Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial

Abstract

Purpose: The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m²). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m²) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown.

Patients and methods: In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m²) or with weekly cisplatin (40 mg/m²) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32.

Results: Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm.

Conclusion: Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.

FIG 1.

CONSORT diagram. AE, adverse event.

FIG 2.

(A) The Kaplan-Meier curve for OS for all randomly assigned patients at the third interim analysis. The symbols indicate censored observations. The boundary for statistical significance of noninferiority for OS required a P value of < .00433 (CI 99.1%). HRs were computed using a stratified Cox proportional hazards model and the P values were from a stratified log-rank test. (B) The plot of unstratified HRs for death in the analysis of treatment, with effect according to baseline demographic and clinical subgroups. (C) The Kaplan-Meier curve for OS for all randomly assigned patients at the updated analysis. ^aOne patient in each arm is missing. ECOG PS, Eastern Cooperative Oncology Group performance status; ENE, extranodal extension; HPX, hypopharynx; HR, hazard ratio; ICR, incomplete resection; LX, larynx; NE, not evaluable; OC, oral cavity; OPX, oropharynx; OS, overall survival.

FIG 3.

(A) The Kaplan-Meier curve for RFS for all randomly assigned patients. The symbols indicate censored observations. HRs were computed using a stratified Cox proportional hazards model. (B) The plot of unstratified HRs for death or recurrence in the analysis of the treatment effect according to baseline demographic and clinical subgroups. ^aOne patient in each arm is missing. ECOG PS, Eastern Cooperative Oncology Group performance status; ENE, extranodal extension; HPX, hypopharynx; HR, hazard ratio; ICR, incomplete resection; LX, larynx; NE, not evaluable; OC, oral cavity; OPX, oropharynx; RFS, relapse-free survival.