- Cisplatin-ineligible unresected disease:
- Most guideline-concordant RT partner:
- Cetuximab
- Most guideline-concordant RT partner:
- Anchor trials and what they show:
- Proof that EGFR antibody + RT beats RT alone:
- Establishes cetuximab as a curative RT partner
- Bonner et al., NEJM 2006; 5-yr update 2010:
- In locoregionally advanced, unresected HNSCC, adding cetuximab to definitive RT over RT alone improved:
- Locoregional control:
- Median 24.4 months vs 14.9 months:
- HR 0.68, p=0.005 over RT alone
- Median 24.4 months vs 14.9 months:
- Overall survival:
- Median 49.0 months vs 29.3 months:
- HR 0.74, p=0.03 over RT alone
- Median 49.0 months vs 29.3 months:
- This occured without excess severe mucositis
- Locoregional control:
- This is the randomized dataset that legitimized cetuximab as a radiosensitizer when chemotherapy can’t be given:
- In locoregionally advanced, unresected HNSCC, adding cetuximab to definitive RT over RT alone improved:
- Proof that substituting cetuximab for cisplatin is harmful in HPV+ OPSCC:
- So only use when truly ineligible
- Trials:
- RTOG-1016 (Lancet 2019):
- RT + cetuximab failed non-inferiority vs RT + cisplatin
- It produced worse OS and PFS in HPV-positive OPSCC
- Investigators conclude cisplatin remains the standard for eligible patients:
- De-ESCALaTE HPV (Lancet 2019):
- Similarly showed inferior OS and higher recurrence with cetuximab – RT vs cisplatin – RT:
- Ending the practice of “de-escalation by substitution”
- Similarly showed inferior OS and higher recurrence with cetuximab – RT vs cisplatin – RT:
- RTOG-1016 (Lancet 2019):
- Attempts to replace cetuximab in the cisplatin-ineligible setting haven’t beaten it:
- NRG-HN004 (2024):
- In patients contraindicated for cisplatin, RT + durvalumab:
- Did not improve outcomes over RT + cetuximab:
- Cetuximab – RT remained the reference:
- Did not improve outcomes over RT + cetuximab:
- In patients contraindicated for cisplatin, RT + durvalumab:
- NRG-HN004 (2024):
- Proof that EGFR antibody + RT beats RT alone:
- Guideline through-line (how this translates to practice):
- NCCN (2025):
- For definitive management when cisplatin is contraindicated:
- For example:
- Renal dysfunction, grade ≥ 2 SNHL, significant neuropathy
- RT + cetuximab is a listed option:
- Substitution for convenience or “de-escalation”;
- Is not recommended given RTOG-1016 / De-ESCALaTE trials;
- Substitution for convenience or “de-escalation”;
- For example:
- For definitive management when cisplatin is contraindicated:
- NCCN (2025):
- Practical takeaways for your pathway:
- Most guideline – concordant partner when cisplatin is off the table:
- Cetuximab with RT:
- Supported by the only randomized trial showing benefit over RT alone (Bonner) PubMed
- Cetuximab with RT:
- Do not swap out cisplatin in HPV+ disease unless truly ineligible:
- Expect worse survival with substitution PubMed+1
- If cetuximab isn’t feasible:
- Severe infusion reactions:
- Some centers use carboplatin – based CRT (often AUC 1–2 weekly ± partner):
- But high-level randomized evidence with RT is limited relative to cetuximab:
- Data are mainly retrospective / phase II (Guideline nuances vary by site and risk) Cancer Treatment Reviews
- But high-level randomized evidence with RT is limited relative to cetuximab:
- Some centers use carboplatin – based CRT (often AUC 1–2 weekly ± partner):
- Severe infusion reactions:
- Most guideline – concordant partner when cisplatin is off the table:
- Bottom line:
- In cisplatin-ineligible, unresected HNSCC:
- RT + cetuximab remains the most evidence-based, guideline-aligned radiosensitizer:
- Chosen because it improves outcomes vs RT alone:
- While trials show it must not replace cisplatin in eligible HPV+ patients
- Chosen because it improves outcomes vs RT alone:
- RT + cetuximab remains the most evidence-based, guideline-aligned radiosensitizer:
- In cisplatin-ineligible, unresected HNSCC:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 