Background
Phase III randomized trial (EORTC 22931). N=334, resected HNSCC (oral cavity or oropharynx) with high-risk pathologic features: ECE, positive margins, perineural invasion, vascular invasion, oral cavity pT3–T4, or ≥2 positive LN. Enrolled 1994–2000, 22 European centers. Published simultaneously with RTOG 9501 (same NEJM issue, July 2004). Both used cisplatin 100 mg/m² D1, D22, D43 concurrently.
Interventions and follow up
Arm A: Post-operative RT (66 Gy/33 fx) + cisplatin 100 mg/m² D1, D22, D43
Arm B: Post-operative RT alone (66 Gy/33 fx)
Primary endpoint: PFS
mFollow up: 60 month
Arm B: Post-operative RT alone (66 Gy/33 fx)
Primary endpoint: PFS
mFollow up: 60 month
Results
PFS: HR 0.75 (95% CI 0.57–0.99), P=.04 — significant
OS: HR 0.70 (95% CI 0.52–0.95), P=.02 — significant
5-year OS: 53% (CRT) vs 40% (RT alone)
5-year LRC: 82% vs 69%, P=.007
OS: HR 0.70 (95% CI 0.52–0.95), P=.02 — significant
5-year OS: 53% (CRT) vs 40% (RT alone)
5-year LRC: 82% vs 69%, P=.007
Adverse events
Grade 3–4 acute AEs: 41% (CRT) vs 21% (RT)
Predominant: mucositis, dysphagia, nausea, hematologic toxicity
Treatment-related deaths: none in either arm
Predominant: mucositis, dysphagia, nausea, hematologic toxicity
Treatment-related deaths: none in either arm
Conclusions
Post-operative CRT with cisplatin significantly improved PFS, OS, and locoregional control vs RT alone in resected high-risk HNSCC. EORTC 22931 showed a stronger, statistically significant OS benefit (HR 0.70) than RTOG 9501, strengthening the case for adjuvant CRT in ECE and/or margin-positive disease.
Key Limitations
In the pooled Bernier 2005 analysis, benefit was restricted to ECE and/or positive margins; patients with only ≥2 LN without ECE had no significant benefit. Radiation dose (66 Gy) and eligibility differed slightly from RTOG 9501. HPV status not assessed. 5-year OS in both arms reflects poor outcomes of advanced HNSCC in the pre-HPV-awareness era.
Clinical Context
EORTC 22931 and RTOG 9501 are the twin foundation trials establishing adjuvant cisplatin + RT as standard of care for high-risk resected HNSCC. The pooled Bernier/Cooper analysis showed only ECE and positive margins warrant chemotherapy addition. KEYNOTE-689 (2025) added perioperative pembrolizumab in this setting with EFS benefit (HR 0.73), potentially expanding the standard of care.