This was a single arm, phase II clinical study. The main purpose of this study was to evaluate the conversion effect of SOX regimen combined with apatinib in the treatment of unresectable gastric cancer. The primary endpoints were R0 resection rate and safety. The secondary outcome measures were the objective response rate (ORR) and overall survival rate (OSR) of the whole group. Although the follow-up time was < 5 years, we believe that the analysis of short-term survival effect would help to identify the improvement of prognosis of the combined regimen at an earlier stage.
In terms of safety, given that the pre-operative course of transformation treatment was up to six cycles, and oral maintenance was needed for half a year after operation, only three patients (8.1%) in this study had adverse reactions of grades III and IV, one patient withdrew due to grade IV severe thrombocytopenia, one patient withdrew due to emergency operation for upper gastrointestinal hemorrhage and perforation, and one patient with grade III hypertension could maintain the treatment after drug reduction. Apatinib is an anti-angiogenic drug that may induce gastrointestinal perforation and bleeding, which is most likely to cause treatment interruption. However, in this study, except for one patient with upper gastrointestinal hemorrhage and perforation, only one patient had black stool symptoms in the sixth cycle of pre-operative treatment. After short-term conservative treatment with apatinib, the patient recovered and successfully underwent R0 resection. Therefore, the combined therapy does not highlight the side effects of apatinib on anti-angiogenesis. The main adverse reactions were myelosuppression, oral mucositis and asthenia. Myelosuppression was mainly leukopenia and granulocytopenia, mostly grade I and II, which were tolerable. Oral mucositis was also mild, and could be relieved after vitamin C treatment and local symptomatic treatment. The incidence of adverse reactions was not higher than that of oxaliplatin and S-1 alone [5, 7]. The incidence of asthenia, hypertension, albuminuria and hand foot syndrome was higher than that of oxaliplatin and S-1 alone reported in the literature [5, 7], but could be easily controlled due to the mild degree of I and II, which did not affect its clinical use.
Among the patients who underwent R0 resection, one patient achieved pathological complete remission (PCR), which indicated that the scheme had a good conversion effect. No serious complications occurred in any patient during the peri-operative period. The pathological response rate (PRR) reached 68.2%. This standard is widely used in postoperative pathological evaluation of gastric cancer in Asia [11–13]. For the evaluation of primary gastric cancer, the PRR objectively reflects the effectiveness of the combined treatment scheme for patients with advanced gastric cancer.
In terms of survival benefits, the 1-year survival rate of the surgical group was 71.1%, and the 2-year survival rate was 41.1%. The median survival time was 21 months, which was much longer than that of the non-surgical group in this study, and also longer than patients with advanced gastric cancer who received chemotherapy alone reported in the literature [2, 4], suggesting that the successful conversion and concurrent operation can improve the prognosis of the patients. However, there was no significant difference in survival between the peritoneal and non-peritoneal metastasis patients after treatment, suggesting that anti-angiogenesis therapy combined with chemotherapy is also one of the feasible schemes of conversion therapy, even for peritoneal metastasis patients. The 1-year survival rate and 2-year survival rate of the R0 resection group were 88.9% and 74.1%, respectively, which were similar to the short-term survival of stage III gastric cancer [14–20], which is the ultimate goal of gastric cancer transformation treatment. However, the R1/R2 resection group did not show survival advantage compared with the non-surgical group, which indirectly indicated that if the patients fail to achieve R0 resection after the conversion therapy, surgery may not improve the prognosis. The 1-year survival rate of patients who achieved PRR was 84.6%, while the 1-year survival rate of patients who failed to achieve PRR was only 30.0%, which means that the PRR is not only an objective index of efficacy evaluation but also an option for prognosis evaluation.