This study showed that the cumulative dose of postoperative DS chemotherapy for stage III gastric cancer affects RFS and that postoperative PS and perioperative body weight loss rate are independent predictors of tolerability. To our knowledge, there have been no reports on the predictors of tolerability for postoperative DS chemotherapy. We aimed to elucidate on this by analyzing several parameters in a multicenter study.

Gastrectomy with D2 lymph node dissection is performed as a curative surgery for gastric cancer in Japan. Adjuvant therapy has been developed to improve the survival of patients with advanced gastric cancer. The addition of S1 chemotherapy after surgery in patients with stage II and III gastric cancer has been shown to improve OS better than surgery alone [12]. For patients with stage III gastric cancer, S1 alone was considered inadequate, and the addition of docetaxel was shown to be effective [4]. Postoperative DS therapy is considered one of the standard treatments for stage III gastric cancer according to the Japanese guidelines [3]. Adequate administration of both drugs is necessary. In this study, postoperative PS and weight regain were found to be significant. Although further development of effective postoperative treatments is expected, more aggressive postoperative chemotherapy is burdensome and difficult due to the deterioration of the physical and nutritional conditions of patients after gastrectomy. In this study, DS therapy was indicated for patients with PS 0 or 1, as in the JACCRO-GC-07 study (Table 4). Nevertheless, 40 patients (39%) were classified as intolerant. In Europe, the efficacy of perioperative chemotherapy has been reported [13,14,15] and is recommended in the ESMO guidelines [2]. In Japan, additional pre-operative chemotherapeutic regimens have been developed and tested in clinical trials. The maintenance and improvement of PS and weight in the perioperative period in patients with gastric cancer may become more important in the future.

In previous reports, the duration of administration and cumulative dose were used as indicators for chemotherapy tolerability, and studies on factors affecting the tolerability for postoperative S1 chemotherapy used the duration of administration as an indicator [8, 10, 11, 16]. There are several problems with the duration of administration as a measure of tolerability for DS chemotherapy. S1 and docetaxel have different durations of administration (1 year for S1 and 6 months for docetaxel), and categorizing each separately would yield less statistical power and would be complicated. Simply dividing the patients into two groups based on the duration of chemotherapy was also problematic because the discontinuation of one drug did not affect the analysis. This was because patients who received one drug for a long period and the other for only a short period were considered the same as patients who received both drugs sufficiently. Because of these difficulties in using the duration of administration as an indicator, the cumulative dose was used as an indicator for tolerability. Because the addition of docetaxel to S1 has been shown to improve prognosis [4], elucidating the factors that might allow the administration of both drugs rather than one or the other was considered to be important. Therefore, we classified the patients into two groups: those who received sufficient doses of both drugs and those who did not. The dose cutoffs were set at cumulative doses of 8400 mg/m2 for S1 and 120 mg/m2 for docetaxel. The results showed a significant difference in the RFS between the two groups. Therefore, we find this classification method to be legitimate and useful.

Although the effectiveness of postoperative adjuvant chemotherapy in patients with gastric cancer has been demonstrated [4, 12], in practice, some patients are unable to receive adequate doses. The need to clarify the factors affecting tolerability has been recognized. The effects of older age, postoperative infectious complications, PNI, and postoperative weight loss on the tolerability for postoperative S1 adjuvant chemotherapy for gastric cancer have been previously reported [7, 8, 16]. These results suggest that the postoperative physical condition and nutritional status of patients affect the tolerability for chemotherapy, which may represent the characteristics of post-gastrectomy patients who are prone to these declines. Poor S1 efficacy owing to weight loss also leads to poor survival in gastric cancer [17]. In the current study, we evaluated only postoperative DS chemotherapy with poorer compliance than S1 monotherapy and analyzed several factors related to the physical condition, degree of surgical invasion, inflammatory system markers, and nutritional status of patients. Among the many factors analyzed, the influence of PS and weight loss was particularly significant. In the univariate analysis at the end of second courses of DS chemotherapy, PS was the only factor that showed a significant difference. The smaller number of intolerant group of patients may have weakened the statistical difference. Because not a few patients discontinued treatment before the end of the second course, tolerability evaluation before chemotherapy may be useful. We hope that attention to these factors will enable appropriate care, condition assessment, chemotherapeutic drug selection, and timing decisions regarding chemotherapy initiation in patients with gastric cancer.

The current study had several limitations. This was a retrospective, multi-institutional study, and there may have been some differences in treatment protocols at each institution. However, all participating institutions treated the patients according to the Japanese Gastric Cancer Treatment Guidelines [3, 18], and the adverse events and completion rates of DS chemotherapy were similar to previous reports [4]. We believe that differences between institutions did not significantly affect the results of the current study. Selection bias was evident in the study. Only patients selected for postoperative DS chemotherapy were included in this study, and many patients were excluded from the study because they did not receive postoperative chemotherapy or S1 alone. Only patients who were expected to be tolerable for DS chemotherapy may have been selected. The follow-up period of the study was short (median, 33.6 months). It is possible that some patients will relapse in the future, which may affect the results of the RFS analysis. Due to the low incidence of death, OS was not able to analyze. However, not enough time has passed since the efficacy of postoperative DS chemotherapy has been demonstrated, and further follow-ups are needed. We will continue to analyze and evaluate in the future. Patients who discontinued chemotherapy due to recurrence were excluded from this study to analyze tolerability, and the site of recurrence was not analyzed.

In conclusion, postoperative PS and weight loss rate were independent predictors of DS chemotherapy tolerability after curative surgery for gastric cancer. Efforts to maintain and restore these factors in the perioperative period may contribute to improved tolerability and outcomes for DS chemotherapy.