Strategies to overcome accelerated repopulation and hypoxia—what have we learned from clinical trials?

Accelerated repopulation and tumor hypoxia are significant causes of treatment failure following radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). Accelerated fractionation schedules were designed to counter accelerated repopulation. Review of the randomized trials of accelerated fractionation reveals that the best results have been obtained with regimens that deliver the full conventional dose with a modest degree of acceleration by use of either a concomitant boost or 6 days/week treatment. However, the role of accelerated fractionation when chemoradiation is used has not been established. Although tumor hypoxia is an established adverse prognostic factor in head and neck cancer treated with radiotherapy, progress has been hampered by the lack of a widely available and reproducible method of hypoxia detection and by the limitations of previous treatments designed to overcome hypoxia. The advent of noninvasive hypoxic imaging with positron emission tomography (PET), and new treatment approaches, such as accelerated radiotherapy with carbogen and nicotinamide (ARCON) and hypoxic cytotoxins, has led to renewed optimism that hypoxia can be overcome or exploited to improve the outcomes in locally advanced head and neck cancer.