Background
Phase III RCT (Intergroup 0116 / INT-0116 / SWOG-directed). 559 patients with resected adenocarcinoma of the stomach or gastroesophageal junction (≥T3 and/or node-positive) randomized to postoperative chemoradiotherapy vs observation after R0 resection. Notably, 54% of patients received less than a D2 dissection (D0 in 36%), reflecting real-world US surgical practice at the time.
Interventions and follow up
Arm A: Adjuvant chemoradiotherapy — 5-FU 425 mg/m²/day + leucovorin 20 mg/m²/day × 5 days (cycle 1) → 45 Gy in 25 fractions (with modified 5-FU/LV on days 1–4 and last 3 days) → 5-FU/LV × 2 more cycle
Arm B: Observatio
Primary endpoint: Overall survival
mFollow up: >10 years (updated analysis)
Arm B: Observatio
Primary endpoint: Overall survival
mFollow up: >10 years (updated analysis)
Results
OS: HR 1.32 (95% CI 1.10–1.60), P=.0046 favoring chemoRT; median 36 vs 27 months
RFS: HR 1.51 (95% CI 1.25–1.83), P<.001
Locoregional recurrence reduction: Substantial; LRR reduction appears to account for majority of overall relapse benefit
RFS: HR 1.51 (95% CI 1.25–1.83), P<.001
Locoregional recurrence reduction: Substantial; LRR reduction appears to account for majority of overall relapse benefit
Adverse events
Main adverse events: Grade 3 toxic effects 41%, grade 4 32%; 3 treatment-related deaths (1%). Hematologic and GI toxicities predominant. Second malignancies: 21 (chemoRT) vs 8 (observation), P=.21.
Conclusions
Adjuvant chemoradiotherapy (5-FU/LV + 45 Gy) after curative resection significantly improved OS and RFS compared to observation in high-risk gastric cancer, with durable 10-year benefit, establishing postoperative chemoradiation as the North American standard of care.
Key Limitations
Key Limitations: High rate of inadequate nodal dissection (D0 in 36%) — the radiation may compensate for insufficient surgery rather than add benefit to optimal D2 resection. Both ARTIST (after D2 resection) and CRITICS (after adequate surgery) failed to show added benefit of postoperative radiation over chemotherapy alone. 5-FU/LV chemotherapy backbone is outdated; no comparison with modern regimens. Grade 3/4 toxicity rates were high by modern standards.
Clinical Context
INT-0116 established postoperative chemoradiotherapy as standard care in the US after R0 gastric resection, particularly in patients with inadequate nodal dissection. In centers with routine D2 dissection (Korea, Japan), adjuvant chemotherapy alone (CLASSIC, S-1) or adjuvant CRT in node-positive patients (ARTIST subgroup) is preferred. CRITICS and ARTIST-II results have modulated indications for adjuvant CRT.