- Positive deep margin + ENE(+):
- Best adjuvant plan:
- Cisplatin–Post-op RT (CRT):
- Why:
- These are the classic high-risk pathologic features that derived clear benefit from adding concurrent high-dose cisplatin to adjuvant RT in the two landmark randomized trial:
- EORTC 22931 and RTOG 9501, and in their comparative analyses
- These are the classic high-risk pathologic features that derived clear benefit from adding concurrent high-dose cisplatin to adjuvant RT in the two landmark randomized trial:
- Why:
- Cisplatin–Post-op RT (CRT):
- Best adjuvant plan:
- What the trials showed:
- EORTC 22931 (Bernier et al., NEJM 2004):
- Population:
- Resected stage III to IV HNSCC with high-risk features:
- Definition broader than RTOG 9501
- Resected stage III to IV HNSCC with high-risk features:
- Arms:
- RT alone (66 Gy) vs RT + cisplatin 100 mg / m² q3wk ×3
- 5-yr outcomes (Kaplan–Meier):
- Overall survival:
- 53% (CRT) vs 40% (RT) (significant)
- Progression-free survival:
- 47% (CRT) vs 36% (RT) (significant)
- Locoregional control:
- Improved with CRT
- Overall survival:
- Interpretation:
- Clear KM curve separation favoring CRT for DFS / OS in the high-risk post-op setting New England Journal of Medicine+2PubMed+
- Population:
- RTOG 9501 (Cooper et al., NEJM 2004; 10-yr update 2012):
- Population:
- Resected HNSCC with prespecified high-risk factors
- Arms:
- RT 60 Gy/6 wk vs RT + cisplatin 100 mg / m² on days 1, 22, 43
- Entire cohort (10-yr KM):
- OS and DFS not significantly different overall
- LRF numerically lower with CRT but not significant
- Crucial prespecified subset:
- Positive margins and / or ENE(+):
- Locoregional failure:
- 33.1% (RT) vs 21.0% (CRT), p = 0.02
- Disease-free survival:
- 12.3% (RT) vs 18.4% (CRT), p = 0.05
- Overall survival:
- 19.6% (RT) vs 27.1% (CRT), trend in favor of CRT
- Locoregional failure:
- Positive margins and / or ENE(+):
- Interpretation:
- KM curves diverge in R+ / ENE(+):
- Establishing concurrent cisplatin as the adjuvant standard exactly for these features New England Journal of Medicine+2PMC+2
- KM curves diverge in R+ / ENE(+):
- Population:
- Combined / Comparative analyses (what ties it together):
- Bernier et al., Head & Neck 2005 (comparative look at EORTC 22931 and RTOG 9501):
- Concluded that the greatest and most consistent benefit from adjuvant CRT accrues to patients with:
- Extranodal extension and / or positive margins: PubMed+1
- Concluded that the greatest and most consistent benefit from adjuvant CRT accrues to patients with:
- Updated combined analysis (Zumsteg et al., 2025, Annals of Oncology—abstract):
- Pooling EORTC 22931 + RTOG 9501:
- Shows OS improvement with postoperative CRT overall:
- ENE and margin status were prognostic but not strictly predictive:
- Patients without these features may still benefit
- ENE and margin status were prognostic but not strictly predictive:
- While cancer-specific mortality fell with CRT:
- But some benefit was offset by other-cause mortalit:
- Underscoring need for careful patient selection Annals of Oncology+1
- But some benefit was offset by other-cause mortalit:
- Shows OS improvement with postoperative CRT overall:
- Pooling EORTC 22931 + RTOG 9501:
- Bernier et al., Head & Neck 2005 (comparative look at EORTC 22931 and RTOG 9501):
- EORTC 22931 (Bernier et al., NEJM 2004):
- Practical plan for positive deep margin + ENE(+):
- Adjuvant CRT:
- RT with cisplatin 100 mg / m² q3wk ×2 to 3:
- Goal cumulative ≥ 200 mg / m²:
- Is guideline-concordant and evidence-based to improve LRC / DFS and likely OS vs RT alone in this risk profile New England Journal of Medicine+1
- Goal cumulative ≥ 200 mg / m²:
- If cisplatin-ineligible:
- Acknowledge that randomized survival benefit in this setting is with cisplatin:
- Alternatives (e.g., RT alone or RT+cetuximab) are considered when cisplatin cannot be given:
- But are not proven equivalent post-op (See NCCN.) NCCN
- Alternatives (e.g., RT alone or RT+cetuximab) are considered when cisplatin cannot be given:
- Acknowledge that randomized survival benefit in this setting is with cisplatin:
- RT with cisplatin 100 mg / m² q3wk ×2 to 3:
- Adjuvant CRT:
- Bottom line:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 