The incidence of gastric cancer continues to be high in countries in Asia, South America and Eastern Europe. Among the first clinical diagnosis of gastric cancer, 1/3 have regional lymph node metastasis, 1/3 have visceral metastasis, and only 1/4-1/3 of tumor lesions are confined to the stomach wall. The limitation and extensiveness of lesions determine the 5-year survival rate of patients. Therefore, the stage of gastric cancer is the main factor to determine the patient’s prognosis and the key factor to choose the treatment method.
I. Postoperative adjuvant treatment of gastric cancer
The 5-year survival rate of patients after radical gastric cancer surgery is not high. In order to improve the survival rate, theoretically, adjuvant therapy should be provided to patients after surgery. However, for a long time, clinical studies have not confirmed that adjuvant therapy can prolong the survival (OS) of gastric cancer patients. A meta-analysis of randomized clinical studies of adjuvant chemotherapy published before 1992 also showed that adjuvant chemotherapy did not prolong patients’ OS. in summary, the accuracy of these trials may have been affected by the relatively small number of patients enrolled, the weak chemotherapy regimens used, and the biased selection of patients in the trial and control groups.
In contrast, the vast majority of recently completed studies in Western countries still concluded that adjuvant chemotherapy after surgery did not significantly prolong patients’ OS, except for a few that concluded that adjuvant chemotherapy after surgery had proximity to statistically significant prolongation of patients’ OS compared with surgery alone. in the phase III clinical study of INT0116 in the United States, 556 patients with gastric or gastroesophageal adenocarcinoma were randomized to receive fluorouracil after radical surgery (5 Fu) combined with calcium folinic acid (LV) plus radiotherapy and the control group who received radical surgery only, the results showed that the median OS of the postoperative adjuvant radiotherapy group was 36 months, which was significantly longer than that of the control group (27 months, P=0.005); the disease-free survival (DFS) of the postoperative adjuvant radiotherapy group was 30 months, which was also significantly longer than that of the control group (19 months, P<0.001).
Therefore, adjuvant radiotherapy is recommended as the standard treatment option for gastric cancer after radical surgery in the United States. However, many scholars in China and abroad have doubts about the findings of this study, believing that local recurrence after gastric cancer surgery is closely related to the way of surgery, the extent of resection, and the surgical technique. The design of this study required all patients to undergo D2 surgery, but only 10% of the patients in the trial underwent D2 surgery; therefore, radiotherapy in postoperative radiotherapy is more beneficial for patients who underwent only D0 or D1 surgery, while the benefit may be less for those who underwent D2 surgery.
Therefore, scholars concluded that the INT0116 study could only prove the benefit of chemotherapy for patients who underwent D0 or D1 surgery. In the UK MAGIC trial, 68% of patients underwent D2 surgery, and the results showed that the 5-year survival rate of 36% for patients receiving perioperative radiotherapy remained significantly higher than that of 23% for patients in the surgery-only group (P<0.001 supplemented with specific survival rates and P values). Currently, scholars in both Eastern and Western countries generally agree that surgery alone is not the standard treatment for resectable gastric cancer, but whether to perform adjuvant therapy after surgery is still recommended according to the guidelines of the National Comprehensive Cancer Network (NCCN), based on the patient's general condition, preoperative and postoperative staging and the modality of surgery to make the decision.
The results of studies from Asian countries tend to agree more with the adjuvant treatment of gastric cancer than those from Western studies. This may be related to the different proportions of proximal and distal gastric cancer in patients from the East and West, the different rates of early diagnosis, the different preoperative staging, and the different degrees of surgical lymph node dissection [9-10]. Recently, in a randomized phase III clinical trial (ACTS-GC) in Japan enrolling 1059 patients, the survival of patients with stage II and III gastric cancer after D2 surgery who received adjuvant chemotherapy in the S1 group was compared with that of patients in the control group without chemotherapy, and the results showed that the 3-year survival rate of patients in the S1 group was 80.5%, which was significantly higher than that of the control group (70.1%, P=0.0024), and the adjuvant chemotherapy group patients had a 32% lower risk of death.
Preoperative neoadjuvant therapy for gastric cancer
Among gastrointestinal tumors, preoperative neoadjuvant chemotherapy for locally advanced gastric cancer has attracted early attention. Theoretically, preoperative chemotherapy can reduce the risk of peritoneal metastasis, decrease the stage and increase the R0 resection rate. Some phase II clinical trials have shown that the efficiency of preoperative chemotherapy is 31%-70%, and the R0 resection rate after chemotherapy is 40%-100%, thus prolonging the OS of patients. however, the above conclusions have yet to be confirmed by phase III clinical studies.
For locally advanced gastric cancer that cannot be resected by surgery, it is recommended that a more intense chemotherapy regimen should be chosen if the patient is young and in good general condition. Once the treatment is effective, the tumor becomes surgically resectable. In order to create this resectable chance, it is worthwhile to choose intense chemotherapy and take some risk of chemotherapy toxicity. Due to the altered physiological function of the upper gastrointestinal tract after radical gastric cancer surgery, it is difficult for the patient to recover physically for a long period of time, and adjuvant chemotherapy cannot be implemented as scheduled
. Therefore, the opportunity of preoperative chemotherapy should be grasped, the process and effect of chemotherapy should be closely monitored, and once it is effective, the number of cycles of chemotherapy should be appropriately increased to try to kill microscopic lesions throughout the body in order to prolong the postoperative DFS or even OS. of course, after the preoperative chemotherapy is effective, the best timing of surgery should not be delayed due to excessive pursuit of the best chemotherapy efficacy and over-chemotherapy. The number of cycles to control neoadjuvant chemotherapy should vary from person to person and from efficacy to efficacy. Although there is no evidence of evidence-based medicine yet, generally do not exceed 4 cycles, and for those who think they can achieve R0 resection, preoperative chemotherapy should be even more modest.
Relief treatment of advanced gastric cancer
For advanced gastric cancer that cannot be operated, systemic chemotherapy should be the main treatment. Compared with the best supportive treatment, chemotherapy can improve the quality of life of some patients and prolong OS, but the effect is still limited. Chemotherapeutic agents available for gastric cancer treatment include 5Fu, adriamycin (ADM), epoetin (EPI), cisplatin (PDD), pedialyte glycoside (VP-16), mitomycin (MMC), etc., but the efficiency of single agent application is not high.
Among the combination regimens, FAMTX (5Fu+ADM+MTX), ELF (VP-16+5Fu+LV), CF (PDD+5Fu) and ECF (EPI+PDD+5Fu) were commonly used in the past for the treatment of advanced gastric cancer, but are not the accepted standard regimens. the ECF regimen has higher efficiency, longer median time to tumor progression (TTP) and OS, and is more effective than The ECF regimen is often used by European scholars as a reference regimen for the treatment of advanced gastric cancer because of its lower toxicity compared with the FAMTX regimen. The CF regimen commonly used in clinical practice also has an efficiency rate of about 40% and a median OS of 8-10 months. Therefore, most scholars use CF and ECF regimens as reference regimens for the treatment of advanced gastric cancer [13].
New cytotoxic drugs such as paclitaxel (PTX), doxorubicin (DTX), platinum oxalate, and irinotecan (CPT-11) have been used for the treatment of advanced gastric cancer. Relevant clinical studies showed that the efficiency of PTX first-line treatment was 20%, PCF (PTX+PDD+5Fu) regimen was 50%, and OS was 8-11 months; the efficiency of DTX treatment was 17%-24%, and DCF (DTX+PDD+5Fu) regimen was 56%, and OS was 9-10 months.
In addition, the end-stage results of the V325 study showed that the DCF regimen was superior to the CF regimen, and the efficiency of the DCF regimen (37%) was higher than that of CF (25%, P=0.01), and the TTP (5.6 months versus 3.7 months, P=0.0004) and OS (9.2 months versus 8.6 months, P=0.02) were also longer than those of CF. gastric cancer as the first-line treatment option. However, the hematologic and non-hematologic toxicity of DTX is a major factor limiting its clinical application. Exploring the most appropriate dose for Chinese gastric cancer patients will be a problem for clinicians to solve. As a 3rd generation platinum drug, platinum oxalate is not completely cross-resistant with PDD and also has synergistic effects with 5Fu. FOLFOX6 regimen (5Fu+LV+platinum oxalate) has an efficiency of 50% in the treatment of gastric cancer therapy.
The efficiency of CPT-11 in combination with PDD or with 5Fu+CF was 34% and 26%, respectively, and the median OS of patients was 10.7 and 6.9 months, respectively. Currently, oral 5Fu derivatives are of interest for their convenience, efficacy and low toxicity. Among them, the efficiency of capecitabine or S1 alone is 24%-30%; the efficiency in combination with PDD is >50%, median TTP >6 months, and median OS >10 months.
In addition, individual reports of trastuzumab targeting Her-2/neu have also shown better efficacy of trastuzumab. The effect of trastuzumab in combination with chemotherapy versus chemotherapy alone has been compared in the ongoing phase III ToGA trial, but no conclusions have been reached.
Bevacizumab targeting vascular endothelial growth factor (VGFR) in combination with chemotherapy in first-line treatment of advanced gastric cancer is approximately 65% effective, with a median patient OS of 12.3 months. International multicenter clinical studies are also evaluating the effect of bevacizumab in combination with chemotherapy versus chemotherapy alone. From the current results, although the toxicity of molecularly targeted drugs for gastric cancer is not significant, the cost is high, the efficacy is uncertain, and more data are needed to evaluate the clinical effects.
Some new chemotherapeutic drugs have different mechanisms of action from previous drugs, no cross-resistance, and no significant overlap in toxicity, and therefore have the potential to replace older generations of drugs or combine with older drugs. Even so, the current efficiency of first-line chemotherapy for advanced gastric cancer is only 30% to 50%. After the benefit of chemotherapy, the median TTP is only 4-6 months even if the original regimen of chemotherapy is continued. Therefore, the continued chemotherapy after the benefit of chemotherapy can only play the role of consolidation and maintenance of therapeutic effect.
Due to the poor general condition of patients with advanced gastric cancer, after chemotherapy benefit, should the original treatment regimen be continued according to the traditional pattern until tumor progression; or until the drug reaches the maximum cumulative dose or the patient develops intolerable toxicity; or until the tumor achieves maximum remission; or should a single drug be chosen as maintenance after intense chemotherapy benefit and then switched back to intense chemotherapy after tumor progression? To answer these questions, studies similar to OPTOMOX1 and OPTOMOX2 in advanced colorectal cancer must be conducted to evaluate the advantages and disadvantages of continuous chemotherapy, continuous chemotherapy followed by single-agent maintenance therapy, or “hit-and-miss” intermittent therapy. However, the current status of chemotherapy is “chemotherapy-disease progression-change chemotherapy regimen”, which leaves most patients with a poor quality of life.
A survey of 212 medical oncologists in Canada on the efficacy of chemotherapy for advanced gastric cancer showed that only 41% of them believed that chemotherapy could prolong patients’ OS and only 59% believed that chemotherapy could improve patients’ quality of life [15]. Then, how significant is chemotherapy for patients with advanced gastric cancer? According to the literature [16], conventional regimen chemotherapy prolongs OS for patients by only 4 months more than best supportive care, while regimens based on new chemotherapeutic agents such as CPT-11, PTX and DTX prolong OS by only 6 months more than best supportive care. In general, three-drug combination chemotherapy regimens such as ECF, DCF, PCF and FAMTX are more intense chemotherapy regimens; while single- or two-drug combination chemotherapy such as PF (PTX+5Fu), CPT-11+5Fu and capecitabine are non-intense regimens.
Meta-analysis showed that the survival advantage of the three-drug combination was obvious, such as a three-drug regimen with an anthracycline combined with PDD and 5Fu compared with a two-drug regimen with PDD and 5Fu combination, which increased the OS of patients by 2 months. However, chemotherapy regimens containing PDD, EPI or DTX are relatively more toxic. Currently, the clinical treatment of advanced gastric cancer focuses on the following two aspects: (1) controlling tumor growth, improving patients’ quality of life, and enabling patients to coexist with the tumor. Therefore, in the selection of treatment options, it is necessary to consider both the physical condition and economic status of individual patients and the efficiency, type and degree of toxicity of the selected options, weighing the pros and cons of efficacy and toxicity. (2) Exploring new therapeutic regimens to achieve increased efficacy and reduced toxicity. For example, the phase III clinical study of REAL-2 concluded that the EOX regimen consisting of platinum oxalate instead of cisplatin and capecitabine instead of 5Fu was the best after weighing the efficacy and toxicity through a 2×2 design, using the standard ECF regimen as a control.
The ideal model of gastric cancer treatment is individualized treatment, including individualized selection of drug type, dose, and duration of treatment. Recently, a group of patients with surgically resectable esophageal cancer and cancer of the esophageal and gastric junction were studied at the Royal Marsden Hospital for analysis of preoperative gene expression profiling in relation to preoperative chemotherapy and postoperative prognosis. 35 patients underwent preoperative endoscopic extraction of tumor tissue for gene profiling, and 25 of them underwent surgical treatment through preoperative chemotherapy. Preliminary results showed that the difference in OS between the two groups of patients with good and poor prognosis predicted according to genetic profiling was statistically significant (P<0.001), indicating that pharmacogenomics or proteomics research is an important tool to achieve truly individualized treatment of gastric cancer.
In conclusion, the current medical treatment paradigm and treatment level of gastric cancer have not undergone revolutionary progress compared with those of 10 years ago, which is largely related to the low incidence of gastric cancer in western developed countries and the insufficient investment in gastric cancer research by all parties. Therefore, physicians in countries with high incidence of gastric cancer such as Asia and South America, especially our Chinese physicians, should take advantage of the large number of patient resources and devote more efforts to in-depth research on the internal medicine treatment of gastric cancer while they are busy with their routine clinical work.