title: The influence of HPV-associated p16-expression on accelerated fractionated radiotherapy in head and neck cancer: evaluation of the randomised DAHANCA 6&7 trial.
abstract: OBJECTIVE
  Tumour HPV-positivity is a favourable prognostic factor in the radiotherapy of HNSCC, but the optimal radiotherapy regimen for HPV-positive HNSCC is not yet defined. Reducing overall treatment time is known to improve outcome in the radiotherapy of HNSCC as was also demonstrated in the randomised DAHANCA 6&7 trial. We aimed to assess the influence of tumour HPV-status, expressed by p16, on the response to accelerated fractionated radiotherapy in HNSCC through evaluation of the DAHANCA 6&7 trial.
  
  
  METHODS
  Immunohistochemical detection of HPV-associated p16-expression was performed on FFPE-pre-treatment tumour-tissues from 794 patients enrolled in the DAHANCA 6&7 trial. The influence of tumour p16-status on loco-regional tumour control and survival as a function of fractionation schedule (5Fx/week vs 6Fx/week) was evaluated 5years after the completion of radiotherapy.
  
  
  RESULTS
  The significant and independent prognostic value of tumour p16-positivity in HNSCC radiotherapy was confirmed, with adjusted hazard ratios (HR) of 0.58 [0.43-0.78], 0.47 [0.33-0.67] and 0.54 [0.42-0.68] for loco-regional control, disease-specific and overall survival, respectively. Accelerated radiotherapy significantly improved loco-regional tumour control compared to conventional radiotherapy, adjusted HR: 0.73 [0.59-0.92] and the benefit of the 6Fx/week regimen was observed both in p16-positive (HR: 0.56 [0.33-0.96]) as well as in p16-negative tumours (HR: 0.77 [0.60-0.99]). Disease-specific survival was also significantly improved with accelerated radiotherapy in the group of p16-positive tumours (adjusted HR: 0.43 [0.22-0.82]).
  
  
  CONCLUSIONS
  Accelerated radiotherapy significantly improves outcome in HNSCC compared to conventional fractionation. The observed benefit is independent of tumour p16-status and the use of a moderately accelerated radiotherapy regimen seems advantageous also for HPV/p16-positive HNSCC.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. pernille@oncology.dk
authors.forename: Pernille
authors.initials: P
authors.lastname: Lassen
authors.forename: Jesper G
authors.initials: JG
authors.lastname: Eriksen
authors.forename: Annelise
authors.initials: A
authors.lastname: Krogdahl
authors.forename: Marianne Hamilton
authors.initials: MH
authors.lastname: Therkildsen
authors.forename: Benedicte P
authors.initials: BP
authors.lastname: Ulhøi
authors.forename: Marie
authors.initials: M
authors.lastname: Overgaard
authors.forename: Lena
authors.initials: L
authors.lastname: Specht
authors.forename: Elo
authors.initials: E
authors.lastname: Andersen
authors.forename: Jørgen
authors.initials: J
authors.lastname: Johansen
authors.forename: Lisbeth J
authors.initials: LJ
authors.lastname: Andersen
authors.forename: Cai
authors.initials: C
authors.lastname: Grau
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000401:mortality / Q000532:radiotherapy* / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019583:Dose Fractionation, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000401:mortality / Q000532:radiotherapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D027383:Papillomaviridae / Q000302:isolation & purification*; D016016:Proportional Hazards Models; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins