Randomized phase 3 trial of the hypoxia modifier nimorazole added to radiation therapy with benefit assessed in hypoxic head and neck cancers determined using a gene signature (NIMRAD).
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Author
Thomson, David JSlevin, Nick J
Baines, Helen
Betts, Guy
Bolton, Steve
Evans, Mererid
Garcez, Kate
Irlam, Joely
Lee, Lip
Melillo, Nicola
Mistry, Hitesh
More, Elisabet
Nutting, Christopher
Price, James M
Schipani, Stefano
Sen, Mehmet
Yang, Huiqi
West, Catharine M
Other Contributors
Aynsley, EleanorBanner, Russel
Barnett, Gill
Cardale, Kate
Christian, Judith
Fresco, Lydia
Grant, Warren
Hartley, Andrew
Lester, James
McCloskey, Paula
Prestwich, Robin
Shenoy, Aditya
Thiagarajan, Sridhar
Wood, Katie
Publication date
2023-12-09Subject
Oncology. Pathology.
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Purpose: Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT). Methods and materials: NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m2 daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level. Results: Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P = .35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P = .88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P < .05). Conclusions: Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival.Citation
Thomson DJ, Slevin NJ, Baines H, Betts G, Bolton S, Evans M, Garcez K, Irlam J, Lee L, Melillo N, Mistry H, More E, Nutting C, Price JM, Schipani S, Sen M, Yang H, West CM; NIMRAD Trial Group. Randomized Phase 3 Trial of the Hypoxia Modifier Nimorazole Added to Radiation Therapy With Benefit Assessed in Hypoxic Head and Neck Cancers Determined Using a Gene Signature (NIMRAD). Int J Radiat Oncol Biol Phys. 2024 Jul 1;119(3):771-782. doi: 10.1016/j.ijrobp.2023.11.055.Type
ArticleAdditional Links
http://www.sciencedirect.com/science/journal/03603016PMID
38072326Publisher
Elsevierae974a485f413a2113503eed53cd6c53
10.1016/j.ijrobp.2023.11.055