An international placebo-controlled randomized multicenter trial of nimorazole with accelerated chemo-radiotherapy for locally advanced HPV-negative squamous cell carcinoma of the head and neck (HNSCC).

Abstract

To evaluate the benefit of the hypoxic radiosensitizer nimorazole (NIM) with accelerated concomitant chemo-radiotherapy in patients with advanced squamous cell carcinoma of the head and neck (HNSCC). Patients with stage III-IV laryngeal, hypopharyngeal or HPV-negative oropharyngeal SCC were randomized between NIM or placebo, given concomitantly with moderately accelerated chemo-radiotherapy delivered using IMRT (70 Gy in 6 weeks). Total cisplatin dose was 200 mg/m² either weekly (40 mg/m²) or 3-weekly (100 mg/m²). NIM/placebo was given with 1.2 mg/m² daily. Between Aug 2014 and Jan 2018, when the trial closed prematurely, a total of 194 patients (92 oropharynx, 59 hypopharynx and 43 larynx) were randomized (97 NIM, 97 placebo) out of 640 planned. Most patients had T3-T4 (76%) and N2-3 (66%) tumors. The three-year incidence of locoregional failure was 20.7% (95% Cl: 12.8-29.8) in the NIM arm and 33.8% (24.1-43.8) in the placebo arm. Corresponding disease specific survival were 76.7% and 74.3% and overall survival 62.4% and 61.5% for NIM and placebo, respectively. Multivariable analysis demonstrated significant locoregional benefit of NIM (adjusted HR 0.51; 95% Cl: 0.27-0.95) together with good WHO performance and weekly cisplatin. Compliance with treatment did not differ significantly depending on NIM/placebo allocation and cisplatin regimen, nor did treatment related morbidity except for acute nephrotoxicity which appeared to be higher in the 3-weekly cisplatin regimen. NIM improved locoregional control in advanced HPV-negative HNSCC, but without significant survival improvement. This finding underscore that hypoxic radiosensitization plays a role in chemo-radiotherapy for HNSCC. The incompleteness of the study precluded further detailed analysis.