Five-year update of the gastric cancer adjuvant therapy JCOG1104 trial: how much therapy is enough?

Yoshikawa and colleagues report 5-year updated results of JCOG1104 (OPAS-1), a seminal phase 3 trial in resected stage II gastric cancer comparing 6 months of adjuvant S-1 to the conventional 1 year of S-1 (1). The update continues to support superiority of 1 year of S-1 in stage II disease over 6 months of therapy as the standard of care. How do we put these results in the context of contemporary adjuvant therapy options and outcomes in resected gastric cancer?

A high degree of survival in stage II disease was reported for the original ACTS-GC trial of 1 year of adjuvant S-1 chemotherapy (2,3). In the subset of patients with stage II disease, an incremental survival benefit of 12.9% was observed with an 84.2% 5-year survival [hazard ratio (HR) 0.509]. This observation raised the potential for de-escalation and potential shorter duration of therapy in good prognosis patients.

A shorter duration of therapy and use of the combination of capecitabine oxaliplatin were addressed in the Korean CLASSIC trial published in 2012 and updated in 2014 (4,5). Six months of adjuvant capecitabine/oxaliplatin after D2 gastrectomy in resected stage II and III gastric cancer improved 5-year overall survival by 9% in all patients compared to surgery alone. A greater incremental benefit was also observed on this trial for stage II patients (HR 0.550). For resected stage II or III gastric cancer therefore two adjuvant care standards emerged, 1 year of S-1 or 6 months of capecitabine oxaliplatin.

Two subsequent trials directly compared single agent S-1 vs. combination chemotherapy focusing on higher risk patients with either node positive or stage III disease. JACCRO GC-07 compared 1 year of S-1 with or without the addition of 6 months of docetaxel in resected stage III gastric cancer (6). Docetaxel plus S-1 achieved significantly improved 3-year relapse free survival over S-1 alone (HR 0.715), translating into a 10.3% improvement (6). Overall survival was also significantly improved (HR 0.742). The second less well-powered study, ARTIST 2 from Korea, treated node positive stage II or III resected gastric cancer comparing 1 year of S-1 vs. 6 months of S-1/oxaliplatin (SOX) (7). Disease free survival was significantly improved with 6 months of SOX over 1 year of S-1 (HR 0.693) with an incremental benefit of 9.5% at 3 years. Similar superiority for SOX over 1 year of S-1 was seen for stage II (HR 0.715) and stage III disease (0.721). Although overall survival results from this trial are awaited, in addition to supporting the superiority of combination chemotherapy over single agent S-1 ARTIST 2 validates a shorter duration therapy of 6 months of therapy in node positive gastric cancer. In stage III or node positive resected gastric cancer, both JACCRO GC-07 and ARTIST 2 endorse combination chemotherapy as superior adjuvant treatment over single agent S-1.

Yoshikawa and colleagues argue that the results from JCOG1104 continue to endorse 1 year of adjuvant S-1 therapy in stage II disease. The protocol specified margin for noninferiority of 4 courses of therapy was an HR of 1.37 allowing for a 37% difference in 3-year relapse free survival. The 95% confidence limits observed for 3-year relapse free survival for 4 courses, an HR ranging from 1.11–5.77, exceeded the cutoff to declare noninferiority for shorter duration therapy. The actual benefit for longer duration therapy, although statistically significant, is arguably quite marginal. At a median follow up of 5.8 years, in 590 patients treated relapse free survival at 3 years was 92.2% for 12 months and 90.1% for 6 months, and at 5 years 87.7% vs. 85.6% (HR 1.265). Overall survival at 5 years was 89.7% for 12 months vs. 88.6% for 6 months (HR 1.21), an absolute survival difference of 1.1% and representing 3 of 295 patients. Are such differences clinically meaningful? Should we treat all patients with 1 year of therapy for a 1.1% difference in 5-year overall survival? Given the small patient numbers identifying a subset of patients from the trial achieving a survival benefit is not possible. Therapy was generally well tolerated beyond neutropenia and only 6% of patients experienced grade 3 adverse events. However, quality of life of patients on study, the cost of therapy, and the impact on patient social factors are not addressed by the authors on this trial. It also seems somewhat counterintuitive that a more favorable prognosis group of patients really benefits from a more protracted duration of adjuvant treatment. If 1 year of therapy with S-1 is advocated by clinicians in treating resected favorable prognosis stage II gastric cancer, an informed consent discussion with patients should be made carefully given the small potential incremental benefit for longer therapy.

What then is the optimal adjuvant therapy and duration of therapy for resected lower risk stage II gastric cancer? Although underpowered to determine relative outcomes in patient subsets, ARTIST 2 trial suggests that 6 months of SOX was superior to 1 year of S-1 chemotherapy in stage II patients. Two care standards may be argued in stage II resected gastric cancer, 6 months of fluorinated pyrimidine oxaliplatin or 1 year of S-1. Arguably consideration could also be made for 6 months of S-1, depending on practitioner and patient assessment of the relevance of the small added benefit of extended S-1 therapy.

What is the future direction of adjuvant therapy in gastric cancer? In parallel with the preoperative therapy approach in the West, in higher risk patients, there is increasing interest in Asia for administering perioperative chemotherapy vs. adjuvant chemotherapy alone in gastric cancer. Results from the RESOLVE trial from China randomizing patients with clinical T4N0/+ gastric cancer to perioperative chemotherapy vs. postoperative chemotherapy showed an improved 3-year disease free survival for perioperative compared to postoperative chemotherapy (8). A recent update suggested a potential improvement in overall survival favoring perioperative chemotherapy (9). It is likely both in the East and West that preoperative followed by postoperative chemotherapy will increasingly be employed in the treatment of gastric cancer.

Future progress will be driven by incorporating specific molecularly targeting agents in biomarker selected patients, including to name a few the new generation of human epidermal growth factor receptor 2 (HER2) targeted therapies, agents that target the gap junction protein claudin 18.2, and agents targeting the fibroblast growth factor receptor (FGFR) receptor. To date, adding immune checkpoint inhibitors to perioperative or adjuvant therapy has not yielded a survival improvement compared to chemotherapy alone (10,11). Identifying higher risk patients who may benefit from therapy intensification or a change in therapy, such as the testing for persistence of circulating tumor DNA to identify very high-risk patients for recurrence, will be explored in future trials.

Acknowledgments

Funding: This research was funded in part through the NIH/NCI Cancer Center Support Grant (P30 CA008748).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-113/coif). D.H.I. reports consulting fees from AMGEN, Bayer, Lilly, Roche, Astra-Zeneca, Bristol Myers Squibb, Astellas, Merck, Daiichi Sankyo, Taiho, Oncolys, and Regeneron. The author has no other conflicts of interest to declare.

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References

1. Yoshikawa T, Terashima M, Mizusawa J, et al. 5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer. Gastric Cancer 2024;27:155-63. [Crossref] [PubMed]
2. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810-20. [Crossref] [PubMed]
3. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011;29:4387-93. [Crossref] [PubMed]
4. Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:1389-96. [Crossref] [PubMed]
5. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012;379:315-21. [Crossref] [PubMed]
6. Kakeji Y, Yoshida K, Kodera Y, et al. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer 2022;25:188-96. [Crossref] [PubMed]
7. Park SH, Lim DH, Sohn TS, et al. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial Ann Oncol 2021;32:368-74. [Crossref] [PubMed]
8. Zhang X, Liang H, Li Z, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol 2021;22:1081-92. [Crossref] [PubMed]
9. Zhang X, Li Z, Liang H, et al. LBA78 Overall survival of perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy: An updated analysis of RESOLVE trial. Ann Oncol 2023;34:S1318-9. [Crossref]
10. Shitara K, Rha SY, Wyrwicz LS, et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol 2024;25:212-24. [Crossref] [PubMed]
11. Terashima M, Kang YK, Kim YW, et al. ATTRACTION-5: A phase 3 study of nivolumab plus chemotherapy as postoperative adjuvant treatment for pathological stage III (pStage III) gastric or gastroesophageal junction (G/GEJ) cancer. J Clin Oncol 2023;41:4000. [Crossref]