The incidence rate of gastric cancer and colorectal cancer ranks among the top ten common tumors in China. Foreign data show that the incidence rates of liver metastasis of gastric cancer, liver metastasis of colorectal cancer and lung metastasis of colorectal cancer are 4%~14%, 50%~75% and 10%~25% respectively. Due to the huge population base in China, the above metastatic cases are common, so how should clinicians correctly understand the situation of these diseases and how to select reasonable treatment strategies?
After the failure of first- and second-line treatment for metastatic colorectal cancer, the choice of strategy for third-line treatment has equally troubled many clinicians. New drugs, protocols and technologies have improved patients’ survival time and quality of life. To this end, we have invited renowned experts in the field of gastrointestinal oncology in China to explain the latest advances in these fields for readers’ reference.
Gastric cancer is the fourth most common malignant tumor in the world, with about 1 million new cases each year. It ranks 2nd in the mortality rate of tumors in men and 4th in women. It is well known that the adequacy of local control is the key to the treatment of gastric cancer. The incidence of liver metastasis in patients with primary gastric cancer ranges from 4% to 14%. At present, liver metastasis of gastric cancer is still incurable, and the 5-year survival rate of patients is only 10%. How to reasonably treat gastric cancer liver metastasis with surgery, radiotherapy and chemotherapy alone or in combination is the focus of doctors’ attention. This article reviews the current status and latest progress of treatment for liver metastases from gastric cancer.
Surgical treatment: suitable for those who can be completely resected, the rate of intrahepatic recurrence is high
When liver metastasis occurs in gastric cancer, it is often accompanied by peritoneal dissemination, lymph node metastasis or direct invasion of other organs by the tumor, so there are few reports about resection of liver metastases from gastric cancer. In contrast to colorectal cancer, liver metastases in the majority of gastric cancers tend to suggest that the disease has spread extensively. Some reports show that only 1 in 5 of all patients with liver metastases from gastric cancer can undergo elective liver metastasectomy. The survival rate after liver resection is relatively poor, and intrahepatic recurrence can occur in 2/3 of patients. Such a high recurrence rate within 2 years after surgery implies that potential intrahepatic metastases may be present at the time of hepatectomy. Few studies have shown that patients have a better prognosis after repeat resection of liver metastases.
The main prognostic factors for surgical treatment of liver metastases from gastric cancer include the stage of the primary gastric cancer, the number of liver metastases, and the surgical margins. ochiai et al. suggest that the indications for resection of liver metastases are concurrent or heterochronic liver metastases without plasma surface invasion in the gastric primary and heterochronic liver metastases without vascular and lymphatic vessel dissemination in the gastric primary. sakamoto et al. suggest that single and/or tumor Sakamoto et al. suggested that liver metastases with a diameter <4 cm could be considered for hepatic metastasectomy. In addition, simultaneous liver metastases are not a contraindication to hepatectomy. With regard to the surgical margins of liver metastases from gastric cancer, some authors believe that positive surgical margins should be avoided; others believe that enlarged surgical margins do not indicate a better clinical prognosis.
Cheon et al. reported that there was no significant difference in patient survival after radical and palliative resection of liver metastases. However, if careful preoperative staging shows that liver metastases from gastric cancer can be completely resected, surgical resection of metastases is justified. Therefore, metastasectomy should be a treatment option for patients with liver metastases from gastric cancer.
Given that the recurrence rate of intrahepatic tumors after resection of liver metastases from gastric cancer is as high as 62%-79%, regular follow-up of residual liver after surgery, close observation of secondary recurrence in the liver and postoperative adjuvant chemotherapy are better ways to improve the survival rate. For most recurrent metastases in the liver, systemic chemotherapy is usually given rather than secondary surgical resection.
Systemic chemotherapy: the efficacy of new drugs such as S-1 is worth exploring
Many new drugs such as oxaliplatin, paclitaxel, irinotecan, and S-1 offer more effective and safer treatment options for patients with advanced gastric cancer. A phase II study showed that 5-FU + calcium folinic acid (CF) combined with oxaliplatin has an efficiency of 38% to 54%, an overall survival of 8 to 11 months, and a good safety profile. The efficiency of paclitaxel in the treatment of advanced gastric cancer was 11% to 24%. Another phase II study showed that the efficiency of single-agent irinotecan in treating gastric cancer was 20%. Various chemotherapy regimens containing irinotecan have shown good remission rates.
S-1 is an oral anticancer agent of fluorouracil derivatives, which has the following advantages over 5-FU: (1) the ability to maintain high blood levels and improve anticancer activity; (2) significantly reduced drug toxicity; and (3) ease of administration. In Japan, S-1 was approved for the treatment of advanced gastric cancer in 1999. In Japan, S-1 is currently used in more than 80% of cases of chemotherapy for advanced gastric cancer, and its efficiency can reach 44.6%. Phase II clinical trials have shown that the efficiency of S-1 for liver metastases from gastric cancer is 25% to 31%.
Recently, a phase III clinical trial conducted by the Japanese Clinical Oncology Group (JCOG9912) showed that the efficacy of S-1 alone was not inferior to that of 5-FU alone; while the efficacy of irinotecan combined with cisplatin was not superior to that of 5-FU alone. Subgroup analysis showed that irinotecan combined with cisplatin significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with liver metastases or lymph node metastases. In addition, the SPIRITS study showed that for first-line treatment of advanced gastric cancer, S-1 in combination with cisplatin was more effective than S-1 alone, with median OS of 13 and 11 months in the two groups, respectively. Therefore, S-1 in combination with cisplatin has become one of the standard regimens for the first-line treatment of advanced gastric cancer in Japan. a randomized controlled phase III clinical trial (GC0301/TOP-002) reported by Imamura et al. showed that the efficacy of S-1 in combination with irinotecan was not superior compared with S-1 alone. A phase II clinical trial of S-1 in combination with docetaxel showed that the type of organ involved and histopathological type of gastric cancer did not affect the efficacy of the regimen, in which the overall remission rate for liver metastases from gastric cancer was 64.7%.
In addition, chemotherapy regimens for the treatment of advanced gastric cancer vary from country to country. For example, docetaxel + cisplatin + 5-FU is often used in the United States, epirubicin + cisplatin + 5-FU or epirubicin + oxaliplatin + capecitabine is often used in Europe, while cisplatin + capecitabine is recommended in Korea. However, the efficacy of the above regimens in treating liver metastases from gastric cancer has not been reported.
Interventional chemotherapy: higher local control rate
Compared with intravenous systemic chemotherapy, liver interventions such as hepatic artery infusion chemotherapy (HAI) and hepatic artery embolization chemotherapy can significantly increase the local drug concentration in the liver with low systemic toxic side effects and higher quality of life for patients. The first-pass effect of commonly used chemotherapeutic agents such as 5-FU and cisplatin in the liver is significant. Some studies have shown that 5-FU given via the hepatic artery has a hepatic uptake rate of 95%. If the local drug dose is increased, the uptake of the drug by extrahepatic organs can be significantly reduced, thus reducing the systemic toxic effects.
Some domestic scholars have reported that the total efficiency of hepatic arterial intervention for liver metastases can reach 50%. Foreign studies have shown that the efficiency of arterial embolization chemotherapy with soluble starch microspheres and mitomycin-C after transarterial infusion of epirubicin hydrochloride was as high as 62.5%. Although liver intervention can effectively reduce local recurrence in the liver, the effect on systemic recurrence and long-term survival of patients has not been reported. Therefore, for patients with liver metastases from gastric cancer, hepatic artery perfusion has been proposed to be performed simultaneously with systemic chemotherapy.
Radiofrequency ablation: mostly suitable for metastases <5 cm
Under the guidance of direct vision, ultrasound or CT, radiofrequency ablation (RFA) technology can place radiofrequency electrodes into the tumor site and generate heat by ionic shock and friction in the tumor tissue after energization, thus increasing the temperature of the tumor area and causing necrosis of the tumor tissue to achieve the treatment purpose. The advantages of this technique are that the device is portable, the electrode diameter is small, it can be performed percutaneously or lumpectively, and it is inexpensive and easy to promote; the disadvantage is that the ablation range is small.
Yamakado et al. conducted a prospective study to evaluate the efficacy of hepatic artery infusion chemotherapy versus radiofrequency ablation in the treatment of liver metastases from gastric cancer. A total of seven patients with gastric cancer without extrahepatic metastases were enrolled and all were given radiofrequency ablation of liver metastases. The results showed complete necrosis of tumor tissue and the median survival time of patients was 16.5 months. Therefore, radiofrequency ablation may be an effective palliative treatment for patients with liver metastases from gastric cancer that are difficult to be treated surgically. The size of liver metastases is the most important factor in determining the completeness of local ablation. It is generally believed that the degree of ablation can reach more than 90% when the metastases are <2.5 cm in diameter, while the degree of ablation is less than 50% when the diameter is >5 cm. Therefore, radiofrequency ablation therapy is mostly applied to patients with metastases <5 cm in diameter. With the improvement of ablation technology and the update of equipment, the quantity and degree of radiofrequency ablation will make progress. However, so far, there are no studies with large samples to clarify the efficacy, indications and limitations of radiofrequency ablation technology in patients with liver metastases from gastric cancer.
Targeted therapy: the efficacy of combined chemotherapy needs to be confirmed
In recent years, the application of targeted therapy in malignant tumors has become more and more widespread. Targeted drugs mainly include monoclonal antibodies targeting certain specific markers, drugs targeting certain oncogenes and genetic markers of cancer cells, growth factor receptor blockers and anti-tumor angiogenesis drugs.
Bevacizumab, a recombinant human monoclonal antibody against the vascular endothelial growth factor receptor, has been shown in previous studies to improve survival in several solid tumors in combination with chemotherapy. manish et al. conducted a multicenter phase II clinical study in patients with metastatic gastric or esophagogastric union cancer to evaluate the efficacy of the combination of irinotecan, cisplatin, and bevacizumab. The results showed that patients achieved significant improvements in remission rates, time to disease progression (TTP) and overall survival, with a 75% increase in TTP compared to historical controls. Therefore, the investigators concluded that bevacizumab in combination with chemotherapy can safely treat metastatic gastric cancer and esophagogastric union cancer.
Cetuximab is an inhibitor that targets the epidermal growth factor receptor. A phase II clinical study of cetuximab in combination with FOLFIRI regimen for advanced gastric cancer and esophagogastric union cancer was conducted. The results showed that the combination regimen had a synergistic effect in patients with advanced gastric cancer, with the most significant adverse effect being neutropenia. Trastuzumab is a human monoclonal antibody targeting Her-2, and some studies suggest that trastuzumab in combination with chemotherapy can be used in patients with Her-2-positive advanced gastric cancer. However, the application and indications of the above targeted drugs in patients with liver metastases from gastric cancer need to be further investigated.
Conclusion
The best treatment option for patients with gastric cancer with liver metastases but not with peritoneal dissemination and metastases from other sites remains controversial. After careful preoperative evaluation, surgery can be given if the operator believes that complete resection of liver metastases is feasible. Concurrent liver metastases are not necessarily a contraindication to hepatectomy.
S-1 can be used alone or in combination with cisplatin for systemic chemotherapy of liver metastases from gastric cancer. Hepatic arterial perfusion chemotherapy and hepatic arterial embolization chemotherapy can increase the local control rate of disease and reduce systemic adverse effects. Although radiofrequency ablation is convenient and safe for treating liver metastases of gastric cancer, it requires that the metastases should be <5 cm. With the improvement of radiofrequency ablation instruments, this indication will be further expanded. Although targeted drugs are becoming more and more important in tumor treatment, their combination with chemotherapy in the treatment of liver metastases from gastric cancer is still inconclusive.
With the rapid development of imaging technology, liver metastases can be detected early through PET-CT and other examinations, and timely early intervention will lead to better prognosis of patients. In the future, through the analysis of clinical data and follow-up data of a large sample of gastric cancer liver metastases, it is expected to explore the best treatment plan for different types of gastric cancer liver metastases and improve the survival and quality of life of patients.