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The randomized DAHANCA 5 trial demonstrated the benefit of the hypoxic cell sensitizer nimorazole (NIM) in Head & Neck Squamous Cell Carcinoma (HNSCC) treated with conventional fractionated radiotherapy alone. Subsequently a hypoxic gene signature indicated which patients (pts) with hypoxic tumors may benefit from NIM. The objectives of the present trial were to demonstrate the benefit of NIM with accelerated concomitant chemo-radiotherapy (CRT), and the predictive value of the hypoxic gene signature. 

Pts with stage III-IV laryngeal, hypopharyngeal or p16-negative oropharyngeal SCC were randomized between NIM and placebo, given concomitantly with CRT. Pts were stratified using the hypoxic gene signature. Quality controlled accelerated radiotherapy was delivered using IMRT up to a total dose of 70 Gy in 6 weeks. Cisplatin (CDDP) was delivered either weekly (40 mg/m²on week 1 to 6) or 3-weekly (100 mg/ m²on weeks 1 & 4). NIM or placebo were delivered orally with a daily dose of 1.2 mg/m². The 2 co-primary endpoints were the locoregional control rate 1) for the entire population and 2) for the hypoxic-gene-positive pts. Secondary endpoints included overall survival, disease-free survival, disease-specific survival, and acute and late morbidity.

After two safety reviews, IDMC recommended to only use the weekly CDDP regimen based on the nephrotoxicity of the 3-weekly regimen. At last review, IDMC recommended the early closure of the trial based on the weak conditional power for the hypothesized treatment effect. Thus 194 pts (92 oro, 59 hypo and 43 lar) were randomized out of the 640 originally planned. The majority of pts had T3-T4 (76%) and N2-3 (66%) tumors. Thirty-three % of tumors were hypoxic-gene positive. One hundred and two pts were treated with weekly CDDP (60 with NIM and 62 with placebo), and 72 pts with 3-weekly CDDP (37 with NIM and 35 with placebo). Using the 3-weekly CDDP, 90% of pts developed ≥ grade 3 adverse events (AE) with more nephrotoxicity in the NIM arm (27% compared to 11.4%), and 2 pts had grade 5 AE, 1 with NIM and 1 with placebo. In the weekly CDDP, 94% of pts developed ≥ grade 3 AE, and 7 had grade 5 AE, 3 with NIM and 4 with placebo. A possible relationship to NIM was only described in 1 pt. At 2 years, the locoregional control probability was not clinically different between the 2 arms neither in the entire population (63.8% for NIM and 72.1% for placebo), nor in the hypoxic-gene positive pts. No clinical difference was observed according to the CDDP regimen. For the secondary endpoints, no clinical difference was either observed between the 2 arms. 

The low precision of the estimates precludes any firm conclusion on the effect of NIM versus placebo. However, the data does not show any beneficial effect of NIM in the full pts population, or in the sub-group with hypoxic gene signature. Prohibitive toxicity was observed with the 100 mg/m²CDDP regimen.