Apatinib combined with SOX regimen for conversion therapy in advanced gastric cancer patients: a retrospective cohort study

Gastric cancer (GC) is worldwide one of the most common cancers. It is reported that in 2020, the global incidence and mortality of gastric cancer are 11.1/100 000 and 7.7/100,000, respectively, making it the fifth most common malignant tumor in the world, second only to lung cancer, breast cancer and colon cancer in mortality rate, especially the highest incidence in East Asia [1]. At present, radical surgery remains the first choice for GC patients. According to a large survey in Japan in 2018, the 5-year overall survival (OS) rate of GC patients undergoing resection was 71.1% [2]. However, the early manifestation of GC is hidden, resulting in many patients being diagnosed as advanced stage and losing the opportunity of surgery, which not only has poor treatment effect, but also causes huge economic burden to patients and society [3, 4]. For these patients who have no chance of surgery at first, how to prolong survival through comprehensive treatment is a hot and difficult point in clinical research [5]. In recent years, the advent of conversion therapy has brought the possibility of surgical treatment for patients with advanced GC. Conversion therapy refers to the transformation of unresectable tumors into resectable ones through chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc., prolonging the survival time and improving the quality of life. However, not all patients with advanced GC are candidates for conversion therapy. Those patients with the primary tumor and metastases cannot be resected by R0 (no residue under the microscope), including technically difficult to remove liver metastases, extensive group 16 lymph node metastasis, extensive peritoneal metastases, and tumors that invade adjacent organs and cannot be resected by R0, may opt for conversion therapy [6]. Growing evidence has suggested that the prognosis of patients with initial unresectable GC can be improved by conversion therapy. In 2017, a large retrospective analysis in Japan showed significant results in conversion therapy in patients with inoperable GC using a DCS chemotherapy regimen (docetaxel/cisplatin/S-1) with a median OS of up to 47.8 months [7].

In terms of conversion therapy, how to choose therapeutic drugs is equally crucial. At present, there is no unified standard for conversion therapy of GC. Many therapeutic regimes are selected based on the results of phase III clinical studies of advanced GC, such as a combination of platinum, fluorouracil and taxane.

In recent years, chemotherapy combined with radiotherapy, targeted therapy or immunotherapy, and local treatment for some metastatic lesions has gradually been discussed in the conversion therapy of advanced GC (Fig. 1). The research of Fukuchi et al indicated that compared with chemotherapy alone, conversion surgery after cisplatin combined with S-1 conversion therapy can significantly prolong the OS of patients (median OS, 53.0 versus 14.0 months, p < 0.01) [8]. However, little evidence supports the use of apatinib combined with chemotherapy in conversion therapy.

Apatinib is a small molecule tyrosine kinase inhibitor that selectively targets VEGFR-2, which can inhibit the formation of new blood vessels in tumor tissue, and then inhibit the growth of tumor [9]. Phase III clinical studies of apatinib have shown that apatinib can significantly prolong PFS and OS in patients with advanced or metastatic GC compared with placebo [10]. The research of Xu et al argued that apatinib improves the efficacy of 5-Fu both in vitro and in vivo [11]. Clinical evidence suggested that apatinib combined with chemotherapy may be an efficient and acceptable safety therapy for advanced GC, especially in conversion surgery [11]. In 2021 ASCO Annual Meeting, a research of Li et al about neoadjuvant/conversion therapy with camrelizumab, apatinib, S-1 ± oxaliplatin for locally advanced cT4a/bN+ gastric cancer showed that 79.2% of the 24 patients achieved the tumor descending stage. Of the 18 patients who underwent R0 resection, 44.4% achieved pathological remission [12]. Another study of Xia et al about apatinib plus DS chemotherapy regimen (docetaxel/S-1) in the first-line treatment of metastatic GC showed that the objective remission rates (ORR) of these patients was 60.47%, the disease control rates (DCR) was 81.4%, the median PFS was 7.46 months, the median OS was 12.42 months [13].

According to the above results, we selected unresectable patients with advanced GC and divided them into apatinib plus SOX regimen (S-1/Oxaliplatin) conversion therapy group and SOX regimen conversion therapy group. The baseline characteristics and survival data of the two groups were reviewed and analyzed. The purpose of this study was to evaluate the efficacy and safety of apatinib combined with SOX regimen in the conversion therapy of advanced GC.

In the past, systemic chemotherapy was considered to be one of the best choices for patients with advanced GC who had no chance of operation for the first time [14]. But new researches indicate that conversion surgery may lead to further long-term survival, and patients who receive conversion therapy survive longer than those who receive chemotherapy alone [5‐8, 15]. ESMO Clinical Practice Guidelines also advices that gastrectomy should be actively considered in order to improve the prognosis of patients with good response to systemic chemotherapy [16]. In the research of Professor Fukuchi M et al, the median OS of patients receiving conversion therapy was 37 months, while the median OS of patients who only received chemotherapy was less than 1 year [17]. Kim SW et al. studied GC patients with peritoneal metastasis and discovered that the survival time of those sufferers with complete resection was greatly improved after successful conversion therapy [18]. In this study, more patients in the successful conversion treatment group received PR during preoperative chemotherapy, and the tumor markers CEA and CA199 were significantly reduced. Meanwhile, the median OS and PFS in the successful conversion therapy group were significantly longer than those in the failed conversion therapy group, indicating that patients with advanced inoperable GC could indeed achieve long-term survival from successful conversion therapy.

At present, SOX regimen is mainly used for neoadjuvant therapy and postoperative adjuvant chemotherapy for GC [19]. The use of SOX regimen in the conversion therapy of initial unresectable GC is rare in the literature. Apatinib is only used for the third-line treatment of GC in most cases. Related studies have shown that the combination of anti-angiogenic-targeted drugs and chemotherapy can produce synergistic effect and improve the efficacy of chemotherapy [11, 20, 21]. Our previous case reports have revealed the effectiveness of apatinib combined with SOX regimen chemotherapy in the conversion treatment of advanced GC [22]. However, at present, there is no research report comparing the efficacy and safety of SOX combined with apatinib and SOX alone in the conversion therapy of GC. Our retrospective study shows that the ORR and DCR of the SOX conversion group are 55.2% and 86.2% respectively. The ORR and DCR of the SOX combined with apatinib conversion group are 71.4% and 90.5% respectively. Obviously, apatinib enhances the anti-tumor response of SOX regimen in conversion therapy, and improves the efficacy.

Surgery is the foundation stones of radical cure of GC, and R0 resection is the goal of surgical treatment. Compared with non-R0 resection, R0 resection can significantly improve the survival time of patients. In our study, the conversion rate of SOX combined with apatinib was 76.2%, and the R0 resection rate was 81.3%. The work of Xu et al. included 31 patients with advanced GC who received apatinib combined with PTX/S-1 conversion therapy, with a conversion rate of 60% and a R0 resection rate of 56.7% [23]. Obviously, our results are better. This may be related to the following reasons: Firstly, the proportion of peritoneal metastasis in our patients (9.5%) is less than that in Xu et al.’s study (29.0%). Peritoneal metastasis is considered to be related to the lower conversion rate and R0 resection rate of patients [24]. Secondly, no patients with ovarian metastasis were included in this study. The prognosis of ovarian metastasis from gastric cancer is worse than that of ovarian metastasis from other gastrointestinal sources. The median survival time is only 7–14 months [25], which is one of the main reasons for treatment failure of female gastric cancer patients. However, it is difficult to distinguish primary ovarian tumor and metastatic tumor, especially when the tumor is small and the symptoms are not obvious. In addition, some benign ovarian tumors may also have abdominal tumors, ascites, pleural effusion and the increase of tumor marker CA125, which strongly suggests the symptoms of disseminated malignant tumors [26]. Therefore, depending solely on the clinical manifestation of patients and the increase of tumor biomarkers does not seem to be able to distinguish ovarian masses. Calster et al. integrated clinical predictors (age, serum CA-125 level, type of center) and ultrasound predictors to distinguish primary and metastatic ovarian tumors [27]. Zaccaria et al. even confirmed this diagnosis by laparoscopic surgical resection and pathological examination [28]. In the future, it may further improve the success rate of conversion therapy of gastric cancer patients by combining multiple methods to diagnose primary ovarian tumor or metastatic tumor and stratify patients suitable for transformation treatment. Finally, many of our patients (68.0%) have only one unresectable factor. In the multicenter retrospective study conducted by Sato et al., most of the 33 patients with advanced GC who successfully underwent conversion surgery after DCS conversion therapy had only one unresectable factor, and the R0 resection rate reached 84.8% [7]. This is similar to our research results.

In terms of adverse reactions, Lin et al. indicated that the most common hematological adverse reactions of apatinib combined with SOX regimen were neutropenia and leukopenia, and the common adverse reactions associated with apatinib treatment were hypertension, hand-foot syndrome and albuminuria. The combination of the two did not increase the incidence of grade 3 or more adverse reactions and preoperative mortality in patients [11]. Another small sample study also shows that apatinib can be safely used in combination with SOX regimens [29]. In this research, SOX regimen generally used 3–6 cycles and a median of 4 cycles. The most common adverse reactions observed were vomiting, neutropenia and leukopenia, but most of them occurred in grade 1–2. These events were effectively controlled after symptomatic treatment, and no serious adverse events, especially gastrointestinal perforation and bleeding, were observed. The overall safety results are roughly the same as those of the above two studies. In summary, our data show that preoperative apatinib-targeted therapy combined with chemotherapy is considered safe under proper management.

Conversion therapy is a new treatment concept, the literature reference of conversion therapy is still insufficient. We have provided an idea for the choice of conversion treatment, but this study is a retrospective study, the number of patients involved is relatively small, and there is a certain selection bias in the process of sample selection. A large sample, multi-center randomized controlled trials are still needed to verify our results.

Patients with advanced inoperable gastric cancer could benefit from conversion chemotherapy and subsequent conversion surgery, and apatinib-targeted therapy combined with SOX chemotherapy may be a safe and feasible option for conversion therapy.