Altered fractionation: limited by mucosal reactions?

The effectiveness of accelerated fractionation and hyperfractionation in cancer of the head and neck has been confirmed by randomized studies. These new fractionation strategies are almost invariably accompanied by an increase of early normal tissue reactions, in particular mucosal reactions. This paper presents a survey of the available experimental and clinical mucositis data and aims to assess to what extent the upper aerodigestive tract mucosa is limiting to treatment intensification by altered fractionation. The rate of dose delivery is the most important determinant for early radiation reactions. With accelerated radiotherapy, relative to a conventional treatment of 7 weeks, the achievable gain in treatment time is 2 weeks at most with the mucosa being the limiting tissue. Any further acceleration requires a reduction of dose. Manipulations with the temporal distribution of dose, fraction dose, and optimization of interfraction intervals can improve tolerance but probably do not allow significant further intensification of the existing accelerated schedules. Dose escalation by hyperfractionation does not seem to be directly limited by early mucosal reactions. Late reacting tissues are more likely to limit intensification of these schedules. Suggestions for further improvement of treatment outcome include: the generation of a potent agent which can ameliorate radiation mucositis and so permit further intensification of radiotherapy schedules; combination of altered fractionation schedules with hypoxic modifiers; and tailoring of the treatment strategy based on patient and tumour characteristics.