoanal anastomosis), at this time consists only of case reports and a few small case series [62-68]. The predominant indication for this type of operation has been ulcerative colitis followed by polyposis coli [64,65,67]. Overall, 36 single-incision total colectomies have been reported in the literature: these studies have demonstrated the feasibility and safety of single-incision technique even in these more complex colonic procedures but cannot provide any comparative results with traditional laparoscopy. It is likely that cosmetic results will be magnified by single-incision total colectomy since patients suffering from ulcerative colitis or polyposis coli are usually young and may prefer a small incision hidden in the umbilicus. If an ileostomy is scheduled, the single incision is usually performed in the right lower quadrant of the abdomen and the terminal ileum is brought out through this port-site, thus minimizing the traumatic

**4. Comparison between single-incision and conventional laparoscopic**

As all these data indicate, there are still several limitations to an analysis of the adequacy of single-incision technique in the treatment of colorectal cancer. The most important limiting factor in the interpretation of reported outcomes is the careful selection of patients, with an almost 3-fold predominance of right-sided pathology, a low to average BMI and non-bulky colonic disease. If this case-selection bias is taken into account and the oncological adequacy of a single-incision procedure is hypothetically accepted, this innovation would be justified only in the presence of clear short-term benefits over conventional laparoscopic colonic surgery. These benefits should comprise a lower complication rate, reduced postoperative

To date, only two randomized trials have compared short-term outcomes after single-incision and conventional laparoscopic colectomies for colon cancer. In 2011, Huscher et al. [69] reported the results of a study conducted on 32 patients, with 16 in the single-incision and 16 in the conventional laparoscopic group. Although the authors confirmed the safety and technical feasibility of single-incision colectomy, they did not show any superiority of the procedure over conventional laparoscopy in terms of postoperative morbidity, resumption of

ticular disease rather than to the complexity of single-incision procedure.

and cosmetic impact of the procedure.

pain, faster recovery and better cosmesis.

oral liquid/solid food intake and length of hospital stay.

**colectomy**

The data regarding left sided procedures, in particular anterior resection of the rectum for cancer, are much more limited. This is mainly due to the complexity of these procedures, in particular some surgical steps such as mobilizing the splenic flexure and dissection of the mesorectum. The fairly great distance of the spleen and the deep pelvis from the umbilicus amplify the difficulty of creating instrument triangulation, especially when standard, straight laparoscopic instruments are used. Even adequate traction of the rectum and stapling proce‐ dures have been associated with technical difficulties and adjunctive methods of traction and suspension such as transparietal suture, are frequently needed to achieve adequate surgical exposure [51-56]. Bulut et al. [57] have recently reported their early experience in singleincision surgery for rectal cancer treatment. This study was conducted on 10, highly selected patients: the mean tumor diameter was very small (3.2 cm), BMI was ≤25 in all patients and 8 of them were females, thus providing the advantages of a wide pelvis and relative lack of visceral fat. Although the authors stated that single-incision surgery for rectal cancer can be performed safely in this kind of patient, the overall mean operation time was quite long (240 min) and 6 patients received stomas (4 had diverting ileostomy after anterior resection of the rectum and 2 had colostomy after Hartmann procedure and abdominoperineal resection). Moreover, mesorectum excision was classified as nearly complete in 4 patients and the median number of examined lymph nodes was quite low, namely 14.

One of the most challenging maneuvers in single-incision rectal surgery is maintaining an adequate operative field during TME. Uematsu et al. [54] have proposed a new rectumsuspending system composed of a suspending bar and a bowel clamp with an extracorporeal magnetic tool. This apparatus, along with single access through the right iliac fossa instead of the umbilicus, allowed the authors to perform TME and transect the rectum by ensuring a proper tension. Nevertheless, the proposed new technique is actually complex and, as the authors stated, is not recommended for males with narrow pelvis or obese individuals or when mobilization of the splenic flexure is required because of the distance between the spleen and the single access through the right iliac fossa. Altogether, these data clearly show that some unresolved issues still remain in performing SILS for the treatment of rectal cancer.

There are more data, which are somewhat more reliable regarding other less complex leftsided procedures, such as left hemicolectomy or sigmoidectomy [52,58-60]. In fact, sigmoi‐ dectomy is the most frequent procedure performed for benign left-side pathology, predominantly diverticular disease or large colonic polyps not suitable for endoscopic removal. Recently, Vestweber et al. [61] have reported the largest series of patients undergoing single-incision colorectal surgery in a single institution. One hundred and fifty out of 244 procedures were sigmoidectmy (n = 145) with left hemicolectomies (n = 4) and high anterior resection of the rectum (n = 1). Most of these patients were operated on for diverticular disease (n = 142) followed by colonic polyps (n = 4) and colonic cancer (n = 4). The mean operative time for left-sided procedures was 146 ± 48 min and in all cases standard straight, non-articulating laparoscopic instruments along with ultrasonic or radiofrequency dissector/sealer were used. It seems that the authors did not experience any particular technical problems in performing these types of procedures that do not actually need wide splenic flexure mobilization or mesorectal dissection. The fairly higher incidence of early postoperative complications (12.6%) than rates stated in the literature, was imputed to the high rate of severe, complicated diver‐ ticular disease rather than to the complexity of single-incision procedure.

patients in the two groups. The authors found that single-incision right hemicolectomy is a feasible and safe procedure with equivalent outcomes in terms of operative time, oncological adequacy, postoperative morbidity, and conversions when compared with conventional laparoscopic right hemicolectomy. In particular, there were no differences in lymph node retrieval (median value of 18 and 19 lymph nodes for multi-port and single-port surgery,

The data regarding left sided procedures, in particular anterior resection of the rectum for cancer, are much more limited. This is mainly due to the complexity of these procedures, in particular some surgical steps such as mobilizing the splenic flexure and dissection of the mesorectum. The fairly great distance of the spleen and the deep pelvis from the umbilicus amplify the difficulty of creating instrument triangulation, especially when standard, straight laparoscopic instruments are used. Even adequate traction of the rectum and stapling proce‐ dures have been associated with technical difficulties and adjunctive methods of traction and suspension such as transparietal suture, are frequently needed to achieve adequate surgical exposure [51-56]. Bulut et al. [57] have recently reported their early experience in singleincision surgery for rectal cancer treatment. This study was conducted on 10, highly selected patients: the mean tumor diameter was very small (3.2 cm), BMI was ≤25 in all patients and 8 of them were females, thus providing the advantages of a wide pelvis and relative lack of visceral fat. Although the authors stated that single-incision surgery for rectal cancer can be performed safely in this kind of patient, the overall mean operation time was quite long (240 min) and 6 patients received stomas (4 had diverting ileostomy after anterior resection of the rectum and 2 had colostomy after Hartmann procedure and abdominoperineal resection). Moreover, mesorectum excision was classified as nearly complete in 4 patients and the median

One of the most challenging maneuvers in single-incision rectal surgery is maintaining an adequate operative field during TME. Uematsu et al. [54] have proposed a new rectumsuspending system composed of a suspending bar and a bowel clamp with an extracorporeal magnetic tool. This apparatus, along with single access through the right iliac fossa instead of the umbilicus, allowed the authors to perform TME and transect the rectum by ensuring a proper tension. Nevertheless, the proposed new technique is actually complex and, as the authors stated, is not recommended for males with narrow pelvis or obese individuals or when mobilization of the splenic flexure is required because of the distance between the spleen and the single access through the right iliac fossa. Altogether, these data clearly show that some

unresolved issues still remain in performing SILS for the treatment of rectal cancer.

There are more data, which are somewhat more reliable regarding other less complex leftsided procedures, such as left hemicolectomy or sigmoidectomy [52,58-60]. In fact, sigmoi‐ dectomy is the most frequent procedure performed for benign left-side pathology, predominantly diverticular disease or large colonic polyps not suitable for endoscopic removal. Recently, Vestweber et al. [61] have reported the largest series of patients undergoing single-incision colorectal surgery in a single institution. One hundred and fifty out of 244 procedures were sigmoidectmy (n = 145) with left hemicolectomies (n = 4) and high anterior resection of the rectum (n = 1). Most of these patients were operated on for diverticular disease

respectively) and resection margin clearance.

130 Colorectal Cancer - Surgery, Diagnostics and Treatment

number of examined lymph nodes was quite low, namely 14.

The literature concerning subtotal colectomy or proctocolectomy (with or without ileoanal anastomosis), at this time consists only of case reports and a few small case series [62-68]. The predominant indication for this type of operation has been ulcerative colitis followed by polyposis coli [64,65,67]. Overall, 36 single-incision total colectomies have been reported in the literature: these studies have demonstrated the feasibility and safety of single-incision technique even in these more complex colonic procedures but cannot provide any comparative results with traditional laparoscopy. It is likely that cosmetic results will be magnified by single-incision total colectomy since patients suffering from ulcerative colitis or polyposis coli are usually young and may prefer a small incision hidden in the umbilicus. If an ileostomy is scheduled, the single incision is usually performed in the right lower quadrant of the abdomen and the terminal ileum is brought out through this port-site, thus minimizing the traumatic and cosmetic impact of the procedure.

## **4. Comparison between single-incision and conventional laparoscopic colectomy**

As all these data indicate, there are still several limitations to an analysis of the adequacy of single-incision technique in the treatment of colorectal cancer. The most important limiting factor in the interpretation of reported outcomes is the careful selection of patients, with an almost 3-fold predominance of right-sided pathology, a low to average BMI and non-bulky colonic disease. If this case-selection bias is taken into account and the oncological adequacy of a single-incision procedure is hypothetically accepted, this innovation would be justified only in the presence of clear short-term benefits over conventional laparoscopic colonic surgery. These benefits should comprise a lower complication rate, reduced postoperative pain, faster recovery and better cosmesis.

To date, only two randomized trials have compared short-term outcomes after single-incision and conventional laparoscopic colectomies for colon cancer. In 2011, Huscher et al. [69] reported the results of a study conducted on 32 patients, with 16 in the single-incision and 16 in the conventional laparoscopic group. Although the authors confirmed the safety and technical feasibility of single-incision colectomy, they did not show any superiority of the procedure over conventional laparoscopy in terms of postoperative morbidity, resumption of oral liquid/solid food intake and length of hospital stay.

More recently, Poon et al. [70] reported findings from a randomized controlled trial, which enrolled 50 patients, 25 in each study group. As expected, the patients were carefully selected in regard to BMI (median value, 23.2 kg/m2 ) and tumor size (< 4 cm). On the contrary, there was a predominance of left-sided procedures, with 14 anterior resections, 1 sigmoidectomy, 2 left hemicolectomies and only 8 right hemicolectomies in the single-incision group. The authors did not find any statistically significant difference in operative outcome and oncolog‐ ical adequacy between the single-incision and the conventional laparoscopic group. Interest‐ ingly, they found a lower postoperative pain score and shorter median hospital stay in the single-incision group. Although these findings emerge from a randomized controlled trial, they cannot be considered definitive due the low number of patients involved in the study.

The last but not least important concern about single-incision colectomy regards the costs. It is logical to expect an initial increase in costs associated with SILC over conventional laparo‐ scopic surgery since the additional equipment such as single-incision access ports or flexible/ articulating instruments are still relatively new. In their analysis of single-incision righthemicolectomy, Waters et al. [46] found a marginal increase in direct operative cost of US \$310 to \$410 per case. If patients have a shorter length of hospital stay, and consequently, a quicker return to work and normal activity after single-incision surgery, it is likely there will be an

Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer?

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133

Most of the current studies on single-incision colectomy for cancer are observational and lack statistical power due to the relatively low number of patients studied. Although meta-analyses can increase the statistical power by pooling results of all available trials, only randomized, controlled studies can provide high levels of evidence. To date, only two randomized control‐ led studies have compared short-term results between single-incision and conventional laparoscopic surgery and, unfortunately, even these studies have enrolled a very low number of patients. Bearing in mind these limitations, we can still glean several important factors from

**1.** Colonic SILS is technically demanding but the introduction of new specialized equipment including multilumen ports, angled scopes, articulated instruments and instruments of

**2.** Principles of colonic SILS are attractive and applicable in carefully selected groups of patients, namely with right-sided pathology, low BMI and non-bulky tumors.

**3.** In the hands of experienced laparoscopic surgeons, colonic SILS in the above mentioned patients has been demonstrated to be safe and feasible with rates of surgery-related complications and mortality, operative time and oncological adequacy comparable with

**4.** Two meta-analyses and one randomized controlled study provide evidence in support of some advantages of SILS over conventional laparoscopy, namely, shorter length of hospital stay, significantly shorter incision length and significantly less estimated blood loss; other hypothesized benefits, such as reduction in postoperative pain and improve‐

Further high-powered randomized studies comparing SILS and LCS by using standardized outcome assessment tools are needed to confirm or not the above-mentioned results. But one thing is certain: we will not see the same dramatic clinical advantages with the passage from

Furthermore, the more complex the procedure performed by single-incision surgery, the more likely are there to be advantages in comparison with conventional laparoscopic procedures.

LCS to SILS as we saw with the advent of laparoscopic technique over open surgery.

improvement in the cost-effectiveness of SILS in the future.

variable length, will eventually reduce this difficulty.

those of conventional laparoscopy.

ment of cosmesis remain unproven.

**5. Conclusion**

these published series:

Two recent meta-analyses have addressed the issue of comparison between SILS and LCS for both benign and malignant colorectal diseases [71,72]. Both studies have been published in 2012 and thus have included all the comparative studies published to date with the exception of the above mentioned randomized trial by Poon et al. Notwithstanding the heterogeneity of the analyzed studies (14 by Zhou et al. and 15 by Yang et al) in terms of type of procedures performed, indication for surgery, different patient inclusion and exclusion criteria, neither meta-analysis found any significant difference in the incidence of postoperative complications or operative time between single-incision and conventional laparoscopic colectomy. Impor‐ tantly, they show that patients undergoing single-incision colectomy had a significantly shorter length of hospital stay, significantly shorter incision length, significantly less estimated blood loss, and significantly more lymph nodes harvested during oncological resections. Unfortunately, the two pooled analyses were not able to compare the pain score due to lack of data, the differences in scoring methods and in postoperative care and pain management in the available reported data. However, at least three studies [48,73,74] show a significant decrease in pain scores for patients undergoing single-incision colectomy compared to conventional laparoscopy. The decreased pain score is likely due to less surgical trauma as a consequence of eliminating the additional ports at separate sites on the abdominal wall. There is no meta-analysis regarding cosmetic results due to absence of adequate information on this interesting outcome in the individual studies. Only one study reported cosmetic score results with an advantage for SILS over LCS [23]. However, it is logical to assume that a shorter final incision length in single-incision surgery results in improved cosmetic satisfaction for the majority of the patients.

Another important issue emerging from the literature data is that experienced laparoscopic surgeons have performed almost all single-incision colectomies. This implies that SILS is offered not only to a select group of patients but is also performed by a select group of surgeons. It might appear premature to propose a complex and technically challenging evolution of conventional laparoscopy colectomy when this has yet to be fully accepted as a gold standard in the treatment of colorectal cancer [75]. It must be considered that in 2010, only about 20% of colorectal resections in England and in other countries were performed laparoscopically [76]. Therefore, although the principles of SILS are highly attractive, they might not, at this moment, be transferable and proposed to the general community of surgeons.

The last but not least important concern about single-incision colectomy regards the costs. It is logical to expect an initial increase in costs associated with SILC over conventional laparo‐ scopic surgery since the additional equipment such as single-incision access ports or flexible/ articulating instruments are still relatively new. In their analysis of single-incision righthemicolectomy, Waters et al. [46] found a marginal increase in direct operative cost of US \$310 to \$410 per case. If patients have a shorter length of hospital stay, and consequently, a quicker return to work and normal activity after single-incision surgery, it is likely there will be an improvement in the cost-effectiveness of SILS in the future.

## **5. Conclusion**

More recently, Poon et al. [70] reported findings from a randomized controlled trial, which enrolled 50 patients, 25 in each study group. As expected, the patients were carefully selected

was a predominance of left-sided procedures, with 14 anterior resections, 1 sigmoidectomy, 2 left hemicolectomies and only 8 right hemicolectomies in the single-incision group. The authors did not find any statistically significant difference in operative outcome and oncolog‐ ical adequacy between the single-incision and the conventional laparoscopic group. Interest‐ ingly, they found a lower postoperative pain score and shorter median hospital stay in the single-incision group. Although these findings emerge from a randomized controlled trial, they cannot be considered definitive due the low number of patients involved in the study.

Two recent meta-analyses have addressed the issue of comparison between SILS and LCS for both benign and malignant colorectal diseases [71,72]. Both studies have been published in 2012 and thus have included all the comparative studies published to date with the exception of the above mentioned randomized trial by Poon et al. Notwithstanding the heterogeneity of the analyzed studies (14 by Zhou et al. and 15 by Yang et al) in terms of type of procedures performed, indication for surgery, different patient inclusion and exclusion criteria, neither meta-analysis found any significant difference in the incidence of postoperative complications or operative time between single-incision and conventional laparoscopic colectomy. Impor‐ tantly, they show that patients undergoing single-incision colectomy had a significantly shorter length of hospital stay, significantly shorter incision length, significantly less estimated blood loss, and significantly more lymph nodes harvested during oncological resections. Unfortunately, the two pooled analyses were not able to compare the pain score due to lack of data, the differences in scoring methods and in postoperative care and pain management in the available reported data. However, at least three studies [48,73,74] show a significant decrease in pain scores for patients undergoing single-incision colectomy compared to conventional laparoscopy. The decreased pain score is likely due to less surgical trauma as a consequence of eliminating the additional ports at separate sites on the abdominal wall. There is no meta-analysis regarding cosmetic results due to absence of adequate information on this interesting outcome in the individual studies. Only one study reported cosmetic score results with an advantage for SILS over LCS [23]. However, it is logical to assume that a shorter final incision length in single-incision surgery results in improved cosmetic satisfaction for the

Another important issue emerging from the literature data is that experienced laparoscopic surgeons have performed almost all single-incision colectomies. This implies that SILS is offered not only to a select group of patients but is also performed by a select group of surgeons. It might appear premature to propose a complex and technically challenging evolution of conventional laparoscopy colectomy when this has yet to be fully accepted as a gold standard in the treatment of colorectal cancer [75]. It must be considered that in 2010, only about 20% of colorectal resections in England and in other countries were performed laparoscopically [76]. Therefore, although the principles of SILS are highly attractive, they might not, at this

moment, be transferable and proposed to the general community of surgeons.

) and tumor size (< 4 cm). On the contrary, there

in regard to BMI (median value, 23.2 kg/m2

132 Colorectal Cancer - Surgery, Diagnostics and Treatment

majority of the patients.

Most of the current studies on single-incision colectomy for cancer are observational and lack statistical power due to the relatively low number of patients studied. Although meta-analyses can increase the statistical power by pooling results of all available trials, only randomized, controlled studies can provide high levels of evidence. To date, only two randomized control‐ led studies have compared short-term results between single-incision and conventional laparoscopic surgery and, unfortunately, even these studies have enrolled a very low number of patients. Bearing in mind these limitations, we can still glean several important factors from these published series:


Further high-powered randomized studies comparing SILS and LCS by using standardized outcome assessment tools are needed to confirm or not the above-mentioned results. But one thing is certain: we will not see the same dramatic clinical advantages with the passage from LCS to SILS as we saw with the advent of laparoscopic technique over open surgery.

Furthermore, the more complex the procedure performed by single-incision surgery, the more likely are there to be advantages in comparison with conventional laparoscopic procedures. In this prospective, a possible field of investigation might be the assessment of systemic stress response of single-incision versus conventional laparoscopy in colorectal surgery. The reduced parietal trauma and manipulation of the peritoneum could decrease the postoperative inflammatory response to surgical stress and as a consequence, more efficient immunocom‐ petency against tumor cells might be maintained since the earliest postoperative days [77,78]. All these factors might influence the long-term oncological results of SILS with a potential improvement in survival rates of patients operated on for colorectal cancer.

[6] Brunner W, Schirnhofer J, Waldstein-Wartenberg N, Frass R, Weiss H. Single incision laparoscopic sigmoid colon resections without visible scar: a novel technique. Color‐

Single-Incision Laparoscopic Colectomy: A New Era in the Treatment of Colorectal Cancer?

http://dx.doi.org/10.5772/56871

135

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## **Author details**

Fabio Cianchi1,2\*, Fabio Staderini1,2 and Benedetta Badii1,2

\*Address all correspondence to: fabio.cianchi@unifi.it

1 Department of Surgery and Translational Medicine, Center of Oncological Minimally In‐ vasive Surgery, University of Florence, Italy

2 Unit of Endocrine and Minimally Invasive Surgery, AOU Careggi, Florence, Italy

### **References**


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In this prospective, a possible field of investigation might be the assessment of systemic stress response of single-incision versus conventional laparoscopy in colorectal surgery. The reduced parietal trauma and manipulation of the peritoneum could decrease the postoperative inflammatory response to surgical stress and as a consequence, more efficient immunocom‐ petency against tumor cells might be maintained since the earliest postoperative days [77,78]. All these factors might influence the long-term oncological results of SILS with a potential

1 Department of Surgery and Translational Medicine, Center of Oncological Minimally In‐

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2 Unit of Endocrine and Minimally Invasive Surgery, AOU Careggi, Florence, Italy

improvement in survival rates of patients operated on for colorectal cancer.

Fabio Cianchi1,2\*, Fabio Staderini1,2 and Benedetta Badii1,2

\*Address all correspondence to: fabio.cianchi@unifi.it

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**Chapter 7**

**Robotic Colorectal Cancer Surgery**

Ray Swayamjyoti, Jim Khan and Amjad Parvaiz

A robot is a mechanical or virtual agent, usually an electro-mechanical machine that is guided by a computer program or electronic circuitry. Robots have been linked with the future and modern civilization but have been around for more than 2000 years since ancient Greek

Robots were first used in medicine to help people with disabilities to aid in their rehabilitation process. The Edinburgh Modular Arm System [3] was one of the first bionic arm which was

The National Aeronautics and Space Administration (NASA) developed the first telemanipu‐ lator robot in 1985 at the behest of the Defense Department of the United States of America

It was believed that robots could have prevented more than a third of the soldiers from dying

Robotic colorectal operations have gained considerable interest after successful implementa‐ tion in the field of urology and gynaecology. The advantages of a stable platform, better vision and better access has made this an attractive tool in many specialities. [6] Pelvic and rectal

The Federal Drug and Administration approved the use of the da Vinci robotic system for surgical treatment in 2000 and it was first used at the Ohio State University Hospital for

> © 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.

automata. Their real surgical application has been in the last 20 years [1, 2].

with the aim to decrease war casualties using telerobotic surgery [4].

Additional information is available at the end of the chapter

engineered by Dr. David Gow in the early eighties.

during the Vietnam War secondary to haemorrhage [5].

resections are best suited for robotic operations [6].

**2. The Da Vinci surgical robotic system**

oesophageal and pancreatic surgery [22].

http://dx.doi.org/10.5772/58350

**1. Introduction**


## **Robotic Colorectal Cancer Surgery**

Ray Swayamjyoti, Jim Khan and Amjad Parvaiz

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58350

## **1. Introduction**

[74] Vasilakis V, Clark CE, Liasis L, Papaconstantinou HT. Noncosmetic benefits of sin‐ gle-incision laparoscopic sigmoid colectomy for diverticular disease: A case-matched comparison with multiport laparoscopic technique. J Surg Res 2013; 180 (2) 201-207.

[75] Hassan I, Advani V. Single incision laparoscopic colon surgery. Is the ride worth the

[76] National Institute for Health and Clinical Excellence (NICE). NICE Implementation Uptake Report: Laparoscopic Surgery for Colorectal Cancer, 2010; http://

[77] Sammour T, Kahokehr A, Chan S, Booth RJ, Hill AG. The humoral response after laparoscopic versus open colorectal surgery: a meta-analysis J Surg Res. 2010;164(1)

[78] Huang C, Huang R, Jiang T, Huang K, Cao J, Qiu Z. Laparoscopic and open resection for colorectal cancer: an evaluation of cellular immunity. BMC Gastroenterol.

www.nice.org.uk/ media/B4D/4A/UptakeReportColorectalCancer.pdf

curve? Colorectal Dis 2010;12 (9) 847–848.

140 Colorectal Cancer - Surgery, Diagnostics and Treatment

28-37.

2010;28(10) 127.

A robot is a mechanical or virtual agent, usually an electro-mechanical machine that is guided by a computer program or electronic circuitry. Robots have been linked with the future and modern civilization but have been around for more than 2000 years since ancient Greek automata. Their real surgical application has been in the last 20 years [1, 2].

Robots were first used in medicine to help people with disabilities to aid in their rehabilitation process. The Edinburgh Modular Arm System [3] was one of the first bionic arm which was engineered by Dr. David Gow in the early eighties.

The National Aeronautics and Space Administration (NASA) developed the first telemanipu‐ lator robot in 1985 at the behest of the Defense Department of the United States of America with the aim to decrease war casualties using telerobotic surgery [4].

It was believed that robots could have prevented more than a third of the soldiers from dying during the Vietnam War secondary to haemorrhage [5].

Robotic colorectal operations have gained considerable interest after successful implementa‐ tion in the field of urology and gynaecology. The advantages of a stable platform, better vision and better access has made this an attractive tool in many specialities. [6] Pelvic and rectal resections are best suited for robotic operations [6].

## **2. The Da Vinci surgical robotic system**

The Federal Drug and Administration approved the use of the da Vinci robotic system for surgical treatment in 2000 and it was first used at the Ohio State University Hospital for oesophageal and pancreatic surgery [22].


Unlike laparoscopy the da Vinci system allows the surgeon to perform operation seated at the console, with the hands and eyes positioned in line with the instruments. The operating surgeon is able to control the movements of the camera using the foot pedal rather than relying on an assistant. The system is able to filter and decipher surgeon's hand movements into steady

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 143

**Figure 1.** [25]: showing the robotic stack/cart and the monitor used by the assistant to follow the operation

**Figure 2.** [26] : showing robotic and vision carts and the surgeon's console with an additional teaching console

and precise micro movements.

**Table 1.** Development of Robotics to aid in Surgical Procedures.

At present it is extensively used throughout the world and has sold over 2000 units worldwide in 2013. It is estimated then more than 200,000 operations have been performed in 2012 [23, 24].

The initial model of da Vinci was released in the year 1999, later this was updated to "S" in 2007 and in 2009 Si was released with improved functions and better performance. The author uses the da Vinci "Si" robotic system for his colorectal operations.

The da Vinci system consists of a surgeon's console and four interactive robotic arms attached to the robotic cart controlled by the surgeon from the console. One of the arms carries an endoscopic camera via a 12mm port. The camera has two lenses, which gives a 3D image with stereoscopic vision when the surgeon looks through the eyepiece in the console. The three other arms are used to hold tools and tissues i.e. scissors, bovies, electrocautery. The arms are maneuvered using two-foot pedals and two hand controllers.

Unlike laparoscopy the da Vinci system allows the surgeon to perform operation seated at the console, with the hands and eyes positioned in line with the instruments. The operating surgeon is able to control the movements of the camera using the foot pedal rather than relying on an assistant. The system is able to filter and decipher surgeon's hand movements into steady and precise micro movements.

**Figure 1.** [25]: showing the robotic stack/cart and the monitor used by the assistant to follow the operation

At present it is extensively used throughout the world and has sold over 2000 units worldwide in 2013. It is estimated then more than 200,000 operations have been performed in 2012 [23, 24].

• World's first all robotic operation i.e. prostatectomy using the da Vinci robot along with McSleepy robot

1985 • PUMA 560 was used under computerised tomography guidance to orient a needle for brain biopsy [7] 1992 • PROBOT - developed at Imperial College, London and was used to perform prostatic surgery at Guy's and St

1998 • Zeus robotic surgical system – used for reconstruction of the Fallopian tube performed at the Ohio State

1999 • Robotics assisted closed chest bypass on a beating heart was performed at the London Health Sciences

2006 • Unassisted robotic surgery using artificial intelligence to correct atrial fibrillation at a hospital in Milan [15] 2007 • Denervation of spermatic cord for testicular pain using robotic assisted microsurgery performed at Winter

2008 • Magnetic Resonance guided neurosurgical procedure performed at University of Calgary [17]

• The ROBODOC developed by Integrated Surgical Systems was used to curve out accurate fittings in the

The initial model of da Vinci was released in the year 1999, later this was updated to "S" in 2007 and in 2009 Si was released with improved functions and better performance. The author

The da Vinci system consists of a surgeon's console and four interactive robotic arms attached to the robotic cart controlled by the surgeon from the console. One of the arms carries an endoscopic camera via a 12mm port. The camera has two lenses, which gives a 3D image with stereoscopic vision when the surgeon looks through the eyepiece in the console. The three other arms are used to hold tools and tissues i.e. scissors, bovies, electrocautery. The arms are

uses the da Vinci "Si" robotic system for his colorectal operations.

**Year Milestones**

Thomas' Hospital, London [8]

142 Colorectal Cancer - Surgery, Diagnostics and Treatment

femur for hip replacement [8]

University Medical Center [9]

2000 • **FDA approval of da Vinci robotic system**[11]

• **Robotic Right Hemicolectomy** [13] • Robotic bowel resections [14]

Haven Hospital and University of Florida [16]

**Table 1.** Development of Robotics to aid in Surgical Procedures.

• Femoral reconstruction [20]

• Microsurge developed by German Aerospace Center [18]

used for anaesthesia at McGill University Hospital, Canada [21]

2010 • Sophie Surgical System developed by Eindhoven University of Technology [19]

Centre [10]

2002 • Robotic cholecystectomy [12]

maneuvered using two-foot pedals and two hand controllers.

**Figure 2.** [26] : showing robotic and vision carts and the surgeon's console with an additional teaching console

## **3. Evidence of robotics in colorectal surgery**

Robotic colorectal surgery is gaining widespread interest worldwide and in the continent. Data collected in 2012 suggests that most of the reported or published data shows that majority of the robotic colorectal operations have been performed in the United States (32%) followed by South Korea (20%), Italy (15%), Canada, Germany and Netherlands accounted for 5% and the rest of the world less than 2% [13].

**Year Reference Country Study type Number of**

Hashizume et al. Japan 18

Giulianotti et al. Italy 16

Anvari et al. Canada Prospective Comparative 10, D'Annibale Italy Comparative 53

Bonder et al. Austria Case series, 14, Ruurda et al. Holland Case series 23

Spinoglio Italy, Comparative, 50, Huettner et al. USA, Comparative, 70, Soravia et al. Switzerland Case series 40

DeHoog et al. Netherlands Case control 20

Kim and kang Korea, Comparative, 100, Bianchi et al. Italy, Comparative, 56, Pernazza and Morpurgo Italy, Case series, 50, DeSouza et al. USA, Case control, 40, Zimmern et al. USA, Case series, 131, Popescu et al. Romania Comparative 122

2002 Weber et al. USA Case series 2,

2003 Vibert et al. France Case series 3,

2004 Hubens et al. Belgium Case series, 8,

2005 Woeste et al. Germany Comparative, 6,

2007 Heemskerk et al. Netherlands Comparative 19 2008 Baik et al. Korea, Randomized trial, 18,

2009 Baik et al. Korea Comparative, 56,

2010 Tsoraides et al. USA, Retrospective, 102,

2011 Kang and kim Korea Retrospective 204 2012 Antoniou SA et al [28] Germany Case series 39 2013 Casillas MA Jr et al [29] USA Case series 344

**Table 2.** [13]

Germain A et al [30] France Case Series 77 Barrie J et al [31] UK Comparative 34 Wormer BA et al [32] USA Comparative 1809

Talamini et al. USA

**patients**

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 145

3,

The first colorectal surgical publication was published by Weber et al in 2002 [27] and since then there has been a tenfold rise in publication in colorectal surgery [13]. The important landmark studies are summarized in table 2.

Laparoscopic colorectal operations have many advantages over conventional open operations. The benefits in terms of short term outcomes are well established and include shorter hospital stay, faster return to work, better cosmesis, less post operative pain, less risk of bleeding and ileus. Long term outcomes including cancer specific and disease free survival have been subject of many well-designed trials.

The COLOR (COlon cancer Laparoscopic or Open resection) trial (330 stated that laparoscopic colectomy was associated with less significant blood loss, earlier recovery of bowel function, use of fewer analgesics and with a shorter hospital stay when compared with open colectomy. It however took half an hour longer than open operations and had 19% chances of converting to open operation. The reasons for conversion were mainly attributed to tumour size of more than 6cms and in patients who had involvement of adjacent structures.

There were concerns regarding tumour recurrence associated with laparoscopic colectomy. The meta-analysis of four randomized control trials (CLASICC trial, COST trial, Barcelona trial and COLOR trial) where patients with colonic cancers were randomised to either open or laparoscopically assisted colectomy concluded that the positive margins were found in specimens after open operations were 2.1% as compared to 1.3% after laparoscopic operation. The overall disease free survival at three years was 83.5% for open operations and 82.2% for laparoscopic operations [34]. Hence, the evidence shows that laparoscopic colonic operation is oncologically safe and viable with comparable outcomes to open surgery [34, 35].

The safety and viability for rectal cancers is still less clear especially with the higher circum‐ ferential margin (CRM) involvement with laparoscopic rectal operations when compared to open rectal operations as mentioned in the CLASSIC trial [34]. There was however, no difference in local recurrence at three years [36]. There was a higher conversion rate in the laparoscopic rectal subgroup (34%) in comparison to laparoscopic colonic group (25%). Conversions to open operations led to higher mortality and morbidity [34, 37]. Conversions were mainly attributed to bulky tumours [33] and increased technical difficulty [37]. The robot promises to abolish some of these technical problems faced during dissection of rectal tumours using laparoscopy and the ROLARR (RObotic versus LAparoscopic Resection for Rectal cancer) trial results are awaited. It is an international, multicentre, prospective, randomised, and controlled, unblinded, parallel-group trial of robotic-assisted versus laparoscopic surgery for the curative treatment of rectal cancer [37].


**Table 2.** [13]

**3. Evidence of robotics in colorectal surgery**

rest of the world less than 2% [13].

144 Colorectal Cancer - Surgery, Diagnostics and Treatment

of many well-designed trials.

landmark studies are summarized in table 2.

for the curative treatment of rectal cancer [37].

Robotic colorectal surgery is gaining widespread interest worldwide and in the continent. Data collected in 2012 suggests that most of the reported or published data shows that majority of the robotic colorectal operations have been performed in the United States (32%) followed by South Korea (20%), Italy (15%), Canada, Germany and Netherlands accounted for 5% and the

The first colorectal surgical publication was published by Weber et al in 2002 [27] and since then there has been a tenfold rise in publication in colorectal surgery [13]. The important

Laparoscopic colorectal operations have many advantages over conventional open operations. The benefits in terms of short term outcomes are well established and include shorter hospital stay, faster return to work, better cosmesis, less post operative pain, less risk of bleeding and ileus. Long term outcomes including cancer specific and disease free survival have been subject

The COLOR (COlon cancer Laparoscopic or Open resection) trial (330 stated that laparoscopic colectomy was associated with less significant blood loss, earlier recovery of bowel function, use of fewer analgesics and with a shorter hospital stay when compared with open colectomy. It however took half an hour longer than open operations and had 19% chances of converting to open operation. The reasons for conversion were mainly attributed to tumour size of more

There were concerns regarding tumour recurrence associated with laparoscopic colectomy. The meta-analysis of four randomized control trials (CLASICC trial, COST trial, Barcelona trial and COLOR trial) where patients with colonic cancers were randomised to either open or laparoscopically assisted colectomy concluded that the positive margins were found in specimens after open operations were 2.1% as compared to 1.3% after laparoscopic operation. The overall disease free survival at three years was 83.5% for open operations and 82.2% for laparoscopic operations [34]. Hence, the evidence shows that laparoscopic colonic operation

The safety and viability for rectal cancers is still less clear especially with the higher circum‐ ferential margin (CRM) involvement with laparoscopic rectal operations when compared to open rectal operations as mentioned in the CLASSIC trial [34]. There was however, no difference in local recurrence at three years [36]. There was a higher conversion rate in the laparoscopic rectal subgroup (34%) in comparison to laparoscopic colonic group (25%). Conversions to open operations led to higher mortality and morbidity [34, 37]. Conversions were mainly attributed to bulky tumours [33] and increased technical difficulty [37]. The robot promises to abolish some of these technical problems faced during dissection of rectal tumours using laparoscopy and the ROLARR (RObotic versus LAparoscopic Resection for Rectal cancer) trial results are awaited. It is an international, multicentre, prospective, randomised, and controlled, unblinded, parallel-group trial of robotic-assisted versus laparoscopic surgery

is oncologically safe and viable with comparable outcomes to open surgery [34, 35].

than 6cms and in patients who had involvement of adjacent structures.

The skills required for laparoscopic operations are different to open operations.

Limitations of laparoscopic surgery include loss of depth perception, reduced tactile feedback and a declined range of motion [33]. The author believes that limited space in the pelvis, with two-dimensional visions and a bulky specimen can make laparoscopic operations very difficult.

There are however some limitations of the da Vinci system. In particular

longer length of hospital stay causing higher cost for the hospital. [19]

**•** High cost of purchasing as well as maintaining the robotic system [22]

**•** loss of tactile feedback although partly compensated by better vision, still can have its effects

**•** Hospitals that perform less robotic colorectal operations had more complications with

Park et al, 2010 17.3 14.2 *0.06* 2.1 2.3 ns 4.9 3.7 0.5

Kim et al, 2010 14.7 16.6 *ns* 2.7 2.6 0.09 3 2 ns

Kwak et al, 2011 20 21 *0.7* 2.2 2.0 0.8 1.7 0 >0.9

Baek et al, 2011 13 16 *0.07* 3.6 3.8 0.6 2.4 4.9 1

Bianchi et al, 2010 18 17 *0.7* 2 2 1.0 0 4 0.9

Baik et al, 2009 18.4 18.7 *0.8* 4 3.6 0.4 7 8 0.7

Patriti et al, 2009 10.3 11.2 *>0.05* 2.1 4.5 >0.05 0 0 ns

**Table 3.** Oncologic results of robotic and laparoscopic surgery for rectal cancer [52].

**Table 4.** Oncologic results of open and robotic surgery for rectal cancer [52].

(LNs: lymph nodes, CRM: circumferential resection margin, ns: not significant, ROB: robotic procedure, LAP: laparo‐

De Souza et al], 2011 15 16.8 0.26 na na 0 3 0.25 Kim et al, 2012 20 19.6 0.7 2.7 1.9 0.001 1 1 1 Park et al, 2011 19.4 18.5 0.06 2.8 2.3 0.002 1 2 0.9

(LN: lymph nodes, CRM: circumferential resection margin, na: not assessed, ROB: robotic procedure, OPEN: laparoscop‐

**LNs (mean) Distal margin (mean, cm) Positive CRM (%)**

**ROB OPEN** *p* **ROB OPEN** *p* **ROB OPEN** *p*

**LNs (mean N) Distal margin(mean, cm) Positive CRM (%)**

**ROB LAP** *p* **ROB LAP** *p* **ROB LAP** *p*

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 147

**•** there is a definite learning curve for this technique

on the performance and outcomes

scopic procedure.)

ic procedure.)

Laparoscopic TME rectal resections have a steep learning curve [38], requiring precise pelvic dissection with preservation of autonomic nerves. There is higher incidence of male sexual dysfunction due to inadvertent injury to the nerves following TME resections [39]. It is estimated that 50% of colorectal surgeons perform laparoscopic colorectal operations in the UK and only a quarter of them perform laparoscopic TME resections [40]. Approximately 50-70 cases are needed to surmount the laparoscopic colorectal learning curve [35, 38, 41].

The COREAN trail [42] trial compared open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy. There was a conversion rate of 1.2% in the COREAN trial as compared to 34% in the CLASSIC trial. The low conversion rate in the COREAN trial was attributed to greater experience of the surgeons who has performed an average of seventy laparoscopic operations as compared to twenty per average surgeon in the CLASSIC trial [43].

The learning curve for performing robotic colorectal operations is shorter and is achieved after 15-20 cases [37, 38]. There are three phases that has been identified in the learning curve for robotic colorectal operations [44, 45, 46]


The other advantages of robotic colorectal resections are that


There are however some limitations of the da Vinci system. In particular

**•** there is a definite learning curve for this technique

The skills required for laparoscopic operations are different to open operations.

difficult.

CLASSIC trial [43].

robotic colorectal operations [44, 45, 46] **•** Phase 1 – initial learning (1-15 cases)

146 Colorectal Cancer - Surgery, Diagnostics and Treatment

**•** Phase 2 – increased competence (15-25 cases) **•** Phase 3 – period of highest skill (>25 cases)

The other advantages of robotic colorectal resections are that

**•** It is associated with lower conversion rates to open operation [48]

time to start diet. It also causes less postoperative pain [49].

dimensional view and zoom magnification [37]

**•** It has 7 degrees of freedom of movement [37]

rates of postoperative bleeding and ileus [50]

surgical procedure and learn from it [51]

Limitations of laparoscopic surgery include loss of depth perception, reduced tactile feedback and a declined range of motion [33]. The author believes that limited space in the pelvis, with two-dimensional visions and a bulky specimen can make laparoscopic operations very

Laparoscopic TME rectal resections have a steep learning curve [38], requiring precise pelvic dissection with preservation of autonomic nerves. There is higher incidence of male sexual dysfunction due to inadvertent injury to the nerves following TME resections [39]. It is estimated that 50% of colorectal surgeons perform laparoscopic colorectal operations in the UK and only a quarter of them perform laparoscopic TME resections [40]. Approximately 50-70

The COREAN trail [42] trial compared open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy. There was a conversion rate of 1.2% in the COREAN trial as compared to 34% in the CLASSIC trial. The low conversion rate in the COREAN trial was attributed to greater experience of the surgeons who has performed an average of seventy laparoscopic operations as compared to twenty per average surgeon in the

The learning curve for performing robotic colorectal operations is shorter and is achieved after 15-20 cases [37, 38]. There are three phases that has been identified in the learning curve for

**•** It is superior in narrow areas like the pelvis and it's safe and feasible [47] with good three

**•** It has better pathologic and functional outcomes. It is associated with less complication rates, shorter duration of hospital stay, time to recover to normal bowel function or first flatus and

**•** Hospitals who perform high-volume robotic colorectal operations have significantly lower

**•** the double console that comes with the robotic cart allow trainees to take part actively at the

**•** simulators are available than can be attached to the console which provides a platform for surgical trainees to practice their skills before actually performing the procedures

cases are needed to surmount the laparoscopic colorectal learning curve [35, 38, 41].



(LNs: lymph nodes, CRM: circumferential resection margin, ns: not significant, ROB: robotic procedure, LAP: laparo‐ scopic procedure.)

**Table 3.** Oncologic results of robotic and laparoscopic surgery for rectal cancer [52].


(LN: lymph nodes, CRM: circumferential resection margin, na: not assessed, ROB: robotic procedure, OPEN: laparoscop‐ ic procedure.)

**Table 4.** Oncologic results of open and robotic surgery for rectal cancer [52].

## **4. Patient selection**

Patient selection is the key especially in the early stages of the learning curve. The author would recommend choosing patients with

**6. Operating room configuration**

**Figure 3.** [53]: showing operating room set up during colectomy

**•** Legs are abducted and slightly flexed at the knees

**•** Patient is positioned supine in a modified lithotomy position with legs wrapped around

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 149

**7. Positioning**

adjustable stirrups


## **5. Patient preparation**

**•** Bowel preparation – phosphate enema for left sided operations. Bowel preparation not necessary for right sided colonic operations.

Bowel preparation is controversial in colorectal surgery. Surgeons differ in their approach. Mechanical bowel preparation results in a colon that is clear of feces. However, it can leave liquid stool in the bowel that is more likely to contaminate the operative field and the pelvis in the event of an anastomotic leak. In our experience, bowel preparation also results in small bowel distension that can make operations more difficult. The authors do not use bowel preparation for right-sided colonic resections. Two-phosphate enemas are used for left sided colorectal resections.


## **6. Operating room configuration**

**4. Patient selection**

**•** ASA grade 1-3

**•** Age <75 years

**•** T1/T2 tumours

**5. Patient preparation**

colorectal resections.

esophageal Doppler.

**•** BMI <30

recommend choosing patients with

148 Colorectal Cancer - Surgery, Diagnostics and Treatment

**•** No previous pelvic or intra-abdominal surgery

necessary for right sided colonic operations.

**•** low residue diet 3-4 days before operation

**•** 4 high calorie drinks to be taken the night before operation

**•** Eating and drinking normally up to 6 hours before operation

**•** 2 high calorie drinks to be taken up to 2 hours before operation

**•** Tumors that are at or just above the peritoneal reflection of the rectum

**•** Avoid patients who received neo-adjuvant chemo-radiotherapy and

Patient selection is the key especially in the early stages of the learning curve. The author would

**•** Avoid patients who for medical reasons will not be able to tolerate Trendelenburg position

**•** Bowel preparation – phosphate enema for left sided operations. Bowel preparation not

Bowel preparation is controversial in colorectal surgery. Surgeons differ in their approach. Mechanical bowel preparation results in a colon that is clear of feces. However, it can leave liquid stool in the bowel that is more likely to contaminate the operative field and the pelvis in the event of an anastomotic leak. In our experience, bowel preparation also results in small bowel distension that can make operations more difficult. The authors do not use bowel preparation for right-sided colonic resections. Two-phosphate enemas are used for left sided

**•** Intra-operative fluids are restricted to 500 mL per hour as tolerated by the patient. This minimizes the risk of edema of the face and neck that can occur due to the steep Trende‐ lenburg position and excessive fluids. Goal directed therapy is the standard approach using

**Figure 3.** [53]: showing operating room set up during colectomy

## **7. Positioning**


**•** Patient's arms are wrapped alongside the body to reduce possibility of shoulder injury and additional shoulder harness can be placed to support Trendelburg's position

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

LUQ**.**

**PORT PLACEMENTS:** 

**9. Port placements**

**Preparing for Port Placement:** 

**9.1. Preparing for port placement**

technique at LUQ or at camera port site.

the abdomen for port placement after CO2 insufflation.

inferior epigastric vessels.

que at LUQ or at camera port site.

**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.

R1

R3

Optical

R2

Robotic Colorectal Cancer Surgery http://dx.doi.org/10.5772/58350 151

 Port placement is the key for a successful robotic procedure. Narrow space between the ports will result in clashing of the arms and poor ergonomics. We recommend marking of the abdomen for port placement after CO2 insufflation.

**•** Port placement is the key for a successful robotic procedure. Narrow space between the ports will result in clashing of the arms and poor ergonomics. We recommend marking of

The initial pneumopertioneum can be established with a Veress needle or Hassan's

**•** The initial pneumopertioneum can be established with a Veress needle or Hassan's techni‐

**•** Initial assessment of entire anatomy of the abdomen focusing on adhesions, peritoneal seedlings and liver metastasis is carried out once the camera port is inserted. Place remaining

ports under endoscopic vision avoiding injury to the inferior epigastric vessels.

 Initial assessment of entire anatomy of the abdomen focusing on adhesions, peritoneal seedlings and liver metastasis is carried out once the camera port is inserted. Place remaining ports under endoscopic vision avoiding injury to the


**Image 1.** Showing positioning of patient
