**6. Chemotherapy for CRLM**

Systemic chemotherapy in CRLM is administered to attain surgical eligibility, for disease control, peri-operatively, or palliatively; since the treatment alone is rarely curative, with 5-year survival rates less than 10%, and historically less than 1% [25, 30, 117]. Polymetastatic liver disease faces treatment limitations with chemotherapy being the primary treatment. The survival rate is poor and a large demand exists for improved treatment options. As surgical resection offers the best long-term survival rates, the aim of systemic chemotherapy is often to downsize tumors to convert ineligible patients to surgical candidates, with systematic review showing a conversion rate for R0 resection in initially ineligible patients at 23% [118]. Chemotherapy regimens are administered neoadjuvantly prior to hepatectomy for cytoreduction, to reduce metastatic tumor size, allowing smaller resection volumes [119]. The regimens are also administered after resection to reduce recurrence [25, 120]. Hepatic intra-arterial infusion is often beneficial because the liver metastasis is supplied by the hepatic artery network, normal tissue is supplied by the portal vein, and locoregional treatment can be performed without exposing much healthy tissue [121–123]. The liver contains a capillary network of sinusoids that filter the blood as shown in **Figure 4**. Approximately 45% of metastatic tumor cells, predominately arriving from the hepatic arterial network [123], become embedded in the sinusoids [89]. Normal liver parenchyma receive about 80% of the blood supply from the portal vein and about 20% from the hepatic artery. In contrast, about 80% of the tumor blood supply arrives from the hepatic artery [116]. This allows locoregional embolization techniques, like radioembolization and chemoembolization, to both embolize the blood supply to specific tumor segments, and deliver locoregional radiotherapy or chemotherapy. These embolization techniques are suggested to be considered for metastatic CRC limited only to the liver, and after unsuccessful chemotherapy [1].

The chemotherapy regimen depends on a number of factors, including: aim of cytoreduction prior to surgery, aim of disease control, aim of palliation, type of somatic gene mutation, and wild-type or mutant phenotype. Somatic mutations of RAS proto-oncogenes have been found in up to 52% of CRLM hepatic resections, with up to 6–12% of resections expressing BRAF mutations, and co-occurring protooncogene RAS and TP53 tumor-suppressor mutations as common genetic events [1, 94]. According to ESMO guidelines, first-line chemotherapy for cytoreduction in RAS

#### **Figure 4.**

*Histological depiction of liver lobules. These units are microscale components of liver tissue. The liver sinusoids are small capillaries, with blood supplied by small branches of the hepatic artery and portal vein. Deesign/shutterstock.com.*

tumors should be recommended cytotoxic doublets (FOLFOX/CAPOX/FOLFIRI), in combination with VEGF antibody bevacizumab for RAS mutant-type tumors, and EGFR antibodies for wild-type tumors. FOLFOXIRI with bevacizumab are recommended as a first line treatment for cytoreduction in CRLM BRAF mutant tumors [1].

Chemotherapeutics can also exhibit many adverse side-effects on healthy liver tissue. Side-effects include sinusoidal obstruction syndrome and chemotherapyassociated steatohepatitis, that can lead to liver failure or increased mortality rates [119]. Additionally, the chemotherapy can cause missing metastases, making lesions unidentifiable on radiological imaging, complicating surgical decisions, and increasing the chance of recurrence [119]. Chemotherapy has difficulty supplying tumor cells with adequate drug dose. The maximum dose is limited by systemic toxicity effects and inadequate tumor penetration is common [8, 124]. Intrahepatic arterial delivery can exhibit acute side-effects of hepatocellular atrophy causing cirrhosis and necrosis [123, 125].

Doxorubicin is an anthracycline chemotherapeutic that can be administered during combination therapy. A liposomal form was created relatively early due to the need for better treatment in Kaposi sarcoma from autoimmune deficiency syndrome [126]. Clinical trials of FUS-mediated thermosensitive liposomal doxorubicin drug delivery to liver tumors [127, 128] have shown large increases in intratumoral doxorubicin concentration, and there are ongoing trials with MRgHIFU for pediatric tumors [129]. Similar ongoing trials are studying the enhanced ability for microbubbles to improve chemotherapy delivery to metastatic liver tumors [130].

### **7. Radiotherapy for CRLM**

Radiotherapy emits ionizing radiation at tumors, causing DNA damage, and apoptosis. The technique exhibits some similar drawbacks to focused ultrasound. Cumulative radiation exposure can occur in the beam's near and far field, resulting in unwanted tissue damage [8, 131, 132]. Also, systems require computed tomography

### *Magnetic Resonance-Guided Focused Ultrasound in the Treatment of Colorectal Cancer Liver… DOI: http://dx.doi.org/10.5772/intechopen.105906*

guidance and respiratory motion control [8, 133]. Local ablative techniques, including radiotherapy, are generally considered to be limited to patients with unresectable CRLM or oligometastatic disease [1]. CRLM radiotherapy has often been limited by liver parenchyma radio-sensitivity. External beam radiation doses of 70–90 Gy needed for CRLM and HCC tumor treatment exceeds tolerance limits of 35 Gy for radiationinduced liver disease (RILD) [57, 134] that can lead to liver failure and death [25]. The condition occurs two to sixteen weeks after treatment, is identified by ascites, high levels of alkaline phosphatases, and high levels of liver transaminases [135].

Stereotactic body radiation therapy (SBRT) with linear accelerators has recently gained much interest for surgical ineligibility, particularly in oligometastatic disease. With SBRT, fiducial markers are percutaneously placed near the tumor site to allow precise tumor targeting [57]. Though MRI guidance reduces invasiveness, without the need for fiducial markers [116]. SBRT is recommended by ESMO to be considered for patients with oligometastatic disease who are ineligible for surgery and ablative therapy [1]. One major advantage of SBRT compared to ablative therapies is that the treatment is non-thermal, mitigating some of the common side-effects seen in local ablative techniques, such as fluid perfusion effects [116]. Studies have shown that liver failure is infrequent when only a portion of the liver is irradiated [135]. The liver toxicity is mild to moderate, with liver failure in less than 1% of patients [136, 137]. Treatment of oligometastatic CRC in the liver with SBRT, suggests one and two year overall survivability at about 67.1% and 56.5%, respectively [137]. Many early phase clinical trials are recruiting, active, or recently completed, for treatment of primary or secondary hepatic tumors with magnetic resonance guided linear accelerators [138, 139] and magnetic resonance guided SBRT [140–143]. Recent phase I trial results with magnetic resonance guided SBRT, showed improved toxicity, with estimated 2-year overall survival of 51%, and median overall survival of 29 months [144].

### **8. Focused ultrasound clinical studies for liver cancer**

A substantial number of clinical studies, cohorts, and randomized control trials for non-liver MRgHIFU and MRgFUS have been reported, including: treatment with bone osteomas or palliative bone metastasis [145, 146], uterine fibroids [147–151], gynaecological tumor recurrence [152], prostate cancer [153, 154], essential tremor [155, 156], and breast cancer [157]. Many clinical studies have been reported for USgFUS ablation for liver tumors [158–165], with most studies reporting on HCC ablation [166]. Similar to USgFUS, new histotripsy devices using cavitation rather than thermal ablation, are currently being studied for the treatment of primary and secondary tumors, with an active prospective clinical trial [45, 46, 167, 168]. No Phase III trials for USgFUS or MRgHIFU ablation of CRLM have been published [116]. Early USgFUS studies in liver malignancies, not distinguishing between metastatic liver tumors and primary liver tumors, showed a median survival time of 13.4 months, 6-month survival times of 82.6%, and 12-month survival time of 53.4% [159]. More recent systematic reviews of FUS for liver malignancies have given 1 year, 2 year, and 5-year survivability of 81%, 60%, and 39%, respectively [166]. Most studies have been conducted using the Chongqing Haifu JC system, capable of up to 300 W acoustic power and peak intensity up to 20,000 W cm2 [166]. The system has received the mark Conformite´ Europeenne´ (CE), being the most reported system for clinical liver tumor ablation [2, 3]. The permission is granted to individual commercial models rather than general treatment procedures. The magnetic resonance guided

systems that have received regulatory approval for alternative treatments include the ArcBlate (Episonica, Hsinchu, Taiwan), Exablate (Insightec, Tirat Carmel, Israel), and Sonalleve (Profound Medical, Mississauga, Canada) systems.

Local ablative techniques, including focused ultrasound ablation, are generally recommended only in cases of unresectable liver metastases or oligometastatic disease [1]. Most FUS ablation therapy studies for liver tumors are USgFUS for HCC, with less reports of metastatic liver tumor treatment [166]. Particularly advantageous in FUS is the improved side effect profile and reduced morbidity compared to standard treatment options. The treatment can occur multiple times with no cumulative radiation-like side effects. In relation to chemotherapy, it is much more focused, with less toxicity to healthy tissues [8, 169]. Additionally, extracorporeal FUS liver ablation is completely non-invasive and offers very fast recovery times [170]. Benefits of MRgHIFU compared to USgFUS include near real-time temperature mapping, integration into existing imaging systems, less propensity for radiofrequency interference in the imaging system, and capability of assessing treatment response during the procedure. Though ultrasound-guided devices do not provide real-time temperature map-ping, assessment of grey-scale change are indicative of coagulative necrosis [166]. Treatment plans with FUS generally depend on the cancer staging. Curative ablation of early stage tumors often include a 1.5–2.0 cm peripheral tissue margin. The treatment is administered palliatively for late-stage tumors to slow progression or alleviate symptoms [8, 160].

Drawbacks to hepatobiliary focused ultrasound studies have been the need for general anesthesia, long treatment times, scattering by the thoracic cage, high power requirements, respiratory motion, skin burns, osteonecrosis, skin pain, skin edema, rib resection, fever, the need for intrapleural effusion, and reduced thermal dose from fluid perfusion of surrounding vessels [2, 39, 165, 166, 170–177]. A systematic review of USgFUS for the treatment of malignant hepatobiliary tumors indicated the primary complications were skin burns in 15% of cases, followed by localized pain in 5%, then fever at 2% [166]. Major post-treatment complications include fluid and/or air accumulation in the lungs, biliary obstruction, and fistula occurrence [177].

Some studies have reported focused ultrasound ablation in primary and secondary liver tumors in difficult locations, including near major hepatic veins and arteries, and near surrounding organs of the heart, gallbladder, stomach, and intestine [162, 165, 178]. Tumors located near surrounding organs are high-risk. Particularly sensitive are the bowel and gallbladder due to the thin walls and risks of peritonitis [162].

Skin and rib burns have been addressed in a variety of manners. Skin burns have been reported to occur with tumors located near the subcapsular area, resulting from possible rib reflection or reflections from internal gas pockets in the bowel or lung parenchyma [166]. The right lobe is more susceptible as it is predominately located behind the ribs [162]. Intrapleural effusion can distance the tumor site from the subcapsular area, or rib resection can be performed [162, 179]. Particularly troublesome are tumors of the liver dome in Couinaud segments 7 and 8, due to the close proximity to the lungs, the close proximity to the ribs, and that this region tends to remain behind the rib cage under general anesthesia due to reduced respiration [162]. A small cohort for USgFUS reported that proper intraoperative assessment of the soft tissue prevented skin burns in all patients [161].

A variety of techniques have been tested to overcome respiratory motion and rib interaction. Respiratory motion creates complications requiring organ image

### *Magnetic Resonance-Guided Focused Ultrasound in the Treatment of Colorectal Cancer Liver… DOI: http://dx.doi.org/10.5772/intechopen.105906*

registration techniques [180] and MRI motion artifact compensation [174, 181]. Numerous preclinical studies have undertaken new technologies to address respiratory motion and rib interactions [39, 172, 174–176, 180, 182–186]. Previous USgFUS human studies have generally been successful at performing ablation through the ribs; though additional measures have included left lung ventilation with endotracheal intubation and general anesthesia to reduce liver movement, intrapleural effusion, and rib resection [160, 162, 179]. MRgHIFU pilot studies used intermittent sonications, and limited to the treatment to the left liver lobe, in tumor sites not blocked by the ribs [170, 187–189].

Handheld intraoperative HIFU devices under ultrasound-guidance are in development, and being tested in early phase clinical trials for CRLM tumor abla-tion. The technique is similar to intraoperative radiofrequency and microwave ablation, but prevents the need for an intraparenchymal probe. Results have been reported using the device for ablating tissue near tumors in segments prior to surgical resection, to assess accuracy and safety. Applications include reduction of hemorrhaging during surgery and potentially bridging more patients for surgical resection [190–193]. The device was shown capable of in vivo hepatic vessel occlusion for diameters of 2 mm [194], and studies have reported diameters of left hepatic arteries and right hepatic veins between 3 and 4 mm [195].

Several small clinical studies have been reported for MRgHIFU ablation for HCC [170, 187–189, 196, 197]. There is currently an ongoing Phase I clinical trial with MRgHIFU for a variety of pediatric solid tumors, in which hepatic tumors are eligible [198].

In the study from Okada et al. [187], MRgHIFU liver tumor ablation was performed on a single patient. The MRI system utilized respiratory gating and ablation was performed on a 15 mm HCC lesion. The procedure required about two hours to ensure complete coagulation by repeated coverage. Gadolinium contrast agent was administered post-treatment and no increased signal intensity was observed at the tumor site, indicating expected ablation contrast. The authors noted the need for better technology for avoiding bowel loops, ribs, and respiratory liver motion. Though, the patient only complained of slight skin heating discomfort during treatment and was released from the hospital the following day.

Anzidei et al. treated a single HCC patient more comprehensively with MR-FUS [188]. The patient refused surgery and percutaneous ablation, then opted for MR-FUS. The individual had no distant metastases, was treated successfully, and later underwent total liver transplant. Excised liver histopathology showed complete coagulative necrosis with only slight recurrence at the ablation periphery. The investigators noted the procedure can be improved with better respiratory motion control and expected that future applications would use automated feedback algorithms.

Gedroyc conducted a series of pilot studies for MRgHIFU liver tumor ablation [170, 189]. It was reported that the absorption from the ribs was problematic and the treatments were limited to patients with exposed tumor sites, such as below the rib line or in the left lobe of the liver. One case was a female with HCC arising from Hepatitis-B infection. She was previously treated with hepatic arterial chemoembolization and laser ablation. Recurrence occurred with a 1.5 cm HCC lesion in the left lobe within Couinaud segment 3, a position that was not covered by the ribs. The site was ablated with MRgHIFU. In another case, the patient was a male with HCC, Hepatitis-C, extensive cirrhosis, and elevated alpha-fetoprotein levels. He was treated for a 3 cm HCC in the anterior portion of the left liver lobe.
