Abstract
Background/Aim: This study aimed to evaluate the long-term survival outcomes from our previous study: a phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for cT4 or N2-3 advanced gastric cancer. Patients and Methods: The patients with clinical T4 and/or N2 or more lymph nodes received two cycles (3 weeks per cycle) of neoadjuvant chemotherapy with S-1 plus oxaliplatin (oxaliplatin at 130 mg/m2 on day 1 and S-1 at 80-120 mg/day on days 1 to 14), followed by gastrectomy with D2 lymphadenectomy. The final preplanned analysis of long-term outcomes, including overall and relapse-free survival, was performed. This trial has been completed and registered with the University Hospital Medical Information Network Clinical Trials Registry under number UMIN 000024656. Results: Between May 2016 and March 2019, 30 patients were enrolled. All patients completed the protocol. After a median follow-up of 50 months for surviving patients, the 3-year overall and recurrence-free survival rates were 80.0% and 76.7%, respectively, at the last follow-up in March 2023, whereas the 5-year overall and recurrence-free survival rates were 72.7% and 73.0%, respectively. Conclusion: The administration of two cycles of neoadjuvant chemotherapy with S-1 plus oxaliplatin, followed by D2 gastrectomy, was associated with relatively good long-term oncologic outcomes for patients with high-risk gastric cancer.
Over one million new cases of gastric cancer (GC) occurred in 2020, with an estimated 769,000 deaths, thus ranking fifth in incidence and fourth in mortality worldwide. The incidence rate of GC is highest in Eastern Asia, including Japan (1). In Japan, the standard treatment for resectable advanced GC is D2 gastrectomy and adjuvant chemotherapy; this is based on the results of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) (2). However, the 5-year overall survival (OS) rate of patients with stage III GC remains unsatisfactory. Therefore, more effective treatment strategies for stage III GC are needed.
The JCOG0501 study showed that for type 4 and large type 3 GC, the phase 3 trial to evaluate the efficacy of neoadjuvant S-1 and cisplatin (CS) chemotherapy, followed by gastrectomy with D2 or 3 lymphadenectomy, did not confirm the effectiveness of neoadjuvant chemotherapy (NAC) with CS (3). The pathological response and 3-year OS rates were 51% and 60.9%, respectively. However, 12% of patients could not complete two courses of NAC with CS because of adverse events and patient refusal. Cisplatin frequently causes febrile neutropenia, nausea, and impairment of renal function, affecting the continuation of the chemotherapy.
Yamada et al. reported that for unresectable advanced or recurrent GC, oxaliplatin, a third-generation platinum compound, and S-1 (SOX) were safer than and almost as effective as CS; therefore, SOX could replace CS (4). Furthermore, due to the adverse events associated with cisplatin, compliance with and efficacy of chemotherapy are poor; therefore, we concluded that SOX was better than CS as a NAC.
We have previously reported a single-arm, prospective, multicenter, phase II study designed to examine the efficacy and safety of SOX as a NAC for cT4 or N2-3 M0 advanced GC (5). In the previous analysis, all patients could complete two courses of NAC with SOX, and the R0 resection rate was 93.3% [28/30, 95% confidence interval (CI)=77.9-99.2%]. The grade ≥3 adverse events during SOX NAC were anemia (3.3%), non-hematologic toxicities comprising anorexia and fatigue (6.7%), and nausea and vomiting (3.3%). The grade ≥3 surgical morbidities were anastomotic leakage and pancreatic fistula (both 6.7%). The pathological response (Grade 1b-3) rate was 63.3% (19/30) (5). Therefore, the SOX NAC was feasible and effective for advanced GC, with high R0 resection and acceptable pathological response rates. The present study reports the analysis of long-term survival data from our previous trial during follow-up.
Patients and Methods
Study design and cohort. This single-arm, prospective, multicenter, phase II study was conducted at the Tokyo Women’s Medical University Hospital (Shinjuku-ku, Tokyo, Japan) and Tokyo Women’s Medical University, Yachiyo Medical Center (Yachiyo-shi, Chiba, Japan). All enrolled patients provided written informed consent. The study protocol was approved by the Institutional Review Board of Tokyo Women’s Medical University and conducted in accordance with the Declaration of Helsinki. It was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; ID: UMIN000024656).
The main eligibility criteria were an age of 20-80 years, an Eastern Cooperative Oncology Group performance status of 0 or 1, and histologically proven clinical T4a/4b (SE/SI) gastric adenocarcinoma or more than three enlarged (major axis ≥10 mm) lymph nodes on computed tomography (CT). The negative peritoneal lavage cytology test and the absence of peritoneal dissemination were also confirmed by staging laparoscopies for all the patients before enrollment in this study.
Treatment protocol. The treatment protocol was as follows: Patients were scheduled to receive two courses of NAC. NAC consisted of an intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and oral S-1 (twice daily) for 2 weeks (days 1-14), followed by a week of rest. This routine was repeated every 3 weeks. The dosage of S-1 was 80 mg/day for body surface area (BSA) <1.25 m2, 100 mg/day for BSA of 1.25 m2-1.5 m2, and 120 mg/day for BSA ≥1.5 m2. After completing two courses, an abdominal CT scan and upper gastroenterological endoscopy were performed to evaluate the response.
If R0 resection was considered possible based on the comprehensive CT scanning and endoscopy findings, the patients underwent surgery between 21 and 49 days after the last administration of S-1. Distal or total gastrectomy with D2 lymphadenectomy was performed in accordance with the Japanese gastric cancer treatment guidelines (6) and provided a satisfactory proximal resection margin.
The administration of adjuvant chemotherapy after gastrectomy was recommended but not mandatory for patients with R0 resection. If R0 resection was not achieved, the protocol treatment was terminated. After completion of the protocol, no further treatment was given until tumor recurrence. The detailed treatment protocol has been previously reported (5).
Outcomes and statistical analysis. The primary endpoint was the R0 resection rate. The secondary endpoints were the 3-year OS, the 5-year OS, the 5-year recurrence-free survival (RFS), the completion rate of the protocol treatment, the pathological response rate (pRR), and the rate of adverse events.
The OS was defined as the time from the registration date to the date of death from any cause and was censored based on the last contact for a surviving patient. The RFS was defined as the time from the registration date to the first date of relapse and/or date of death from any cause and was censored based on the last contact for a recurrence-free surviving patient.
The pathological response was graded by our institutional pathologists according to the Japanese classification of gastric carcinoma, third English edition (7), as follows: Grade 0 (no evidence of effect); Grade 1a (viable tumor cells remain in more than two-thirds of the tumor); Grade 1b (viable tumor cells remain in more than one-third but less than two-thirds of the tumor); Grade 2 (viable tumor cells remain in less than one-third of the tumor); and Grade 3 (no viable tumor cells). The pathological response was defined as Grade 1b or higher in the present study.
Before this trial, the R0 resection rate of pT4 or pN2 GCs in patients who underwent upfront surgical resection in our institute was 66.2%. Therefore, we set the expected R0 resection rate at 86.2%. The sample size was calculated to be 27 cases with one-sided testing at the 5% significance level with a power of 80% (Simon’s two-stage design). The cutoff date for this long-term analysis was March 31, 2023. OS and RFS were calculated using the Kaplan–Meier method for all eligible patients. Univariate analyses of prognostic factors for OS and RFS were performed using log-rank tests. Multivariate analyses were performed using the Cox proportional hazards model to identify independent prognostic factors. All statistical analyses were performed using JMP Pro Version 16.0 (SAS Institute Inc., Cary, NC, USA).
Results
Between May 2016 and March 2019, 30 patients were enrolled in this study. Table I shows the participants’ baseline characteristics. Notably, 20% of the patients had bulky N2 lymph nodes, 10% had type 4 tumors, 57% had type 3 tumors, and 3% (one patient) had both large type 3 tumor and bulky N2 lymph nodes. In addition, 23% of patients had the cT3 tumor, whereas 77% had the cT4a tumor.
Patient (n=30) and tumor characteristics.
At the cutoff date of March 31, 2023, the median follow-up for the OS analysis was 57 months (range=9-73 months). There were eight cases of death, six of which were due to the progressive disease. The 3- and 5-year OS rates were 80.0% and 72.7%, respectively (Figure 1A). The 3- and 5-year RFS rates were 76.7% and 73.0%, respectively (Figure 1B). Seven patients had cancer recurrences. The most frequent site of recurrence was the peritoneum (five patients). One patient had lymph node recurrence, and one had liver recurrence.
Kaplan–Meier curves of overall survival (A) and recurrence-free survival (B) in all patients. The 3- and 5-year overall survival rates were 80.0% and 72.7%, respectively, whereas the 3- and 5-year recurrence-free survival rates were 76.7% and 73.0%, respectively.
We performed subgroup analyses according to the clinical tumor depth, the clinical numbers of lymph node metastases, and the various tumor types. The 3-year OS rates for cT3 and cT4a were 71.4% and 82.6%, respectively, whereas the 5-year OS rates were 71.4% and 72.8%, respectively. The 3-year RFS rates for cT3 and cT4a were 71.4% and 78.3%, respectively, whereas the 5-year RFS rates were 71.4% and 73.4%, respectively (Figure 2A and B). The 3-year OS and RFS rates for cN0/N1/N2/N3 were 100%/60.0%/92.9%/0% (p=0.0003) and 80.0%/60.0%/92.9%/0% (p=0.0193), respectively.
Kaplan–Meier curves of overall survival (A, C, E) and recurrence-free survival (B, D, F) in subgroup analyses.
The 3-year OS rates for type 1, type 2, type 3, and type 4 GC were 100%, 100%, 82.4%, and 0%, respectively. The 3-year RFS rates for type 1, type 2, type 3, and type 4 were 100%, 87.5%, 82.4%, 0%, respectively. The 5-year OS rates for type 1, type 2, type 3, and type 4 were not applicable, 85.7%, 75.5%, and 0%, respectively. The 5-year RFS rates for type 1, type 2, type 3, and type 4 were not applicable, 87.5%, 76.0%, and 0%, respectively (Figure 2C and D). The patients with type 4 tumors had significantly worse OS and RFS (p<0.001) than those with non-type 4 tumors (Figure 2E and F).
Twenty-eight patients (93.3%) underwent postoperative adjuvant chemotherapy (Table I). The median duration of adjuvant chemotherapy was 7 months (range=1-22 months).
Adverse events associated with NAC and operative morbidities have been previously reported (5). Grade ≥3 toxicities during SOX NAC occurred in four patients (13.3%). Grade ≥3 operative morbidities occurred in seven patients (23.3%). No reoperations, treatment-related deaths, or in-hospital deaths occurred during protocol treatment. Of the two patients with R1, one had positive lavage cytology, and one had positive proximal margin. They died within 1 year due to recurrence.
The univariate analysis showed that R0 resection had better OS and RFS than R1 resection. Furthermore, according to the univariate analysis and the multivariate Cox proportional hazards model for the GC, type 4 was a significant independent predictive factor for poor prognosis in the OS (hazard ratio=15.27, 95%CI=1.20-194.57, p=0.0358) and the RFS (hazard ratio=64.90, 95%CI=1.75-2411.96, p=0.0237) (Table II).
Univariate and multivariate prognostic analyses for overall survival and recurrence-free survival.
Discussion
In the present study, the final analysis showed that two cycles of SOX NAC, followed by gastrectomy with D2 lymphadenectomy, exhibited good survival outcomes for patients with resectable, high-risk, advanced GC.
Table III shows a summary of various trials of NAC for advanced GC. These trials included various regimens, such as the doublet regimens (CS, SOX, paclitaxel plus S-1, and capecitabine plus oxaliplatin) and the triplet regimens (docetaxel, oxaliplatin/cisplatin, and S-1, fluorouracil plus leucovorin, oxaliplatin and docetaxel, and epirubicin, cisplatin, and fluorouracil/capecitabine), and two to four courses. However, all trials, including ongoing trials and different phases, had a relatively high R0 rate (73-100%), pRR (41-68%), and 3-year OS rate (59-80%). A simple comparison of the results for the 3-year OS rate was challenging. This might be because the treatment targets and adjuvant chemotherapy regimens differed slightly in each trial.
Summary of trials of neoadjuvant chemotherapy for advanced gastric cancer.
For type 4 GC in particular, there is still room for improvement in the treatment. In the present study, patients with type 4 GC had a significantly worse 5-year OS than those with non-type 4 GC. Hosoda et al. suggested that the optimal therapy for type 4 and large type 3 GCs may need to be separately developed with consideration of target molecules (8). Therefore, we need to develop a different treatment strategy for type 4 GC.
In many studies, there was little information regarding the long-term prognosis after NAC for GC according to the macroscopic type or Lauren’s classification. In the KDOG1001 trial, 18 patients (45%) had type 4 GC with a 5-year OS rate of 48%, whereas that of those with non-type 4 GC was 86% (p<0.001) (8). Furthermore, the JCOG0501 trial, in which 61% of patients had type 4 GC, failed to demonstrate the efficacy of NAC with CS (3). The possible reasons indicated were the low pathological complete response rate (2.2%), the difference in efficacy of chemotherapy for signet-ring cells (SRC), and the low completion rate of planned treatment (47%), compared with the FLOT4 trial (3). The present study showed a relatively high pRR but a low pathological complete response rate (7%). All patients received the planned treatment, and three had type 4 GC; however, none of their histological types was SRC. The rates of previously reported SRC were 28% (9) and 41% (3), whereas that in our study was 6.7% (two patients). Notably, these differences may have influenced the results of NAC. SRC accounts for >60% of type 4 or large type 3 GC cases and is considered to reflect resistance to chemotherapy (3). However, taxane-based preoperative chemotherapy may have potential benefits for treating SRC (10). Triplet or higher drug combinations, including docetaxel, may help to further improve the outcome of patients with type 4 GC, especially SRC.
In Japan, the number of older patients with GC is increasing with the proportion of older people (11). Therefore, selecting a more suitable regimen for older patients with GC is necessary. In the oxaliplatin regimen, unlike the cisplatin regimen, forced hydration is unnecessary. For this reason, we believe the oxaliplatin-based regimen is useful for older patients. The G-SOX trial showed that for older patients (≥70 years) with advanced GC, grade ≥3 adverse events occurred less frequently with the SOX therapy than with the CS therapy (12). This trial also indicated that SOX demonstrated favorable efficacy and safety compared with CS for older people with advanced GC (12).
Whether the number of NAC cycles is determined is still controversial. PRODIGY suggested delivering more cycles because of the higher platinum dose intensity (13); however, we doubt the suggestion is accurate. The difference between the present study and the RESOLVE trial (S-1: 40-60 mg bid, d1-14; oxaliplatin: 130 mg/m2 d1, q3W) regarding NAC with SOX was the number of cycles (two or three) (14). Table III shows that there were few differences between the two trials. Too many cycles may not improve NAC efficacy but instead increase adverse event rates. Furthermore, the COMPASS trial showed that the pathological complete response was achieved in only 10% of the patients treated with four courses of the CS and paclitaxel plus cisplatin regimens; however, the pathological response was almost equivalent between two and four courses of those regimens (15). In addition, Aoyama et al. showed that the pRR, defined as a complete response or <10% residual cancer remaining, in two and four cycles of CS were 19.4% and 19.4%, respectively; however, in two and four cycles of docetaxel, cisplatin, and S-1 (DCS), they were 12.1% and 18.8%, respectively (16). The RESONANCE-II trial is ongoing to evaluate the efficacy and safety of different cycles of NAC with SOX (17). We await further detailed reports to help select the number of NAC cycles.
Table III shows that the completion rate of the planned protocol (NAC plus gastrectomy) of the oxaliplatin-based regimens tended to be relatively higher than that of the cisplatin-based regimens. This may result from differences in the rate of adverse events (Table IV). In the present study, only 10% of patients (n=3) had grade ≥3 adverse events compared with previous studies that reported 19.7% (3, 18) and 67.5% (8, 19) with CS and DCS regimens, respectively. In the present study, only 6.7% of patients (n=2) had grade ≥3 non-hematological adverse events compared with previous studies that reported 15% (20) and 20.8% (21, 22) with CS and DCS regimens, respectively. Grade ≥3 neutropenia/anorexia occurred in 19-55%/9.4-20% of patients using the cisplatin regimen and 6.4-51%/2.1-8% using the oxaliplatin regimen. Furthermore, six patients who used the docetaxel regimen had chemotherapy-related toxicity resulting in death (9, 13). These severe toxicities may delay the timing of the surgery and cause a negative prognosis. In addition, all patients in the present study completed the planned two courses of NAC with SOX and underwent surgery. The minimal toxicity of SOX and the resulting high relative dose intensity may have contributed to the favorable R0 resection and OS rates. The low frequency of adverse events and high completion rate of our planned protocol suggest that the SOX regimen may be more useful and suitable than the CS regimen, especially in older patients with advanced GC.
Grade 3 or greater adverse events of trials of neoadjuvant chemotherapy for advanced gastric cancer.
Study limitations. First, this trial had a single-arm, phase II design and a limited number of patients. Second, we could not set the same regimen for adjuvant chemotherapy. Twenty-four patients received adjuvant chemotherapy with S-1 after gastrectomy; however, the duration greatly differed (1-24 months, median: 12 months). Furthermore, two patients received adjuvant chemotherapy with docetaxel and S-1, one with capecitabine, and one with capecitabine and oxaliplatin. These differences in adjuvant chemotherapy may have affected OS and DFS. In Japan, the current standard treatment for resectable, high-risk, advanced gastric cancer is upfront gastrectomy with D2 lymphadenectomy, followed by adjuvant chemotherapy (6). The standard regimens of adjuvant chemotherapy are regarded as S-1 for pathological stage II, docetaxel and S-1 for pathological stage III, and S-1/capecitabine plus oxaliplatin for pathological stage II or III based on the ACTS-GS (2, 23), JACCRO GC-07 (24), ARTIST 2 (25), and CLASSIC (26, 27) trial. The analysis of the JCOG1509 trial (28), which is a phase III trial to evaluate the efficacy of NAC SOX, followed by D2 gastrectomy with adjuvant S-1 for locally advanced GC, is awaited.
Conclusion
Our updated analysis showed that two cycles of SOX NAC, followed by gastrectomy with D2 lymphadenectomy, for resectable advanced GC, except type 4, were associated with relatively good long-term oncologic outcomes. We hope that the phase III trial of two cycles of SOX NAC for resectable GC without type 4 will be evaluated in the future.
Acknowledgements
The Authors would like to thank all patients and co-workers for their participation and cooperation in this study.
Footnotes
Authors’ Contributions
Hidekazu Kuramochi and Kei Hosoda are responsible for the study conception and design; Shunichi Ito, Akiko Serizawa, Masaho Ota, Satoshi Katagiri, and Shinsuke Maeda for the acquisition, analysis, and interpretation of data; Shunichi Ito for the drafting; and Hidekazu Kuramochi and Kei Hosoda for the critical revision of the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
This study was supported by funds from the Department of Gastrointestinal and General Surgery, Tokyo Women’s Medical University.
- Received November 22, 2023.
- Revision received December 13, 2023.
- Accepted December 14, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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