Clinical Investigation
Correlation Between the Severity of Cetuximab-Induced Skin Rash and Clinical Outcome for Head and Neck Cancer Patients: The RTOG Experience

The results of this study were previously presented at the Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2014, Chicago, IL.
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Purpose

To evaluate the severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients with head and neck squamous cell carcinoma treated with chemoradiation therapy and cetuximab.

Methods and Materials

Analysis included patients who received loading dose and ≥1 cetuximab dose concurrent with definitive chemoradiation therapy (70 Gy + cisplatin) or postoperative chemoradiation therapy (60-66 Gy + docetaxel or cisplatin).

Results

Six hundred two patients were analyzed; 383 (63.6%) developed grade 2 to 4 cetuximab rash. Patients manifesting grade 2 to 4 rash had younger age (P<.001), fewer pack-years smoking history (P<.001), were more likely to be males (P=.04), and had p16-negative (P=.04) oropharyngeal tumors (P=.003). In univariate analysis, grade 2 to 4 rash was associated with better overall survival (hazard ratio [HR] 0.58, P<.001) and progression-free survival (HR 0.75, P=.02), and reduced distant metastasis rate (HR 0.61, P=.03), but not local-regional failure (HR 0.79, P=.16) relative to grade 0 to 1 rash. In multivariable analysis, HRs for overall survival, progression-free survival, distant metastasis, and local-regional failure were, respectively, 0.68 (P=.008), 0.85 (P=.21), 0.64 (P=.06), and 0.89 (P=.48). Grade ≥2 rash was associated with improved survival in p16-negative patients (HR 0.28 [95% confidence interval 0.11-0.74]) but not in p16-positive patients (HR 1.10 [0.42-2.89]) (P=.05 for interaction). Twenty-five percent of patients with grade 2 to 4 acute in-field radiation dermatitis experienced grade 2 to 4 late skin fibrosis, versus 14% of patients with grade 0 to 1 acute in-field radiation dermatitis (P=.002).

Conclusion

Grade 2 to 4 cetuximab rash was associated with better survival, possibly due to reduction of distant metastasis. This observation was noted mainly in p16-negative patients. Grade 2 to 4 acute in-field radiation dermatitis was associated with higher rate of late grade 2 to 4 skin fibrosis.

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.

Section snippets

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.

References (35)

  • J.A. Bonner et al.

    Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers

    J Clin Oncol

    (2000)
  • S.M. Huang et al.

    Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck

    Cancer Res

    (1999)
  • J.A. Bonner et al.

    Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck

    N Engl J Med

    (2006)
  • J.B. Vermoken et al.

    Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platin-based therapy

    J Clin Oncol

    (2007)
  • J.L. Lefebvre et al.

    Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: The TREMPLIN randomized phase II study

    J Clin Oncol

    (2013)
  • K. Ang et al.

    Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522

    J Clin Oncol

    (2014)
  • L.B. Saltz et al.

    The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies

    Proc Am Soc Clin Oncol

    (2003)
  • 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.

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