title: Five year results of a randomized trial comparing hyperfractionated to conventional radiotherapy over four weeks in locally advanced head and neck cancer.
abstract: OBJECTIVE
  Fractionation strategies delivered over 4 weeks are of clinical and radiobiological interest because treatment is completed before radiotherapy (RT) induced clonogen proliferation commences in earnest approximately 3 to 4 weeks into a course of RT. We wished to test the clinical hypothesis that an increased total dose delivered over 4 weeks with smaller than standard doses per fraction in locally advanced squamous cell carcinoma (SCC) may result in relative protection of late responding tissues and an increased tumor control compared to a conventional daily course in the same overall time.
  
  
  METHODS
  Between 1988 and 1995 a randomized controlled trial employing RT alone was undertaken at the Princess Margaret Hospital that included 331 eligible patients with T3 or T4 N0 or any N-positive oropharynx, hypopharynx, or larynx primary SCC. RT was randomly assigned to one of two 4 week schedules, either 51 Gy in 20 equal daily fractions, termed conventional fractionation (CF), or 58 Gy in 40 equal fractions given twice per day as a hyperfractionated (HF) experimental arm.
  
  
  RESULTS
  The 5-year local relapse rate was reduced in the HF (41%) compared to the CF arm (49%). This difference was marginally not significant (p=0.082) when the effect was not adjusted. When the effect of the treatment was adjusted by Cox model for clinical factors that included N-category, ECOG performance status, site of disease, T-category, age, hemoglobin, and gender the HF achieved a significant effect (p=0.02). Survival (40% vs. 30%) was also improved with HF compared to CF arm. This difference was only marginally not significant (p=0.069) but again achieved statistical significance when the model was adjusted for clinical factors (p=0.01). Similar results were observed for disease free survival. Although reversible acute toxicity was increased with HF, the overall 5-year rate of grade 3 and 4 late toxicity for the CF was 10.5% compared to 7.7% in the higher dose HF arm.
  
  
  CONCLUSIONS
  HF delivered in 4 weeks permits enhanced RT doses achieving improved tumor control, without increased late toxicity, compared to daily fractionated radiotherapy in the same overall time.
authors.affiliation: Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Ontario, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Cummings
authors.forename: Thomas
authors.initials: T
authors.lastname: Keane
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.forename: Padraig
authors.initials: P
authors.lastname: Warde
authors.forename: John
authors.initials: J
authors.lastname: Waldron
authors.forename: David
authors.initials: D
authors.lastname: Payne
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
authors.forename: Randy
authors.initials: R
authors.lastname: Bissett
authors.forename: Michael
authors.initials: M
authors.lastname: McLean
authors.forename: Patrick
authors.initials: P
authors.lastname: Gullane
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
mesh_terms: D000328:Adult; D000368:Aged; D019583:Dose Fractionation, Radiation; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011878:Radiotherapy / Q000009:adverse effects; D013997:Time Factors