In recent years, with the development of multidisciplinary approaches, advances in surgical techniques, and the emergence of new chemotherapeutic agents, liver metastases from colorectal cancer have been recognized as potentially curable diseases. In this article, we will discuss the related methods in the treatment of liver metastasis from colorectal cancer.
I. Surgical treatment
(Although the survival of patients with liver metastases from colorectal cancer has been prolonged with the update of chemotherapeutic drugs, and some patients even have complete response (CR), it is impossible to achieve a cure by chemotherapy alone. The median survival of patients with radical resection of liver metastases can reach 35 months, and the 5-year survival rate can reach 30%-50% (1). 2010 Chinese guidelines for the treatment of liver metastases from colorectal cancer have clearly put forward the following indications for the surgical treatment of liver metastases from colorectal cancer
( 1 ) The primary site of colorectal cancer can be or has been radically resected.
( 2 ) The liver metastases can be completely resected (R0) according to the anatomical basis of the liver and the scope of the lesion, and it is required to retain sufficient liver function with 30% to 50% of the residual volume of the liver.
( 3 ) The patient’s general condition allows for the absence of unresectable extrahepatic metastatic lesions.
With the advancement of surgical techniques, the surgery for patients with liver metastases from colorectal cancer is no longer restricted by the size, number, location, distribution and surgical margins of extrahepatic metastases of metastases. In addition, patients with unresectable liver metastases should be resected as soon as possible if the metastases are resectable after preoperative conversion therapy. Patients whose liver metastases “disappear” after neoadjuvant chemotherapy still need surgical resection.
Non-surgical treatment
1.Chemotherapy
Systemic chemotherapy is the standard treatment to improve the survival rate, reduce tumor-related symptoms and improve the quality of life of patients with liver metastases from colorectal cancer. 5-FU has been the basic drug for systemic chemotherapy for patients with unresectable liver metastases for the past 40 years. 5-FU as monotherapy can extend the median survival by 8-11 months (3). The advent of new oral agents, capecitabine and S1, has made fluorouracil-based agents more accessible and strengthened their position as foundational agents. Fluorouracil combined with oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI ) has resulted in response rates of 30% to 56% and mean survival of 18 to 21 months. These treatment options have become the current mainstream treatment (4-6). Even as second-line agents, combination chemotherapy can prolong survival by up to 12 months (7). The neurotoxicity of oxaliplatin and the diarrhea-causing effects of irinotecan often limit the drug dose and sometimes force the termination of treatment (6,8).
2.Targeted therapy
The targeted drugs used in clinical treatment are bevacizumab, cetuximab and panitumumab. Bevacizumab, a human monoclonal antibody against VEGF, is used as a first- or second-line treatment in combination with chemotherapy to prolong disease-free survival. Bevacizumab in combination with fluorouracil tablets and irinotecan (as first-line therapy) or with FOLFOX (as second-line therapy) prolongs overall survival compared with chemotherapy alone (9). Cetuximab and panitumumab treatment is dependent on K-ras gene expression (10). Cetuximab used in first-line therapy improves overall survival with monotherapy compared with FOLFIRI alone (10,11). First-line treatment studies have confirmed a mean overall survival of nearly 2 years in patients with metastatic bowel cancer (12). Second-line treatment averages survival up to 13 months (13). Panitumumab is limited to third-line therapy. A common side effect of cetuximab and panitumumab is skin damage. Common side effects of bevacizumab are hypertension, arterial embolism, proteinuria, and interference with wound healing (9).
3. Local treatment
Hepatic artery embolization and perfusion chemotherapy
Hepatic artery infusion (HAI), which includes temporary cannulation through the hepatic artery and repeated administration through a permanent cannula, has a complication rate of up to 57%, including bleeding, infection, hematoma, tethered ischemia, and hepatic artery occlusion (14,15), with no associated deaths (16). Hepatic artery perfusion (HAI) as local chemotherapy in combination with systemic chemotherapy did not have much effect on disease progression (17-19). There is also no significant overall survival advantage (20,21), and local chemotherapy is expected to decrease as more effective systemic chemotherapeutic agents become available. Transarterial chemoembolization (TACE): this treatment has been reported to benefit 80% of patients (22,23), with mean survival ranging from 9 to 62 months with therapeutic dosing (22). A recent study reported its two-year survival rate of 28% as second-line treatment (24).
Ablative techniques for treatment
Ablation techniques include thermal ablation, radiofrequency ablation (RFA), laser-induced thermal therapy (LITT), microwave therapy, high-intensity aggregated ultrasound therapy, and cryotherapy.
(1) Thermal ablation method
Thermal ablation is generated by thermal energy waves through the liver tissue, resulting in necrosis by increasing the tissue temperature. Irreversible cellular damage occurs when the cellular temperature reaches 42-45°C for 30-60 minutes. The in situ ablation technique requires a thermally safe range of approximately 0.5-1 cm around the metastases to reduce the possibility of tumor recurrence (25).
(2) Radiofrequency ablation (RFA)
Radiofrequency ablation is widely used and its clinical therapeutic value has been widely recognized. The treatment is performed with a radiofrequency needle pierced into the center of the metastasis as an electrode with 15-50 watts of power and 350-480 Hz of alternating current, and the current causes the tumor cell tissue ions to vibrate, resulting in frictional heat so that the local temperature can rise to 100°C, leading to coagulation necrosis and irreversible tissue damage. Common complications include fever, pain, pulmonary complications (e.g., pleural effusion, pneumothorax), liver failure, liver abscess, bleeding due to vascular or biliary tract injury, bile leak, and gastrointestinal perforation (26). Data show that RFA treatment has a survival rate of 78% at one year, 64% at two years, and 25% at three years (27-29). Radiofrequency ablation combined with systemic chemotherapy has a 5-year survival rate of up to 30% (30,31).
(3) Laser-induced thermal therapy (LITT)
Quartz crystal fibers with a diameter of 400-600 microns are placed into the metastases, and a laser with a wavelength of 800-1064 nm is used to produce a local thermal effect to destroy the metastatic cells. The incidence of complications is approximately 7.5% and includes pleural effusion, pneumothorax, liver abscess, biliary hemorrhage, cholangitis, liver hematoma, bradycardia, pulmonary embolism, fever, and pain. the mortality rate within 30 days is approximately 0.1% (32,33). Local control of the tumor can be achieved in 97% of patients treated (34-36).
(4) Microwave ablation therapy (MWA)
The 900 MHz frequency microwave stirs the water molecules of the tissue to produce heat leading to coagulative necrosis. A coagulative ablation zone of 2 cm can be produced in 1 minute with high energy of 70-90 watts (37). Compared to RFA, microwave ablation produces higher heat within the tumor, shorter treatment time, and more complete tumor inactivation (38). Complications of microwave therapy include asymptomatic pleural effusion, liver abscess, intra-abdominal hemorrhage, tumor implantation, and bile duct stricture (39,40). There are data confirming a three-year survival rate of up to 51% and a five-year survival rate of 32% with microwave therapy (41-43). Compared with chemotherapy alone, microwave therapy combined with hepatic artery perfusion or systemic chemotherapy can significantly improve the survival of patients with unresected liver metastases (44,45).
(5) High-intensity aggregated ultrasound therapy
High-intensity aggregated ultrasound is an innovative technique used for the in vitro treatment of various tumors such as prostate cancer and kidney cancer. It can raise the tissue temperature to 60°C, leading to coagulative necrosis of tumor cells, and its mechanical effect helps to destroy tumor cells in addition to the temperature increase (46). Liver tissue changes such as fatty liver or liver fibrosis are not suitable for this treatment because high-intensity aggregated ultrasound treatment may lead to excessive cellular damage (47).
(6) Cryotherapy
Cryotherapy is the use of liquid nitrogen or argon to bring the tumor tissue to -180°C. Ice crystals are formed inside the cells to mechanically damage the tumor cells, and the tissue at the edge of the ablation zone is destroyed due to dehydration and small vessel blockage. The complication rate of treatment is about 30%, including bleeding, biliary tract infection, liver abscess, pneumonia, transient transaminase elevation, thrombocytopenia, and renal failure. The mortality rate is in the range of 1.5%-4% (48,49). The risk of cold shock is increased if more than 35% of the liver tissue is treated (48,50). Systemic disturbances induced by cytokines can occur, such as fever and tachycardia, shortness of breath, and ARDS and DIC and renal tubular necrosis can occur. Cryosurgery of the liver has a three-year survival rate of 44% and a five-year survival rate of 26% (51-53). The use of this treatment has decreased due to the high rate of local recurrence and complications.
IV. Radiation therapy
External irradiation therapy
External radiation therapy includes conformal radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, proton radiotherapy, heavy ion radiotherapy and brachytherapy. External irradiation is a non-invasive treatment option for patients who are not suitable for surgery or ablative treatment. In the past, this treatment was not very useful mainly because whole liver irradiation was poorly tolerated and the surrounding adjacent tissues were sensitive to radiation and easily damaged. Advances in irradiation technology have made local irradiation of liver metastases safer, including conformal irradiation, image guidance, stereotactic and respiratory motion management. Proton beam irradiation is currently in phase I clinical trials.
(1) Whole liver radiotherapy
It is mainly used for patients with localized painful liver metastases, and its most serious complication is radiation liver disease, which often occurs 3 months after treatment (54), with clinical presentation without jaundiced hepatomegaly, ascites, and elevated transaminases. The effect of whole liver radiotherapy combined with chemotherapy is better than that of radiotherapy alone (55,56).
(2) Stereotactic radiotherapy (SBRT)
That is, 4D treatment, which can achieve a high level of quality assurance such as image guidance, precise positioning, and conformal dose distribution. Phase I and II clinical trials have demonstrated that this treatment can achieve good local tumor control and long-term survival of patients (57-59). SBRT can safely treat liver metastases from intestinal cancer with doses above 47 Gy to control local lesions, but the optimal dose is not clear (57,60). there are complications associated with SBRT.
(3) Brachytherapy with interstitial tissue insertion
The use of iridium-192 as a radiation source for brachytherapy is a highly specialized method of liver radiotherapy that can be performed at only a few centers worldwide. The treatment effect is similar to that of laser-induced thermotherapy (61).
Selective internal irradiation (SIRT)
As a nuclear medicine method, it is a combined application of radiotherapy and embolization, where millions of radioactive microparticles are implanted through the hepatic artery cannula to block small branch vessels of the hepatic artery to reduce the blood supply to the tumor. SIRT is currently used as third and fourth line therapy for patients with unresectable multiple liver metastases. Phase II clinical trials have shown that the combination with chemotherapy significantly prolongs overall survival.