Which Radiosensitizer to Use in Cisplatin-Ineligible Patient Undergoing Chemoradiation for Head and Neck Cancer?

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Cisplatin-ineligible patient (CrCl ~ 42, grade-2 neuropathy / hearing loss) needing radiosensitizer: 
    • Cetuximab-radiation therapy (RT)
      • Why: 
        • Renal insufficiency / neuropathy:
          • Are consensus contraindications to cisplatin
        • Cetuximab-RT:
          • Is a recognized alternative when cisplatin cannot be given
    • Caveat: 
      • Do not swap to cetuximab just to avoid toxicity in otherwise eligible HPV+ patients:
        • Worse survival vs cisplatin
    • Alternatives: 
      • Carboplatin / 5-FU-RT (center-dependent) or weekly carboplatin / taxane-RT protocols
  • Refs: NCCN H&N cisplatin-ineligibility; RTOG-1016/De-ESCALaTE.
  • Who is cisplatin-ineligible (and why it matters):
    • Absolute / near-absolute: 
      • CrCl < 50 mL /min
      • Baseline ≥ grade-2 hearing loss
      • Neuropathy
      • Significant frailty / comorbidity
    • 50 to 60 mL / min:
      • Often treated as relative ineligibility
    • These thresholds are repeatedly endorsed in expert consensus / position pieces PMC+1
    • Implication: 
      • If the patient cannot safely receive cisplatin (e.g., CrCl 42 and G2 neuropathy), you should not try to “dose through” it:
        • Pick a non-cisplatin radiosensitizer
  • What supports cetuximab + radiation therapy (RT), when cisplatin is off the table?:
    • Bonner et al., NEJM 2006 (+ 5-yr update):
      • In LA-HNSCC, RT + cetuximab vs RT alone improved locoregional control and overall survival:
        • 5-yr OS significantly higher with cetuximab
      • Toxicity profile was different:
        • More acneiform rash / infusion reactions:
          • But no global increase in common RT-related toxicities was seen
      • Important:
    • 2024 NRG-HN004 (Lancet Oncology):
      • For cisplatin-ineligible patients:
        • Durvalumab-RT did not outperform cetuximab-RT:
          • The editorial conclusion remains that cetuximab-RT is the standard comparator in the cisplatin-ineligible populationThe Lancet
    • Bottom line: 
      • In a cisplatin-ineligible patient:
        • Cetuximab-RT is a guideline-accepted radiosensitizing regimen with randomized evidence vs RT alone and remains the standard control in contemporary trials of the ineligible population The Lancet
  • Why you should not swap cisplatin to cetuximab in an eligible (especially in HPV+) patient:
    • Two large, definitive, head-to-head trials in HPV-positive oropharyngeal cancer:
      • RTOG 1016 (Gillison et al., 2019):
        • RT + cetuximab failed non-inferiority to RT + cisplatin for:
          • Overall survival:
            • OS HR 1.45, one-sided 95% upper CI 1.94
          • 5-yr OS: 
            • 77.9% (cetuximab) vs 84.6% (cisplatin)
        • No clinically meaningful reduction in overall serious toxicity with cetuximab
        • Conclusion: 
          • Cisplatin-RT is superior:
            • Do not substitute cetuximab for convenience PubMed
      • De-ESCALaTE HPV (Mehanna et al., 2019):
        • 2-yr OS: 97.5% with cisplatin vs 89.4% with cetuximab
        • PFS and recurrence outcomes also favored cisplatin
        • Toxicity not globally lower with cetuximab
        • Conclusion:
          • Cetuximab-RT leads to worse survival:
        • Reinforcing data: 
          • Observational / registry analyses found inferior OS with cetuximab vs cisplatin in non-operative definitive settings, aligning with the RCT signal PMC
        • Guideline posture: 
          • Major guidelines and reviews explicitly caution against elective substitution of cetuximab for cisplatin in HPV+ disease:
            • Reserve cetuximab for cisplatin-ineligible patients PMC
  • What about other non-cisplatin options?
    • Carboplatin / 5-FU + RT (or carboplatin / paclitaxel + RT):
      • Used at some centers for ineligible patients:
        • But randomized data are much thinner than for cetuximab-RT
      • Consider when EGFR-mAb isn’t suitable:
        • Prior severe infusion reaction or per institutional protocols PMC
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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