**9. Nonsurgical treatment of liver metastases of colorectal cancer**

Although surgical treatment ensures the best 5-year survival, only 15–25% of liver metastases are amenable to resection [98]. If surgical treatment is not possible, radiofrequency ablation, cryotherapy, microwave ablation, stereotactic body radiotherapy, radioembolisation or percutaneous alcohol injection canbe used to decrease the tumour burden [101, 102]. Generally, ablation therapies are not recommended for resectable lesions [103].

The liver metastases can be targeted by radiofrequency ablation although the benefits of it are controversial. Positive estimates have been published [104, 105]. However, later data showed that radiofrequency ablation alone or in combination with surgery resulted in inferior survival in comparison with liver resection. The outcome of radiofrequency ablation was only slightly better than the results of chemotherapy [39]. The resulting 5-year survival was around 24% [106–110]. Still later, 5-year survival of 43% has been reported [98]. After the procedure, either local recurrence or new liver metastases can develop. The risk of local recurrence is higher if the lesion is larger than 3 cm: 21.7% vs. 1.6–3.8% [111–113]. The development of new metastases predominates over local recurrence and can be promoted by liver regeneration and production of cytokines [98, 113]. To avoid complications, proximity to bile ducts but not vessels is of utmost importance as the blood vessels are moderately sensitive to heat and can be protected by vascular clamping and Pringle manoeuvre involving alternation of clamping and perfusion. In contrast, bile ducts are very sensitive to heat-induced damage [113].

Radiofrequency ablation belongs to the group of thermal ablation procedures comprising also laser-induced interstitial thermotherapy. In this method, laser light is directly transmit‐ ted to the neoplastic tissue through flexible optic fibres, and the absorption of laser photon energy causes local rise of temperature inducing coagulation necrosis. The results are highly dependent on the completeness of tumour destruction. The 5-year survival after thermal ablation is 44% if the ablation is complete and 20% if it is partial. The frequency of partial ablation ranges from 38% to 52% [114–116]. The size of neoplastic mass is the main predictive factor for the completeness of the ablation, with better results achieved in metastases smaller than 3 cm [116, 117].

Cryoablation involves tissue destruction by low temperature, i.e., intended freezing of the target in order to induce local necrosis. Although percutaneous, laparoscopic or open surgical approach generally is possible, cryotreatment of liver tumours is mostly performed via open surgical access. Occasionally, laparoscopic approach is used [118]. The temperature is de‐ creased by liquid nitrogen or argon gas that is delivered to the target by special probe under US guidance. The freezing is rapid, so the formed ice crystals destroy the cells, including tumour cells. Ice crystals also propagate in the microvessels. The procedure includes alternat‐ ing cycles of freezing and thawing. Multiple masses are treated consecutively rather than simultaneously. Necrosis develops within the next 2 days and is well-demarcated in the third to fourth day after the procedure. Large masses (>5 cm) are not amenable to complete treat‐ ment. Another limitation includes tumours close to large blood vessels [119]. Cryoablation ensures 5-year survival in 17% of patients [109, 120–122].

In microwave ablation, tissue destruction is induced by microwaves. The electrode is inserted in the tumour mass under US or CT guidance using percutaneous, laparoscopic or open surgical access. An alternating high-frequency (900–2450 Hz) electromagnetic field induces vibration of water molecules representing dipoles. The energy created by the induced movement of water molecules is released as heat that results in coagulative necrosis [3]. The method can ensure wider and quicker tissue destruction than radiofrequency ablation. It is not limited by the temperature 100°C, does not rely on the conduction of electricity and is less limited by impedance of the destroyed tissues or scars [123]. The 5-year survival after micro‐ wave ablation was 16% in the older reports [109, 124, 125]. Recently, intraoperative microwave ablation ensured 4-year survival of 35.2% [123] and 3-year survival of 36% [126].

External beam radiation treatment for liver metastases has limited effect due to high sensitivity of hepatocytes towards ionising radiation. Thus, therapeutic radiation doses would induce serious liver damage but small doses lack efficacy. The treatment of liver metastases by external beam radiation is associated with high rate of local recurrence and side effects, both contributing to low survival. Three-dimensional conformal radiotherapy is more targeted. In stereotactic body radiation treatment, a robotic arm is used to target the lesion in synchronisation with the respiratory movements. This allows delivering higher radiation dose to the lesion while retaining appropriate safety profile with only tolerable complications. After stereotactic body radiation treatment, the 1-year survival of complex, pretreated patients with the frequent presence of extrahepatic metastases was 45.5% [110]. The 2-year survival is reported to be 45% [127].

Hepatic arterial infusion can be applied due to the fact that metastases larger than 3 mm receive 95% of blood supply from the hepatic artery. This technique yields higher concentration (up to 16 times higher) of the medication within the metastasis in association with lower systemic toxicity due to concentrated supply and first-pass effect with maximum absorption in the liver. Skilled team and qualitative radiologic imaging are the prerequisites [102]. There are several technically related approaches that also involve direct supply of the therapeutic agent to the target via hepatic artery, such as placement of hepatic arterial infusion pumps, selective internal radiation therapy, drug-eluting bead embolisation and irinotecan-containing drugeluting particles [128].

Although successful surgery can yield long term survival, recurrence develops either in liver or in other distant sites in 60–70% of patients [15]. Therefore, adjuvant systemic chemotherapy, hepatic arterial infusion chemotherapy and molecular targeted therapy represent important adjuncts to surgical treatment. Systemic chemotherapy results in significantly better survival [129, 130] but can cause systemic adverse effects along with vascular liver damage and steatosis [131]. Hepatic arterial infusion of specific chemothera‐ peutic agents has the benefits of directly targeting the metastasis within liver and thus causing less systemic toxicity. However, biliary tract damage can follow [132, 133]. Monoclonal antibodies against VEGF and EGFR are attractive by the targeted mechanism [101, 134]. However, bevacizumab, cetuximab and panitumumab have also caused controversies regarding liver metastases of colorectal cancer [13].

### **10. Radiologic evaluation before nonsurgical treatment**

Cryoablation involves tissue destruction by low temperature, i.e., intended freezing of the target in order to induce local necrosis. Although percutaneous, laparoscopic or open surgical approach generally is possible, cryotreatment of liver tumours is mostly performed via open surgical access. Occasionally, laparoscopic approach is used [118]. The temperature is de‐ creased by liquid nitrogen or argon gas that is delivered to the target by special probe under US guidance. The freezing is rapid, so the formed ice crystals destroy the cells, including tumour cells. Ice crystals also propagate in the microvessels. The procedure includes alternat‐ ing cycles of freezing and thawing. Multiple masses are treated consecutively rather than simultaneously. Necrosis develops within the next 2 days and is well-demarcated in the third to fourth day after the procedure. Large masses (>5 cm) are not amenable to complete treat‐ ment. Another limitation includes tumours close to large blood vessels [119]. Cryoablation

In microwave ablation, tissue destruction is induced by microwaves. The electrode is inserted in the tumour mass under US or CT guidance using percutaneous, laparoscopic or open surgical access. An alternating high-frequency (900–2450 Hz) electromagnetic field induces vibration of water molecules representing dipoles. The energy created by the induced movement of water molecules is released as heat that results in coagulative necrosis [3]. The method can ensure wider and quicker tissue destruction than radiofrequency ablation. It is not limited by the temperature 100°C, does not rely on the conduction of electricity and is less limited by impedance of the destroyed tissues or scars [123]. The 5-year survival after micro‐ wave ablation was 16% in the older reports [109, 124, 125]. Recently, intraoperative microwave

External beam radiation treatment for liver metastases has limited effect due to high sensitivity of hepatocytes towards ionising radiation. Thus, therapeutic radiation doses would induce serious liver damage but small doses lack efficacy. The treatment of liver metastases by external beam radiation is associated with high rate of local recurrence and side effects, both contributing to low survival. Three-dimensional conformal radiotherapy is more targeted. In stereotactic body radiation treatment, a robotic arm is used to target the lesion in synchronisation with the respiratory movements. This allows delivering higher radiation dose to the lesion while retaining appropriate safety profile with only tolerable complications. After stereotactic body radiation treatment, the 1-year survival of complex, pretreated patients with the frequent presence of extrahepatic metastases was 45.5% [110].

Hepatic arterial infusion can be applied due to the fact that metastases larger than 3 mm receive 95% of blood supply from the hepatic artery. This technique yields higher concentration (up to 16 times higher) of the medication within the metastasis in association with lower systemic toxicity due to concentrated supply and first-pass effect with maximum absorption in the liver. Skilled team and qualitative radiologic imaging are the prerequisites [102]. There are several technically related approaches that also involve direct supply of the therapeutic agent to the target via hepatic artery, such as placement of hepatic arterial infusion pumps, selective internal radiation therapy, drug-eluting bead embolisation and irinotecan-containing drug-

ablation ensured 4-year survival of 35.2% [123] and 3-year survival of 36% [126].

ensures 5-year survival in 17% of patients [109, 120–122].

186 Recent Advances in Liver Diseases and Surgery

The 2-year survival is reported to be 45% [127].

eluting particles [128].

In general, the metastatic process must be characterised similarly as before the operation. If ablation is planned, the relation between the metastasis and the intrahepatic bile ducts and vessels must be carefully established to avoid heat-induced damage [1]. If the medical centre has the necessary skills to provide hepatic artery infusion with chemotherapeutic agents for neoadjuvant therapy to decrease lesion size and allow resection, for adjuvant for treatment after resection or treatment of unresectable liver disease, hepatic artery must be visualised by CT angiography [18].

### **11. Radiologic assessment of the treatment outcome**

Classically, the tumour response to treatment is measured by decrease of the tumour mass diameter as defined by the Response Evaluation Criteria in Solid Tumours (RECIST). The RECIST criteria, described in 2000 and refined in 2009 [1, 135, 136], necessitate one-dimensional measurements to detect the sum of maximal diameter of five lesions. The relative difference of this parameter before and after treatment is interpreted as follows: progressive disease, increase of at least 20% and at least 5 mm in the sum, or appearance of a new lesion; stable disease, lack of dynamics or changes within the borders between progressive disease and partial response; partial response, decrease for at least 30%; and complete radiologic response, disappearance of all lesions. It must be emphasised that radiologic complete response is not always equivalent to pathologic complete response; therefore, all the responded lesions still must be removed surgically [17]. Several controversies exist regarding RECIST criteria. First, it is suggested that early response for 10% correlates with the outcome better than the border of 30% [17, 137]. Further, not only size but also the composition of the mass lesion matters as it can include not only viable tumour but also necrosis, fibrosis, granulations or haemorrhage. By ablation techniques, the surrounding liver tissue is intentionally damaged and fuses together with the metastatic mass. After intra-arterial treatment by chemotherapy, drugeluting beads, irinotecan drug-eluting beads or radio embolisation, the response evaluation is confounded by haemorrhage, necrosis resulting in size enlargement, peripheral thin rim of granulation tissue mimicking metastasis, fibrosis, peritumoural ischemia or hepatitis [1]. Therefore, the evaluation of treatment response includes not only the changes in the lesionsize, but also its morphology and functional status [17].

Morphologic radiologic features, including changes in tumour heterogeneity and internal structure, enhancement and margins, can indicate favourable tumour response to treatment [138]. On CT, CRC metastases in the liver have heterogeneous structure and ill-defined margins. Responding lesions obtain homogeneous structure and outlined margins [17]. The morphologic response on CT correlates with pathologic response and with the survival [138].

PET-CT characterises the metabolic activity in the lesions [1], suggesting pathogenetically substantiated accurate estimate of tumour response. However, the sensitivity of PET decreases after chemotherapy [17]. Clinically importantly, PET can identify lack of chemotherapy efficacy just after 1 cycle [139].

Preceding treatment can induce not only tumour shrinkage but also liver parenchymal damage. By CT, steatosis that affects more than 30% of parenchyma can be diagnosed by the liver attenuation index characterising the difference in the attenuation between liver and spleen. By MRI, the analysis of water and fat proton signals is possible, leading to more accurate estimates of steatosis than by CT and US [1, 140]. Sinusoid obstructive syndrome can be caused by oxaliplatin-based chemotherapy. It is characterised by sinusoidal injury that may lead to fibrosis or veno-occlusive disease. The radiologic findings are nonspecific [1].
