title: HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer.
abstract: BACKGROUND
  HPV/p16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using p16-status as a retrospective stratification parameter, we aimed to assess the influence of p16-expression on the response to nimorazole in HNSCC.
  
  
  METHODS
  Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for p16-expression. The influence of p16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5 years after radiotherapy.
  
  
  RESULTS
  Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52-0.93]. Positive expression of p16 also significantly improved outcome after radiotherapy (0.41 [0.28-0.61]). In the subgroup of patients with p16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50-0.95]). However, in the p16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45-1.91]).
  
  
  CONCLUSIONS
  HPV/p16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/p16-negative tumours but was of no significant benefit in HPV/p16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark. pernille@oncology.dk
authors.forename: Pernille
authors.initials: P
authors.lastname: Lassen
authors.forename: Jesper Grau
authors.initials: JG
authors.lastname: Eriksen
authors.forename: Stephen
authors.initials: S
authors.lastname: Hamilton-Dutoit
authors.forename: Trine
authors.initials: T
authors.lastname: Tramm
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000994:Antitrichomonal Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000532:radiotherapy* / Q000821:virology; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000532:radiotherapy* / Q000821:virology; D006801:Humans; D000860:Hypoxia; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009554:Nimorazole / Q000494:pharmacology; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000994:Antitrichomonal Agents; D009554:Nimorazole