Colorectal cancer (CRC) in combination with liver metastases is common. Unlike other tumors that develop liver metastases, CRC liver metastases can occur early in the disease and may be confined to the liver. 20%-35% of patients have liver as the only site of metastasis [1]. The treatment of CRC liver metastases includes surgery, chemotherapy, local physical methods, biological and Chinese medicine treatments, etc. This paper reviews the current status of treatment of CRC liver metastases.
1.Surgical treatment of CRC liver metastases
It was originally thought that liver metastasis was the result of advanced hematologic dissemination of cancer, so once liver metastasis appeared, whether it was simultaneous or heterochronic, it meant that it was incurable and lost the chance of treatment. This current therapeutic understanding has now been disproved by many RCT findings [4]. Unlike liver metastases from other tumors, CRC liver metastases, whether concurrent or heterochronic, are often the only organ of metastasis, often isolated in 30-60% of patients, and extrahepatic metastases without liver metastases are rare. Surgical resection is the treatment of choice for the radical treatment of CRC liver metastases. Comprehensive data from recent studies show that surgery is the radical method for CRC liver metastases, and the 5-year survival rate after surgery is 24%-40.5%, but the resection rate is only 15%-25% [3, 5-9]. patients with CRC liver metastases mostly have no primary lesions in the liver and good liver function reserve, so they can have more resection margins, and their results are better than primary liver cancer. The hepatic segment concept has brought an anatomical revolution in liver resection, not only allowing the resection of liver lesions previously considered unresectable, but also preserving as much normal liver as possible. The new view is that the indications for hepatic resection are mainly determined by the feasibility of surgical resection, which will be further expanded with the development and application of new techniques [10]. There are many specific incision methods, and the results of applying the Pang multifunctional dissector, argon knife, and ultrasonic knife are reliable. The application of hepatic blood flow blocking technique is important to reduce intraoperative blood loss and cancer recurrence, and this technique includes selective hepatic blood flow blocking, whole liver blood flow blocking, hemi-hepatic and whole liver into hepatic blood flow blocking [11]. With the increasing refinement of surgical techniques and enhanced perioperative management, the operative mortality and complication rates have been significantly reduced.
1.1 Case selection and surgical approach Clinical indications for surgery of liver metastases are generally considered as long as the patient can tolerate surgery, the primary site has been eradicated, and radical resection of liver metastases is possible. The absolute contraindications for liver resection for colon cancer liver metastases are patients with concomitant extrahepatic metastases or liver metastases that cannot be completely resected, including hilar lymph node metastases, concomitant extrahepatic tumors and intrahepatic tumors greater than four [12, 13]. However, it has been suggested that the number of intrahepatic metastases greater than four should not be a contraindication to surgery, and many studies have reported no significant difference in survival after surgical resection of single and multiple intrahepatic metastases with complete resection [14-17], and the number of lesions is not a contraindication to resection of liver metastases in CRC. In addition to this, relative contraindications include local recurrence, concomitant pulmonary metastases, or direct invasion of other organs.
The surgical approach for liver metastases can be based on the location, size, and number of metastases by choosing irregular wedge resection or hepatic segmental or lobectomy, etc. In principle, the surgery should emphasize the radical nature of the surgery and the absence of cancer residue at the cut edge. As for anatomical resection (standard lobectomy, segmental resection) or non-anatomical resection (wedge resection, excision, etc.), there is no definite conclusion yet, as long as the resection margin reaches more than 1 cm and at least 30% of normal liver tissue is preserved, it is not necessary to be demanding if it is close to large blood vessels. The extent of resection should not be expanded indefinitely to avoid increasing surgical morbidity and mortality. The extent of safe margins is controversial, but Elias et al [18] reported that the 5-year survival rates for those with surgical margins >1.0 cm, ≤1.0 cm and positive margins were 42%, 25% and close to 0, respectively, so adequate margins should be left as much as possible. Therefore, as long as R0 resection can be obtained by surgery and sufficient residual liver function can be ensured, liver metastasectomy can be considered as the only possible means to obtain a radical cure. Intraoperative ultrasonography helps to detect metastases that were not detected preoperatively, facilitates complete resection of the lesion, reduces omissions, and helps to understand more clearly the relationship between the metastases and the hepatic vessels, making the operation safer and leaving adequate margins.
Recurrence is possible in 55%-80% of patients after resection of CRC liver metastases, of which 15%-40% are isolated liver recurrences. The outcome, surgical safety and prognostic factors of reoperation are similar to those of initial liver metastasectomy. Recurrence without treatment has a poor prognosis, with a median survival of only about 4 months. yamamoto et al [19] reported that in 90 reoperative patients (75 in 2, 12 in 3, and 3 in 4) after second liver metastasectomy, the 3-year survival rate was 48% and the 5-year survival rate was 31%, and 73% of patients had recurrence after surgery, of which 40% had liver-only recurrence; third liver The 5-year survival rate after metastasectomy was 37.9%, with no surgical death and a surgical complication rate of 15%. The prognosis was poor in those with more than 4 metastases, extrahepatic metastases, lymph node metastases, and residual tumor from surgery.Imamura et al [20] reported that 22 patients with recurrent reoperation had a median time between 2 operations of 16 months, a surgical mortality rate of 0, a complication rate of 18%, a median follow-up of 25 months, 2-, 3-, and 5-year survival rates of 73%, 59%, and 22%, recurrence-free survival rates of 26%, 19%, and 19%, and a median survival of 44 months. Those with liver recurrence only had a 2-year survival rate of 70% and a 5-year survival rate of 31%. Therefore, if there is no clear contraindication to surgery, the recurrent foci should be re-excised if possible. In cases involving the hepatic veins or bilateral portal trunks, surgery, although resectable, should be a contraindication to surgery.
1.2 Timing of surgery Some investigators [21] advocate second-stage surgery to remove liver metastases for the following reasons: first, the surgical incisions are different between the two, and first-stage resection is often unsatisfactory in terms of exposure; second, intestinal resection and abdominal contamination can cause abdominal and subdiaphragmatic infections; third, the hemodynamic changes caused by vascular blockade and portal hypertension have a great impact on digestive system function; in addition, after 2-3 months, the metastatic lesions In addition, after 2-3 months, the biological characteristics of metastatic lesions are more obvious, and extrahepatic metastases as well as intrahepatic metastases can be ruled out after the second-stage surgery, which can achieve the purpose of radical treatment and avoid unnecessary surgery with multiple lesions in a short period of time. Most scholars believe that primary cancer and liver metastases should be resected at the same time if they can be resected simultaneously to reduce the tumor load. Some scholars [3] believe that if liver metastases are found at the same time, the primary foci and metastases should be resected together if the situation allows. The difficulty lies in the surgical treatment of the primary foci, if the metastases are not found preoperatively but are found intraoperatively, it is more difficult to decide whether to remove them together. Robert, Capussotti et al [22, 23] reported that there was no significant difference in survival rates at 1, 3, and 5 years between simultaneous and non-simultaneous surgical resections, and there was no increase in complications, but more information needs to be accumulated.
Some CRC multiple liver metastases are not suitable for primary resection because sufficient normal liver tissue cannot be left after resection to maintain normal liver function, and the major liver metastases can be removed as much as possible at the first surgery, and the remaining metastases can be resected after a period of liver tissue regeneration and compensation + chemotherapy, which can give some patients a chance of long-term survival.Adam et al [24] reported that 16 cases of multiple liver metastases that were not suitable for primary patients with multiple liver metastases that were not suitable for complete resection (12 of whom received systemic chemotherapy, including 5-FU + CF + oxaliplatin chemotherapy regimen, before the first surgery) were given chemotherapy 3 weeks after the first partial resection of liver metastases to control residual tumor growth. The timing of the second metastasectomy depends on the degree of liver regeneration and liver function, chemotherapy control of the residual tumor, and the likelihood that the second surgery will result in curative resection. The median interval between the two surgeries was 4 months (2-14 months), among which 3 cases were not suitable for second liver resection due to disease progression, and 13 cases underwent second-stage metastasectomy with a perioperative mortality rate of 0 and a 3-year survival rate of 35% after second-stage surgery, among which 4 cases had survived disease-free for 7, 22, 36, and 54 months, respectively, at the final follow-up.
1.3 Factors affecting prognosis There are many factors affecting the outcome of treatment after surgery for CRC liver metastases, and there is much controversy. These include the coexistence of primary and metastatic foci, size and number of liver metastases, Dukes stage of primary foci, primary foci with multiple lymph node metastases, interval between detection of liver metastases and primary resection, whether re-liver metastases or extrahepatic metastases occur, distance of cut margin from tumor/positive cut margin, blood CEA value, mode of surgical resection, and amount of perioperative blood transfusion [25-27]. In the past, it has been considered as an important poor prognostic factor when there are more than 3 or 4 liver metastases that cannot be treated surgically, but now this factor has been confirmed by most studies that it is not a poor prognostic factor, and the cutting edge condition has become a more important prognostic factor. The ideal margin is more than 1 cm from the metastasis, but this is often technically difficult to achieve. Nakamura et al [28] analyzed the prognostic factors in 79 patients undergoing surgery for CRC liver metastases and found that the 5-year and 10-year survival rates were 37% and 21%, respectively, for patients with margins 0.1-0.9 cm from the tumor, compared with 43% and 28%, respectively, for patients with margins >1 cm from the tumor. Cady et al [29] reported that the postoperative recurrence rate was twice as high for patients within 1 cm of the tumor as for those more than 1 cm away.
The presence of hilar lymph node metastases is usually considered an important poor prognostic factor and an absolute contraindication to surgery. beckurts et al [30] reported that in 129 patients with CRC liver metastases who underwent resection of liver metastases combined with hilar lymph node dissection, the 5-year survival rate was 0% for those with positive lymph nodes and 22% for those with negative lymph nodes. Therefore, patients with hilar lymph node metastases are not suitable for hepatic metastasectomy.
Some other risk factors affecting prognosis include: (1) presence of significant advanced tumor symptoms; (2) elevated preoperative CEA; (3) presence of peripheral satellite metastases (multiple fine metastases 2 cm around the primary metastases); and (4) appearance of liver metastases from disease less than 12 months after resection of the primary site [31]. In most studies of CRC liver metastases, these prognostic factors have basically achieved consensus, and different grading systems have been developed based on these factors to classify patients with liver metastases into high-risk and low-risk patients, whose 5-year postoperative survival rates are about 14% and 40%, respectively, and these grading systems provide some reference value for the selection of surgical cases of liver metastases from intestinal cancer and the design of clinical trials [32].
2. chemotherapy for CRC liver metastases
2.1 Neoadjuvant chemotherapy and surgery Surgery is the radical treatment for CRC liver metastases, but the resection rate is only 15-25% [3, 5-9]. With the advent of new chemotherapy regimens, the efficiency of chemotherapy has been increasing. As mentioned above, preoperative neoadjuvant chemotherapy can make some previously unresectable liver metastases operable, shrink previously resectable lesions to ensure adequate margins, reduce parenchymal resection and maximize preservation of liver function, and may also eliminate microscopic intrahepatic metastases and provide the best regimen for postoperative chemotherapy as preoperative drug sensitivity screening. The resectability assessment of surgery after neoadjuvant chemotherapy in patients with inoperable CRC liver metastases is mostly the result of retrospective studies and there is a lack of large-scale prospective studies.Adam [23] meta-analysed 701 patients with inoperable CRC liver metastases treated with systemic chemotherapy between 1996 and 2001, of whom 95 (13.6%) were able to undergo radical surgery after chemotherapy, with a The 5-year postoperative survival rate was 34.0%. Although prospective clinical trials are still lacking, it is widely accepted that liver metastasectomy after chemotherapy in patients with CRC liver metastases offers a chance of cure, and physicians should be careful to assess the efficacy of metastasis treatment during chemotherapy and continuously evaluate surgical resectability.
Chemotherapy regimens for CRC liver metastases are evolving as new and more effective chemotherapeutic agents become available, such as OXA, CPT-11, epirubicin, and irinotecan. In the past 30 years, the chemotherapy regimen of 5-FU±CF was the only choice for CRC and metastatic CRC, but its efficiency was only about 20%; the results of several phase III clinical trials revealed that OXA combined with 5-FU/CF and CTP-11 combined with 5-FU/CF had significantly higher efficiency than 5-FU/CF alone in liver metastases from intestinal cancer (56% vs. 25% ) [21 ]. The application of these new chemotherapy regimens has enabled more patients with liver metastases to be cured by neoadjuvant chemotherapy with a chance of reoperation.Tournigand et al [33] compared 220 patients with liver metastases from intestinal cancer treated with FOLFOX and FOLFIRI sequentially, respectively, and found no significant difference between FOLFOX and FOLFIRI as neoadjuvant chemotherapy regimens. A study by Goldberg et al [34], on the other hand, confirmed the higher efficiency of the FOLFOX regimen compared to the IFL regimen in neoadjuvant chemotherapy (45% vs. 31% ).
Despite the high efficiency of first-line chemotherapeutic agents in CRC liver metastases, the prognosis is poor when chemotherapy is ineffective to receive second-line chemotherapy, with a median survival time of 8-12 months and an efficiency rate of less than 20%, and patients are unlikely to be surgically resected if they have to receive second-line regimens of chemotherapy. Therefore, it is now considered that patients who are not effective with first-line chemotherapy regimens using chemotherapy regimens are no longer considered to achieve operability with second-line regimens. The emergence of biotherapeutic agents such as bevacizumab (Bev-acizumab) and Cetuximab in recent years has also achieved remarkable results in palliative chemotherapy for CRC liver metastases, but it has not been reported in preoperative neoadjuvant chemotherapy for intestinal cancer liver metastases in China yet, and further studies are needed.
2.2 Intraoperative chemotherapy Currently, intraoperative chemotherapy is highly valued by surgeons [35-36] for three reasons: (1) CRC is most prone to liver metastasis, abdominal implantation and anastomotic recurrence, which are related to intraoperative microscopic dissemination, and if anticancer drugs can be applied intraoperatively to kill microscopic lesions or shed cancer cells at that time, postoperative metastasis and recurrence can be prevented or reduced; (2) intraoperative chemotherapy will not delay the surgical arrangement or affect postoperative recovery; (3) intraoperative (3) intraoperative chemotherapy takes less time and has few side effects with the methods currently used. Therefore, many surgeons are happy to administer adjuvant chemotherapy intraoperatively. The main methods are: intestinal chemotherapy, abdominal chemotherapy and portal vein chemotherapy.
2.3 Postoperative adjuvant chemotherapy The study of CRC micrometastases has provided a theoretical basis for postoperative chemotherapy. Micrometastases generally refer to tiny foci of tumor cells that spread and survive in the lymphatic system, blood circulation, bone marrow, liver, lung and other tissues and organs during the development of non-hematological malignant tumors, which often have no clinical manifestations and are difficult to be detected by conventional examination methods such as CT, MRI, monoclonal radiography and general pathological examination. In recent years, it has been found that early CRC can have distant metastases, and the dissemination of cancer cells during surgery can be directly observed with the help of in vivo microscopic television system, especially among Duke′s stage B patients with “no lymphatic metastases”, nearly 30.0% died of local recurrence or distant metastases within 5 years, suggesting the existence of micrometastases in the lymphatic system or the whole body [ 37-38]. Therefore, for CRC liver metastases belonging to Duke′s stage D, surgical resection minimizes the tumor load as much as possible, while regional and systemic chemotherapy can kill systemic micrometastases and prolong survival.
The physiologic cycle chemotherapy approach for CRC liver metastases developed in recent years is more pharmacokinetic, less toxic and more effective than ordinary continuous chemotherapy, and is a promising chemotherapy modality [39-40]. Recently OXA has been used in combination with 5-FU and CF using conventional dosing regimens to improve the efficiency of treatment. Based on the results of clinical studies of OXA in platinum formulations, where the effective dose and toxicity varied with the time of day of administration, a time-adjusted regimen was designed for administration (OXA 25 mg/(m2?d) administered from 10:00 am to 10:00 pm with a peak at 4:00 pm, CF 300 mg/(m2?d) with 5-FU 600 mg/(m2?d) administered from 10:00 pm to 10 :00 am, peaking at 4:00 am, for 5 days in cycles of 21 days), reduced the neurotoxicity of platinum, while allowing higher doses of 5-FU with less mucosal toxicity, thus further improving efficiency and patient tolerance, with severe gastrointestinal reactions reduced from 89% to 18%, mucosal toxicity reduced by 5-fold, peripheral sensory neuropathy reduced by half, and efficacy improved from 29 percent to 51 percent [41].
2.4 Transarterial interventional therapy (TAIT): hepatic artery infusion chemotherapy (HAI), hepatic artery embolization therapy (HAE) Over the past two decades, TAIT has developed rapidly and has become a new branch of medicine. With the advancement of technology and the updating of materials, selective arterial cannulation can now reach almost any site with relatively improved efficacy and decreased toxic side effects, and is the main local treatment for liver tumors that cannot be surgically resected, and is recognized as the preferred method for non-surgical treatment of CRC liver metastases. It can significantly improve the postoperative survival rate and reduce the recurrence of CRC liver metastatic cancer.
Hepatic metastatic cancer is supplied with blood from the hepatic artery [42-44], and normal liver tissue is mainly supplied with blood from the portal vein, and the liver obtains higher drug concentrations and lower systemic toxicity locally after transhepatic arterial pumping of drugs. Super-selective cannulation via the hepatic artery and direct infusion of high-dose chemotherapeutic drugs into the hepatic lobar (segmental) arteries where the tumor is located can reduce the chance of drug binding to plasma proteins in the blood, thus greatly improving the efficacy.
The clinical efficacy of hepatic artery chemoembolization is more advantageous than that of hepatic artery infusion chemotherapy alone. With HAI therapy, the local tissue drug concentration in the liver can reach 100-400 times the systemic concentration, while the drug concentration in the tumor area is 5-20 times higher than that in normal liver tissue [45], and the chemotherapeutic drugs injected through the artery can also re-enter the body circulation and have an effect on clinical or subclinical metastases throughout the body. It can also flow into the tumor site again through venous reflux to play a secondary chemotherapeutic role [46] and reduce the systemic toxic effects of chemotherapeutic drugs, which is the treatment of choice for patients with CRC liver metastases that cannot be surgically resected. The more commonly used embolic agents include iodinated oil, gelatin sponge, collagen, starch, polyethylene particles or spring steel rings. Chemotherapeutic agents commonly used include 5-FU, MMC, EPI/THP, and DDP/OXA. It has been newly reported [47] that continuous arterial perfusion with OXA-containing regimen is safe and effective in the treatment of metastatic hepatocellular carcinoma. The iodinated oil used for embolization enters the tumor blood vessels with blood flow and aggregates, and stays in the tumor tissues for a long time, completely embolizing the blood vessels and causing ischemic necrosis of the tumor tissues; meanwhile, iodinated oil is also a good carrier to load the drugs into the tumor area, so that the high concentration of chemotherapeutic drugs can act on the cancer cells for a long time, thus achieving better therapeutic effects.
The Cancer Hospital of the Chinese Academy of Medical Sciences, Shanghai Zhongshan Hospital and Nanjing PLA Hospital 81, in order to further improve the local action time of antitumor drugs in liver tumors, have jointly done a clinical study of magnetically adsorbed adriamycin (MTC-DOX) for the treatment of primary liver cancer that cannot be surgically resected [48]. Magnetic particles are tiny particles composed of iron and carbon, and when adriamycin is added to the magnetic particles, adriamycin adsorbs to the carbon in the magnetic particles, while the iron in the particles is magnetic and can immobilize the adsorbed adriamycin in the specific tumor site by an external high magnetic field. Once the MTC-DOX is retained in the tumor area, the adriamycin adsorbed on the magnetic particles enters the tumor tissue through the vascular wall and acts off the magnetic particles on the tumor cells, thus providing a more effective treatment for patients with CRC liver metastases. The results of the clinical study showed that the patients tolerated well, no obvious toxic side effects, most of the patients had no detectable adriamycin in the serum, and the recent clinical efficacy was remarkable. 13 patients were treated in Cancer Hospital of Medical Academy of Sciences, and the recent efficiency reached 46.2% (including pathological CR 23.1% and PR 23.1%), and the long-term efficacy is still under observation.
2.5 Portal vein infusion chemotherapy (PVI) Recent studies [49-51] have demonstrated that tiny metastases (diameter <0.05 mm) and tumor margins in the liver are mainly supplied by the portal vein; also, the growth of liver tumors can cause arterial occlusion, which is more effective when administered via the portal vein, and the portal vein blood supply will be significantly increased after hepatic artery embolization [52]; this provides a theory for treatment via PVI after radical CRC surgery to prevent and early treatment of CRC liver metastases after radical CRC surgery provides a theoretical basis. Wei Xiaogang [53] demonstrated in a group of case studies using PVI treatment after simultaneous resection of liver metastases from colon cancer that it could significantly improve the efficacy and prolong the survival.
3. Biological treatment of CRC liver metastases
3.1 Immunotherapy Immunotherapy is mainly used for progressive cancer in which other therapies are ineffective. Levamisole is a non-specific immunomodulator and is often used in combination with 5-FU. In a clinical phase I-II trial of preoperative interleukin-2 combined with chemotherapy in patients with liver metastases from CRC, a decrease in postoperative immunity was seen in the control group [54]. Results of clinical trials with the monoclonal antibody 17-1A in patients with stage C CRCDukes and CRC liver metastases suggest effectiveness in improving postoperative survival [55].
3.2 Gene therapy There are four main types of gene studies for colorectal liver metastases: (1) CD suicide gene therapy, which accounts for about 1/5 of oncogene therapy; (2) immunogene therapy mediated by cytokines such as interleukin-2 or the major histocompatibility complex 1 gene HLA-B7; (3) tumor suppressor gene p53 therapy with wild-type gene replacement therapy; (4) lysis of p53 mutations viral genes, such as Onyx-015, adenovirus d9122-947 and mutant herpes simplex virus, are currently hot spots in gene therapy. Five CRC gene therapies are now approved for clinical trials in the United States.
3.3 Molecularly targeted tumor therapy (MTT) Although cytotoxic anticancer drugs have considerable efficacy, their toxic side effects and drug resistance often affect their application. In recent years, due to the rapid progress of molecular biology, people have recognized some “dead spots” in the process of cancer development to break the “targets” of cancer cells, and designed a series of new tumor molecular targeted therapy drugs, and achieved encouraging results in the treatment of certain tumors. The results are encouraging. The so-called MTT is a new biotherapeutic modality that targets the key aspects of tumor occurrence and development and blocks or reverses its malignant biological behavior at the molecular level, thus inhibiting tumor cells or even making them completely regress. Currently, there are two main types of molecularly targeted drugs used in clinical treatment of CRC: EGFR monoclonal antibodies (Cetuximab, Pnitumumab) and Bevacizumab.
The safety and efficacy of EGFR monoclonal antibodies in the treatment of chemotherapy-resistant metastatic CRC have been demonstrated in many clinical studies.The BOND study [56] is one of the most important clinical studies, and its results showed that OS was significantly prolonged in those who applied Cetuximab in combination and in those who applied Cetuximab at a later stage.The results of the BOND-2 study [57] showed that Cetuximab in combination with Bevacizumab was also efficacious and well tolerated. It has also been shown [58] that Cetuximab not only overcomes irinotecan resistance but also has a reversal effect on OXA resistance, but the final conclusion needs to be confirmed by phase III clinical studies. A phase III clinical study on Pnitumumab [59] showed that the Pnitumumab monotherapy group was significantly better than the supportive therapy group, while 75% of patients in the supportive therapy group switched to Pnitumumab after disease progression making no difference in their overall survival.
Based on the results of numerous clinical studies, Cetuximab is approved for the treatment of EGFR-positive, irinotecan-resistant metastatic CRC as a single agent or in combination with irinotecan, while Pnitumumab is approved for the treatment of EGFR-positive, 5-Fu, irinotecan and OXA-resistant metastatic CRC as a single agent.
4. Local physical methods of treatment for CRC liver metastases
4.1 Cryotherapy Cryotherapy is one of the local treatment methods for CRC secondary hepatocellular carcinoma. The main features of cryotherapy for CRC liver metastases are: (1) the formation of ice crystals inside and outside the cells, cell metaplasia and crumpling, electrolyte toxicity concentration and pH change, denaturation of the components of cell membrane lipoproteins, blood flow stasis and microthrombus formation after freezing are sufficient to cause irreversible necrosis of hepatocellular carcinoma cells; (2) preoperative B-ultrasound localization and making The relationship between the cancer and large blood vessels is clearly distinguishable, thus it is not easy to cause accidental damage; (3) Regular blood AFP and ultrasound/ or CT review are performed after cryotherapy, and those with recurrence of liver metastases can be treated by cryotherapy again according to the situation, and those who need to be resected can be operated conveniently and easily because the cancer becomes smaller and the surrounding fibrous tissue proliferation zone is formed; (4) After cryotherapy, liver metastases can be treated again by cryotherapy. (4) the cancer is treated by cryotherapy and then surgically removed to reduce the recurrence rate after surgery; (5) the coagulation and necrosis of cancer tissue after freezing can induce the body to produce the corresponding antibodies. The application of cryotherapy has been used for many years to treat liver cancer, and the initial method is to pour liquid nitrogen directly on the tumor site or liver section. Due to the poor controllability and complications of this method, it has been infrequently used in recent years. Newer cryosurgical devices place liquid nitrogen in a closed tube system and allow intraoperative or even extracorporeal freezing of inoperable liver metastases through one or several very small cryoprobes (3.2 mm in diameter). Since this probe is insulated except for the front end, it has a better safety during use.
4.2 Radiofrequency ablation therapy Radiofrequency ablation for liver tumor treatment started in 1995. Rossi in Italy was the first to apply it clinically, and it is one of the latest liver tumor-directed treatment methods today. Its principle is to generate thermal energy to destroy tumor cells. When tumor cells are heated to 45-50℃, cell protein denaturation and cell membrane lipid bilayer dissolution lead to cell membrane destruction and thus cell structure change. The mechanism of tumor cell damage caused by high temperature may also include: high temperature affects the biological properties and functions of tumor cell biofilm, high temperature increases the activity of lysosomes in tumor cells, and destroys a variety of cell organelles. While killing the local tumor cells, it can make the vascular tissue around the tumor coagulate, which is helpful to cut off the blood supply of cancer cells and prevent tumor metastasis. The thermal effect of radiofrequency can enhance the immunity of the body, while the absorption of necrotic material as endogenous thermogenic substance can stimulate the anti-tumor immune function of the body, and then improve the immune ability of the body. It uses small diameter electrodes, can be performed by percutaneous or laparoscopic route, and the instruments are portable and cheap, thus it is easier to promote. It is a safe and reliable treatment method for localized liver metastases, and its efficacy on liver metastases with diameter <3.0 cm has been fully confirmed. Its disadvantage is that the ablation range is small, and it can usually be used only for lesions with a diameter of 5 cm or less [60-61]. It is mainly indicated for patients with small liver tumors who are not suitable for general anesthesia or for patients with limited recurrence after major hepatectomy.
Recently, many RF combination therapies have emerged to improve the efficacy: combination of transhepatic artery and/or portal vein chemotherapy for hepatocellular carcinoma, combination of intravenous systemic chemotherapy, combination of anhydrous alcohol injection therapy, and combination of local thermal chemotherapeutic agents. Radiofrequency ablation therapy is recognized as a new safe and effective method for treating liver tumors in clinical practice at home and abroad. With the further research on the combined application of radiofrequency ablation technology and other treatment methods, the improvement of radiofrequency equipment and the accumulation of treatment experience, radiofrequency ablation combined treatment will play a greater role in the treatment of liver metastases, which will greatly improve the quality of life and prolong the survival of CRC patients with liver metastases.
5.Therapeutic Chinese medicine
Although the continuous improvement of surgical and interventional techniques has prolonged the survival of CRC patients with liver metastases, the treatment effect is still unsatisfactory for most patients with diffuse liver metastases or poor liver function because liver metastases are not sensitive to radiotherapy. Therefore, the combined therapy of Chinese and Western medicine shows its unique advantages.
In terms of treatment, TCM has proposed some treatment rules and methods based on the diagnosis and treatment, including helping to dispel that, activating blood and fatigue, clearing heat and detoxifying, and softening and dispersing knots, etc. Meanwhile, it combines with various therapies such as acupuncture and moxibustion and topical medicine, which have benefited many CRC patients. Chinese medicine, together with chemotherapy or radiotherapy, can enhance the sensitivity of radiotherapy and reduce the toxic side effects of radiotherapy, increase appetite, eliminate fatigue, reduce gastrointestinal reactions, reduce the magnitude of the decrease in total WCB caused by chemotherapy, and reduce the effect of CEA content, which can improve the physical condition of chemotherapy patients and prepare for the next chemotherapy. Its immunomodulation, cancer suppression, anti-recurrence and metastasis, and prolongation of survival are better than radiotherapy alone. Thus, it can improve the therapeutic effect of radiotherapy, reduce the recurrence and metastasis rate of CRC, and improve the quality of life of patients.
Recent experimental studies [62-66] have confirmed that the combination of traditional Chinese medicine with surgery, radiotherapy and chemotherapy has the effect of improving the immediate and long-term efficacy of tumor treatment, and has a significant improvement on the anti-metastatic recurrence and prolongation of survival after CRC surgery. However, we should also see that, from the existing reports, TCM has failed to give full play to its proper role in the prevention of postoperative recurrence and metastasis of CRC. From the current situation of treatment in China, a significant proportion of postoperative CRC patients are still mainly treated with radiotherapy and long-term review after radiotherapy, without the participation of TCM during this period, and the existing clinical studies also mainly use TCM with radiotherapy to reduce its toxic side effects, but less from the perspective of anti-metastatic recurrence, which makes the efficacy of TCM in preventing recurrence/metastasis of CRC not fully reflected. The efficacy of Chinese medicine in preventing recurrence/metastasis has not been fully reflected. At present, the etiology of CRC is not yet precisely understood, and the treatment is still based on surgery, chemotherapy, radiotherapy, and biological therapy, etc. The application of TCM to improve the quality of life of tumor patients is the main direction to bring into play the advantages of TCM in the treatment of tumors, which is also in line with the international trend of anti-cancer treatment research. On this basis, it is still the direction of future efforts to combine the advantages of TCM with its own advantages to play its proper role in the prevention and treatment of CRC and CRC liver metastasis, and to provide protection for the life and health of patients.
6. Summary
Potentially resectable lesions in patients with CRC liver metastases should be evaluated by experienced surgeons from the perspective of comprehensive treatment, because surgical resection is the only curative method, which has caused a change in the concept of treatment of CRC liver metastases, and some scholars even believe that CRC combined with hepatic and pulmonary metastases should not be a reason to abandon treatment. Patients who are not suitable for surgical resection but do not have extrahepatic metastases can be treated with focal therapy such as RFA, cryotherapy, laser, microwave and Chinese medicine. HAC/HACE and perfusion with hepatic flow blockade are preferable to systemic chemotherapy in patients with extensive liver metastases. Portal vein embolization can be used for preoperative adjuvant treatment of large metastases in one lobe. Systemic chemotherapy + molecular targeted biology should be used when there are extensive extrahepatic metastases. The median survival of patients with metastatic CRC is approaching 30 months due to the use of several targeted agents including EGFR monoclonal antibodies with emerging chemotherapeutic agents such as OXA and irinotecan. However, it should be noted that the emergence of new drugs has not only increased the treatment options but also the complexity of treatment, and it is a new challenge for clinicians to rationalize the use of drugs according to the requirements of evidence-based medicine. Immunotherapy can be used to enhance the effectiveness of other therapies. In conclusion, new methods are emerging with remarkable efficacy, and the rational selection and comprehensive application of many methods bring new hope for patients with CRC liver metastases.