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

Abstract

Purpose: Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS).

Patients and methods: Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers.

Results: Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v. 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m2 v. 191.1 mg/m2, respectively); and more grade 3 to 4 radiation mucositis (43.2% v. 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v. 2.0%, respectively; P = .81), 3-year PFS (61.2% v. 58.9%, respectively; P = .76), 3-year OS (72.9% v. 75.8%, respectively; P = .32), locoregional failure (19.9% v. 25.9%, respectively; P = .97), or distant metastasis (13.0% v. 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v. 49.2%, respectively; P < .001) and OS (85.6% v. 60.1%, respectively; P < .001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome.

Conclusion: Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.

Fig 1.

CONSORT diagram. RT, radiotherapy.

Fig 2.

Kaplan-Meier estimates of (A) progression-free and (B) overall survival and cumulative incidence estimates of (C) locoregional failure and (D) distant metastasis by assigned treatment. HR, hazard ratio; RT, radiotherapy.

Fig 3.

Kaplan-Meier estimates of (A) progression-free and (B) overall survival and (C) cumulative incidence estimates of locoregional failure and (D) distant metastasis by p16 expression in patients with oropharyngeal carcinoma. HR, hazard ratio.

Fig 4.

Forest plots of treatment effect for (A) progression-free and (B) overall survival. A hazard ratio of less than 1 indicates a benefit with the addition of cetuximab. Vertical lines are shown at a hazard ratio of 1.0 and the observed hazard ratio for the entire study population. There is a significant interaction (P = .02) between assigned treatment and age (> v ≤ 50 years) for overall survival, indicating a treatment benefit for younger patients receiving cetuximab. EGFR, epidermal growth factor receptor; IMRT, intensity-modulated radiotherapy; 3DCRT, three-dimensional conformal radiotherapy.

Fig A1.

Kaplan-Meier estimates of (A) progression-free and (B) overall survival and (C) cumulative incidence estimates of locoregional failure and (D) distant metastasis by epidermal growth factor receptor (EGFR) expression using a cut point of 80% of tumor cells staining positive. HR, hazard ratio.

Fig A2.

Kaplan-Meier estimates of (A) progression-free and (B) overall survival and cumulative incidence estimates of (C) locoregional failure and (D) distant metastasis by epidermal growth factor receptor (EGFR) expression using a four-level semiquantitative method. HR, hazard ratio.