Postoperative Chemoradiation for High-Risk Head and Neck Cancer

Bernier VS Cooper

Comparing EORTC #22931 and RTOG #9501

Background

• Locally advanced HNSCC: poor outcomes with surgery and postoperative RT alone
•  
• Hypothesis: Adding concurrent chemotherapy may improve outcomes
• Two large randomized trials: EORTC #22931 and RTOG #9501
• Both published in the same issue of NEJM

Europe Vs the USA

Study Designs

Patient Eligibility

Results - Locoregional Control

• EORTC #22931:
  5-year estimate: 82% (CRT) vs 69% (RT), p=0.007

• RTOG #9501:
  2-year estimate: 82% (CRT) vs 72% (RT), p=0.01
  5-year estimate: 84% (CRT) vs 74% (RT)
  10-year estimate: 88% (CRT) vs 71% (RT)

Results - PFS vs DFS

• EORTC #22931: 5-year:
  • 47% (CRT)
  • 36% (RT) p=0.04

• RTOG #9501: 3-year:
  • 47% (CRT)
  • 38% (RT), p=0.04

Results - Overall Survival

EORTC #22931

• 3-year estimate: 65% (CRT) vs 49% (RT)
  5-year estimate: 53% (CRT) vs 40% (RT), p=0.02

RTOG #9501:

• 2-year estimate: 63% (CRT) vs 57% (RT), p=0.19
  5-year estimate: 29% (CRT) vs 27% (RT), p=0.31
• Subset with positive margins or ECE (RTOG #9501):
  10-year estimate: 27% (CRT) vs 20% (RT), p=0.07

Results - Overall Survival

EORTC #22931

• 3-year estimate: 65% (CRT) vs 49% (RT)
  5-year estimate: 53% (CRT) vs 40% (RT), p=0.02

RTOG #9501:

• 2-year estimate: 63% (CRT) vs 57% (RT), p=0.19
  5-year estimate: 29% (CRT) vs 27% (RT), p=0.31
• Subset with positive margins or ECE (RTOG #9501):
  10-year estimate: 27% (CRT) vs 20% (RT), p=0.07

Toxicity

Comparative Analysis - Risk Factors

• ECE and/or microscopically involved surgical margins were the most significant prognostic factors

• Patients with these risk factors benefited most from chemoradiation in both trials

• Patients with ≥2 positive lymph nodes without ECE did not seem to benefit significantly from chemoradiation

• No interaction between number of lymph nodes and benefit with chemo (DM p=0.8, OS p=0.161, DFS p=0.45)

Conclusions

• Postoperative chemoradiation improves outcomes in high-risk HNSCC

• Greatest benefit in patients with ECE and/or positive margins

• Consider chemoradiation for patients with stage III-IV disease, perineural invasion, vascular embolism, or level IV-V nodes (oral cavity/oropharynx)

• No OS benefit if only intermediate risk factors present (p=0.33 in EORTC and p=0.78 in RTOG)

Implications for Practice

• Chemoradiation should be standard for patients with ECE and/or positive margins
• Careful patient selection based on risk factors is crucial
• Balance potential benefits with increased toxicity
• Multidisciplinary approach to treatment decision-making
• Consider updated analysis (Lu 2022) showing no benefit with chemo for rising nodal count in OS or DM

Limitations and Future Directions

• Retrospective subgroup analysis
• Differences in eligibility criteria between trials
• Need for prospective validation of risk stratification
• Ongoing research on de-escalation strategies for lower-risk patients
• Investigation of novel systemic therapies (e.g., immunotherapy) in the adjuvant setting
• Need for updated analysis of intermediate risk factors with modern statistical approaches

Wait but what about lymph nodes..... ??

Impact of Nodal Metastasis Count on Outcomes

• Secondary analysis of RTOG 9501, RTOG 0234, and EORTC 22931 (947 patients)
• Increasing number of positive lymph nodes associated with worse outcomes
• Strongest association up to 5 positive nodes
• The association of +LN on outcomes was strongest up to 5 +LNs, with each metastatic LN being associated with an independent additional 19% increased risk of death

Impact of Nodal Metastasis Count

Should I give chemo for >5+ lymph nodes?