The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial

Gastric cancer remains the third leading cause of malignant tumor death both in China and worldwide [1, 2]. The overall five-year survival rate is about 20% [3]. At present radical gastrectomy is regarded as the only approach to curing gastric cancer. However, about 30% of patients with gastric cancer have recurrence after receiving radical gastrectomy [4, 5]. Thus it is difficult to achieve a cure for gastric cancer through surgery alone.

Several randomized controlled trials have evaluated the efficacy of adjuvant chemotherapy, that is, postoperative chemotherapy, for gastric cancer recently. The ACTS-GC phase III trial enrolled 1059 patients with stage II or III gastric cancer at 109 centers throughout Japan. They were assigned randomly to either the S-1 group for receiving S-1 as adjuvant chemotherapy for 1 year postoperatively or the surgery-only group for receiving surgery alone. The five-year overall survival rates in the S-1 group and surgery-only group were 71.7 and 61.1% respectively, and the five-year relapse-free survival rates were 65.4 and 53.1% respectively. S-1 reduced the risk of death by 33.1% and of relapse by 34.7% [6]. The CLASSIC trial enrolled 1035 patients at 35 cancer centers in South Korea, China Mainland and Taiwan. Patients with stage II-IIIB gastric cancer who underwent D2 radical gastrectomy were assigned randomly to adjuvant chemotherapy with eight cycles of capecitabine and oxaliplatin (XELOX) or observation alone. The results showed that 27% of patients in the adjuvant capecitabine and oxaliplatin group and 39% in the observation alone group had recurrence or died (P< 0.0001) and the estimated five-year disease-free survival rates were 68 and 53% respectively [7]. These two trials from Asia confirmed that adjuvant chemotherapy using S-1 or XELOX could improve survival in patients with gastric cancer who had received D2 gastrectomy.

Unlike in Asia, in western countries, neoadjuvant chemotherapy, that is, perioperative chemotherapy, received widespread interest. The MAGIC trial was the first study to confirm the efficacy of neoadjuvant chemotherapy in gastric cancer treatment. A total of 503 patients with resectable adenocarcinoma of the stomach, esophagogastric junction or lower esophagus were enrolled and then assigned to either the perioperative-chemotherapy group or surgery group. Three cycles of preoperative and three cycles of postoperative chemotherapy using epirubicin, cisplatin and fluorouracil (ECF) were administrated to patients only in the perioperative-chemotherapy group, which resulted in a higher five-year survival rate than that of the surgery group (36% vs 23%, P=0.009) [8]. Afterwards, the FNCLCC/FFCD 9703 phase III trial was conducted in France to investigate the benefit of perioperative fluorouracil plus cisplatin (CF) in resectable gastroesophageal adenocarcinoma. Two hundred twenty-four patients were randomly assigned to either the perioperative chemotherapy and surgery group (CS group) medicated with two or three cycles of CF before surgery and three or four cycles after surgery, or the surgery alone group (S group) for receiving surgery only. The results showed that the CS group had a better five-year overall survival (38% vs 24%, P=0.02) and five-year disease-free survival (34% vs 19%, P=0.003) and that the perioperative chemotherapy significantly improved the curative resection rate (84% vs 73%, P=0.04) [9]. However, the completion rate of perioperative chemotherapy in these two trials was relatively low. Later, the FLOT4 trial altered the situation. It aimed to compare the safety and efficacy of FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) with that of ECF/ECX (epirubicin, cisplatin and fluorouracil or capecitabine). Seven hundred sixteen patients were enrolled and randomly assigned to treatment in 38 German hospitals. Results showed that the median overall survival and chemotherapy completion rate were increased in the FLOT group (50 months vs 35 months, P=0.012; 46% vs 37%), which indicated that FLOT could be preferred compared to ECF/ECX [10].

Although all trials mentioned above had positive findings, the EORTC 40954 study, which was conducted in Europe, showed no survival benefit for neoadjuvant chemotherapy. This trial was for the purpose of proving the superiority of preoperative chemotherapy using cisplatin, d-L-folinic acid and fluorouracil. Compared with the surgery-only group, the neoadjuvant group had higher R0 resection rate (81.9% vs 66.7%, P=0.036) and less lymph node metastases (61.4% vs 76.5%, P=0.018). Survival benefit was not demonstrated after median follow-up of 4.4 years and 67 deaths (HR 0.84, 95% Cl 0.52 to 1.35, P=0.466). Notably, because of the poor accrual, the trial was terminated and only 144 patients were randomly assigned in the neoadjuvant arm or surgery-alone arm (72:72) instead of an estimated total of 360 patients. The low statistical power, the high rate of proximal gastric cancer and the better outcome than expected due to the high quality of surgery were possible reasons for no survival benefit [11].

Recently, S-1 plus oxaliplatin (SOX) as neoadjuvant chemotherapy showed relatively high efficacy and safety in several studies [12‐14]. A phase II trial conducted by our medical center demonstrated that neoadjuvant chemotherapy with SOX regimen yielded an overall response rate of 68.8% and a disease control rate of 93.8%. The D2 lymph nodes dissection rate and R0 resection rate in neoadjuvant chemotherapy group were both higher than those in surgery-only group [15]. Furthermore, fluoropyrimidine plus oxaliplatin was recommended in the National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2020 Gastric Cancer and the Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of gastric cancer (2019) [16, 17]. Therefore, the SOX is considered to have good application prospects.

It should be noted that the number of cycles of preoperative chemotherapy applied in these studies is not standardized and two to four cycles seemed to be acceptable based on previous studies [8‐10]. So, the proper duration for neoadjuvant therapy needs to be settled. A randomized phase II trial conducted in Japan enrolled 83 patients with stage III and IV resectable gastric cancer. They were randomly assigned into two courses of SC (S-1 plus cisplatin), four courses of SC, two courses of PC (paclitaxel plus cisplatin) and four courses of PC. The study found no significant differences between two regimens (P=0.956) or between the two- and four- course treatments (P=0.723). However, the limitations of the study are the relatively small sample size and the inclusion of some stage IV patients, which could lead to the negative result [18].

Based on these findings, the randomized phase III RESONANCE-II trial was designed to evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer, so as to provide a theoretical basis for setting an optimal duration of neoadjuvant chemotherapy.

RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will be conducted in 29 medical centers in China and one medical center in Korea. Chinese PLA General Hospital is the lead center. Lin Chen is the trial principal investigator (PI). All screened patients should state that they are healthy and have no discomfort, then they will sign the informed consent. After signing the informed consent, they will receive consultation from investigator and examinations. Eligible patients will be registered, pre-enrolled. Main possible reasons for screening failure include: (1) The results of physical examination or laboratory tests do not meet the inclusion criteria or meet the exclusion criteria; (2) Patients withdraw informed consent or refuse to participate in the research.

Pre-enrolled patients will receive three cycles of SOX. Then, tumor response evaluation will be carried out according to the Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 [19]. Those who demonstrate stable disease (SD) or progressive disease (PD) will be excluded. Patients achieving complete response (CR) or partial response (PR) will be enrolled and assigned into either group A (six cycles of neoadjuvant chemotherapy with SOX) for another three cycles of SOX followed by D2 surgery or group B (three cycles of neoadjuvant chemotherapy with SOX) for D2 surgery. Figure 1 showed the study flow chart. The trial has been approved by the ethics committee of the Chinese PLA General Hospital, Beijing, China and registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019. All patients are required to sign the written informed consent.

Primary endpoint: Pathological complete response rate (pCR%) based on Ryan’s 0–3 pathological tumor regression grade (TRG) system [20].

Secondary endpoints: R0 resection rate, three-year disease-free survival (3-y DFS), five-year overall survival (5-y OS) and safety.

The study started in October 2019. Local ethics committee approvals are expected in October 2020, the enrollment of the first patient in November 2020, the last patient completing the research in November 2027, database lock in June 2027 and publication in June 2028.

The RESONANCE-II study was conducted to evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. The primary endpoint of the study is the rate of pathological complete response. A study evaluated the histopathological tumor regression in 480 gastric cancer patients who received surgery after neoadjuvant chemotherapy. The results showed that complete or subtotal tumor regression was an independent prognostic factor for survival, which suggested that pathological complete regression could be regarded as a proper endpoint for neoadjuvant trials in gastric cancer [24]. Moreover, our study aims to evaluate the efficacy of preoperative chemotherapy. Using pCR rate as the primary endpoint instead of survival could reduce the influence of surgery and postoperative chemotherapy on the endpoint. Also, less time will be required to get the primary results. Therefore, we chose pCR rate as the primary endpoint. However, to illustrate the relation between tumor regression and survival thoroughly, further research is still needed.

In our study, eligible patients will be pre-enrolled and receive 3 cycles of SOX. Those who achieve CR or PR will be enrolled and considered as subjects with cancer that is sensitive to SOX chemotherapy. As for patients achieve SD or PD, they will be considered as subjects with tumors that are not sensitive to SOX chemotherapy and will be excluded. The purpose of this setting is to answer the question of whether more cycles of preoperative chemotherapy should be applied when it is effective in short-term application. When preoperative chemotherapy shows little effectiveness, other treatments will be recommended instead of continuing to apply chemotherapy. In addition, pre-enrollment can ensure the completion of chemotherapy after randomization and reduce the early termination of chemotherapy due to poor efficacy. Therefore, in our opinion, the design is appropriate.

The total number of cycles of preoperative and postoperative chemotherapy in most trials is about six to eight [8‐10]. In this study, patients in group A who receive 6 cycles of neoadjuvant chemotherapy can be considered to have completed all perioperative chemotherapy. It will be recommended that these patients could not receive adjuvant chemotherapy with close monitoring after surgery if there is no evidence of disease progression. Relevant results of group A may suggest the feasibility of applying only preoperative chemotherapy in gastric cancer.

To avoid bias, uniform inclusion and exclusion criteria will be applied and randomization will be performed. To prevent loss to follow-up, investigators will keep timely and effective contact with patients and provide a user-friendly mobile phone application for patients to contact investigators and record medications. All radiologists, endoscopists and pathologists will not participate in any process relevant to grouping or intervention and they will not have access to any chemotherapy-related or surgery-related records. SOPs will be defined and used with sufficient training. The CRO will monitor throughout the project.

To the best of our knowledge, this study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Due to the relatively high efficacy and safety of SOX neoadjuvant chemotherapy, it can be widely used for treatment of resectable locally advanced gastric cancer. We hope that the results of this trial can provide theoretical basis for setting an optimal duration of neoadjuvant chemotherapy.