Gastric cancer is one of the most common malignant tumors and its prognosis is poor. Complete surgical resection is still the most important means to cure gastric cancer. However, the recurrence rate of gastric cancer after surgery is as high as 50%-70%, and the 5-year survival rate is only 20%-50%. Therefore, people have been seeking methods other than surgery to improve the prognosis of gastric cancer patients. Since the 1960s, chemotherapy has been used in gastric cancer, and since then, chemotherapy drugs and regimens have been “emerging”, but postoperative adjuvant chemotherapy for gastric cancer is still unsatisfactory. However, postoperative adjuvant chemotherapy for gastric cancer is still unsatisfactory. The emergence of new drugs and new treatment strategies has brought new opportunities for the application of chemotherapy in gastric cancer.
1. Evolution of chemotherapy for gastric cancer
1.1 Early progress of chemotherapy for gastric cancer
Chemotherapy for gastric cancer began in the 1960s, and 5-Fu was the most thoroughly studied, but the effect of single-drug application was not satisfactory, with the highest overall response rate reaching 21%. combination chemotherapy began to appear in the 1970s, among which FAM (fluorouracil, adriamycin, mitomycin C) regimen was more widely used. However, randomized controlled studies showed no significant difference in response rate and survival between FAM, FA (5-Fu, Adriamycin), and single agent 5-Fu for gastric cancer.FAMTX was used as the standard regimen of chemotherapy in Europe and America for a while.
In the 1980s, the cytotoxic effect of 5-Fu was confirmed by calcium tetrahydrofolate, which led to a response rate of 33%-44%, and research on chemotherapy regimens based on the concept of biochemical modulation gradually began. The invocation of cisplatin and onychomycin led to the introduction of many combination chemotherapy regimens, such as FUP (fluorouracil, cisplatin) and ELF (pedialyte glycosides, calcium folinic acid, fluorouracil).
In the 1990s, PELF (cisplatin, epoetin, calcium folinic acid, fluorouracil intravenous infusion) and ECF (epoetin, cisplatin, fluorouracil intravenous continuous drip) based chemotherapy regimens emerged. Compared with FAMTX, PELF significantly increased response rates but had no significant prolongation of overall survival. In contrast, ECF for gastric cancer showed an increased response rate and median survival of 46% and 8.7 months, respectively. 5-Fu high-dose continuous intravenous drip for gastric cancer showed a response rate of up to 18%, and the addition of cisplatin resulted in a response rate of 44%, while the combination of epoetin did not increase the response rate, while gastrointestinal and hematologic toxicity was significantly increased.
In terms of the results of the current phase III clinical trials, chemotherapy is more effective when compared with best supportive care; the efficacy of combination chemotherapy is better when compared with single-drug chemotherapy; and ECF in combination chemotherapy is one of the most effective regimens for gastric cancer chemotherapy at present.
1.2 Progress of new chemotherapy drugs for gastric cancer
In recent years, some new drugs have entered the clinic one after another, such as paclitaxel, doxorubicin, fluorouracil oral formulation, oxaliplatin and so on. The new generation of chemotherapeutic drugs have shown better anti-tumor activity in the treatment of gastric cancer alone or in combination.
Paclitaxel (taxanes): mainly inhibits tumor growth by binding to microtubule proteins during cancer cell division, stabilizing and polymerizing microtubules, and blocking mitosis. It includes paclitaxel and docetaxel. The overall response rate for monotherapy ranges from 17% to 29%.
New oral fluorouracil: The advantage of oral chemotherapy is that it eliminates the inconvenience of intravenous drips or deep vein placement and carrying an infusion pump.
Oxaliplatin: Oxaliplatin is a stable, water-soluble, third-generation complex platinum compound that prevents DNA replication and transcription by forming an intra-strand complex. The application of oxaliplatin, calcium folinic acid 5-Fu, resulted in an overall response rate of 38% for treatment.
2.The development of chemotherapy strategy for gastric cancer
When gastric cancer lesions cannot be resected, palliative chemotherapy may improve the quality of survival and benefit patients. If the gastric cancer lesion has the possibility of complete resection, chemotherapeutic drugs also have their reasons for application. The main clinical strategies are adjuvant chemotherapy, neoadjuvant chemotherapy, and adjuvant radiotherapy.
2.1 Adjuvant chemotherapy. Microscopic subclinical metastases are the root cause of recurrence of gastric cancer after surgery. Theoretically, adjuvant chemotherapy can remove residual tumor cells and play the role of preventing tumor recurrence and metastasis. Although adjuvant chemotherapy after gastric cancer surgery is widely used, it is still controversial. Its main drawback is that if the resection is complete, the application of adjuvant chemotherapy is not beneficial, but increases the pain and economic burden of patients. Therefore, there is no good reason to consider adjuvant chemotherapy as the conventional treatment for gastric cancer. The efficacy of adjuvant chemotherapy is expected to be verified by larger phase III randomized clinical trials.
2.2 Neoadjuvant chemotherapy. Neoadjuvant chemotherapy can kill or inhibit the spread of tumor cells at the earliest stage and reduce the tumor stage, which can increase the chance of complete resection and increase the prognosis of patients’ survival.
2.3 Adjuvant radiotherapy. For gastric cancer patients with high risk factors of recurrence or not completely resected after surgery, postoperative adjuvant radiotherapy can destroy known tumor lesions, improve local control rate and prolong survival. Some drugs, such as fluorouracil and cisplatin, are themselves radiosensitizers, which can increase the local effect of radiotherapy.
2.4 Since the efficacy of postoperative radiotherapy or chemotherapy alone is not certain, people have explored the efficacy of adjuvant radiotherapy in the treatment of gastric cancer. Currently, adjuvant radiotherapy is recommended for those who failed in D2 radical surgery and those whose lesions were not completely resected. For patients with stage II or III gastric cancer who have undergone radical lymph node Dl or D2 surgery, if the resection is complete (R0), adjuvant radiotherapy should not be applied.
The combined application of neoadjuvant chemotherapy, adjuvant radiotherapy, neoadjuvant chemotherapy and preoperative radiotherapy has become a new strategy in the treatment of gastric cancer and has achieved certain efficacy. The “three-step” strategy of preoperative chemotherapy, then radiotherapy and finally surgery is beneficial to gastric cancer patients.
3.Outlook
With the in-depth research on gastric cancer and the development of chemotherapeutic drugs, new chemotherapeutic strategies and new chemotherapeutic drugs have shown their better therapeutic prospects and are being validated in phase III and IV clinics. Biologically targeted drugs have also become a hot spot in the treatment of solid tumors and have shown low toxicity and high efficiency in the treatment of breast and colon cancers. Animal experiments have demonstrated the inhibitory effect of biologically targeted drugs on gastric cancer cells, but clinical studies are still rare. Anti-HER2 monoclonal antibody class (CH401), epidermal growth factor inhibitor (cetuximab) and vascular endothelial growth factor inhibitor (bevacizumab) will be potentially used in the treatment of gastric cancer. Another major goal of future clinical studies is to obtain markers that can determine prognosis. Thus, adjuvant chemotherapy and neoadjuvant chemotherapy regimens can be developed to meet individual differences. The molecular mechanism of action of antitumor drugs will be studied by biochemical techniques, which may determine the sensitivity of treatment. It is conceivable that with a better understanding of tumor biology, chemotherapy for gastric cancer will become more effective.