Hyperfractionated radiotherapy for locally advanced squamous cell carcinoma of the head and neck

Questions: 1. Does hyperfractionated radiotherapy improve locoregional control or survival as compared with conventionally fractionated radiotherapy in patients with newly diagnosed, locally advanced (stage III-IV) squamous cell carcinoma of the head and neck who are deemed suitable for radiotherapy with curative intent? 2. What is the toxicity associated with hyperfractionation? 3. Can these novel regimens enhance the therapeutic ratio (benefits to toxicity)? Perspective: Evidence was selected and reviewed by two members of the Head and Neck Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative and by methodologists. This guideline has been reviewed and approved by the DSG, which comprises medical and radiation oncologists, surgeons, and one community representative. A draft version of the guideline was circulated to 112 clinicians for input, using a 21-item feedback questionnaire. The return rate was 50%, and 33% of the practitioners added written comments. Of respondents, 72% agreed that the document should be approved as a practice guideline, and 78% agreed that they would use it in their clinical practice. Methodology: Relevant evidence was identified by a systematic search of the MEDLINE (1966-2000) and CANCERLIT (1983-2000) databases, the Cochrane Library (Issue 3, 2000), and conference proceedings. The evidence review was limited to randomised trials and meta-analyses of randomised trials that compared hyperfractionated radiotherapy with conventional radiotherapy in patients with newly diagnosed, locally advanced (stage III-IV) squamous cell carcinoma of the head and neck deemed suitable for radical radiotherapy with curative intent. Overall survival and locoregional control were the primary outcomes of interest. Results: Search results. Seven randomised controlled trials (two in abstract form) and one published meta-analysis of hyperfractionated radiotherapy versus conventional radiotherapy met the inclusion criteria. Benefits. Only three trials of hyperfractionated versus conventional radiotherapy provided convincing evidence of improved tumour control favouring hyperfractionation. One trial detected an absolute improvement in locoregional control from 40% to 59% at 5 years (p = 0.02). In the other trial, the 2-year local-control rate was 54.4% for hyperfractionation as compared with 46% for conventional radiotherapy (p = 0.045). The 5-year locoregional control rates in the third trial were 45% for hyperfractionation as compared with 37% for conventional radiotherapy (p = 0.01). In one of the three trials, improved locoregional control was accompanied by an increase in overall survival (40% vs. 30% at 5 years; p=0.013). The other two trials documented improved overall survival with hyperfractionation, but both trials have been criticized for failing to report complete data. Harms. Hyperfractionated radiotherapy yields higher rates of acute mucosal and skin toxicity as compared with conventional radiotherapy. Data on the incidence and severity of late complications associated with hyperfractionation are incomplete. It is premature to conclude that hyperfractionation with dose escalation does not increase late tissue complications.