International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationCorrelation Between the Severity of Cetuximab-Induced Skin Rash and Clinical Outcome for Head and Neck Cancer Patients: The RTOG Experience
Introduction
Several preclinical and correlative biomarker studies from various laboratories had detected epidermal growth factor receptor (EGFR) as a predictor of radiation response of head and neck squamous cell cancers (HNSCC) and had identified EGFR and its downstream signaling molecules as appealing targets for therapeutic intervention 1, 2, 3. The efficacy and safety of cetuximab (a chimeric monoclonal antibody that binds to the extracellular ligand-binding domain of EGFR, preventing activation and dimerization of the receptor) have been studied in combination with radiation therapy (RT) in several clinical trials 4, 5, 6, 7. A large international trial testing the efficacy of RT with cetuximab versus RT alone showed that the combination of cetuximab and RT yielded improved locoregional control and reduced mortality without added hematologic and mucosal toxicities (4). Thus, the international trial provided proof of principle for selective tumor targeting in the treatment of locally advanced HNSCC, and phase 2 and 3 prospective randomized trials were designed to assess whether adding cetuximab to a chemoradiation regimen will further improve the outcome in patients with stage III to IV disease (1).
Occurrence of more severe cetuximab-induced skin toxicity has been shown to correlate with better treatment response and longer survival in studies across multiple malignancies 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. Patient- and tumor-related markers predicting cetuximab-induced skin toxicity are still not well defined. This investigation analyzes the prognostic value of cetuximab-induced skin toxicity for treatment efficacy in patients with locoregionally advanced HNSCC enrolled in 2 randomized trials: studies NRG Oncology Radiation Therapy Oncology Group (RTOG) 0522 and 0234.
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Methods and Materials
Study NRG Oncology RTOG 0234, a phase 2 prospective, randomized trial, tested whether RT with concurrent cetuximab and cisplatin or cetuximab and docetaxel improve disease-free survival over a historical patient cohort treated with RT and concurrent cisplatin (Radiation Therapy Oncology Group protocol 9501) in patients with high-risk pathologic features after surgical resection of advanced HNSCC. NRG Oncology study RTOG 0522, a phase 3 prospective, randomized trial, tested the addition of
Incidence and associated risk factors for the cetuximab-related skin rash
Six hundred two patients were analyzed. Five hundred eight (84.3%) experienced cetuximab rash; patient characteristics by grade of cetuximab rash are shown in Tables E1 and E2 (available online at www.redjournal.org). Patients with grade 2 to 4 rash had younger age (P<.001), fewer pack-years smoking history (P<.001), were more likely to be male (P=.04), and had p16-negative (P=.04) oropharyngeal primary site (P=.003).
Prognostic value of the cetuximab-related skin rash for tumor response
When all 406 patients exposed to cetuximab in study NRG Oncology RTOG 0522
Discussion
The patients in our study had been exposed to RT, cisplatin or docetaxel, and cetuximab; the severity of the cetuximab-induced skin toxicity has been correlated with clinical outcomes. Within the present analysis, frequency and grading of cetuximab-induced skin rash were within the range of previously published data 19, 20, 21, 22, 23, 24, 25, 26, 27. Patients developing grade 2 to 4 rash did experience better outcome compared with patients developing grade 0 to 2 rash, with an HR of 0.68 (P
Conclusions
The present analysis demonstrates that grade 2 to 4 cetuximab-induced skin toxicity is associated with better survival in the HNSCC populations studied. Grade 2 to 4 acute in-field radiation dermatitis in our study was associated with a higher risk of late grade 2 to 4 skin fibrosis. These results need to be validated in other trials.
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Cited by (0)
This project was supported by grants U10CA21661, U10CA180868, U10CA180822, and U10CA37422 from the National Cancer Institute and by Bristol-Myers Squibb.
Conflict of interest: V.B.-A. reports research funding from Bristol-Myers Squibb and the Radiation Therapy Oncology Group. Q.(E.)Z. reports that an immediate family member is employed by and owns stock in Pfizer. D.I.R. reports stock or other ownership interest in Concordia, a consulting or advisory position with Merck Serono, and research funding from Merck Serono. C.U.J. reports a consulting or advisory position with Lilly and a speakers' bureau with Bristol-Myers Squibb. R.L.F. reports a patent or intellectual property interest from the Mayo Clinic. D.R. reports a consulting or advisory position with Astra Zeneca, Ferring, and Merck. Q.-T.L. reports research funding from Amgen.