Modelling heat-induced radiosensitization: clinical implications.

Clinically achievable minimum tumour temperatures are in the order of about 41 degrees C. Therefore, it is important to evaluate mechanisms by which temperatures in this range might enhance cytotoxicity. Previous in vitro studies have demonstrated that 1-4 h (depending on the sequencing of modalities) of heating at 41 degrees C produces substantial heat-induced radiosensitization with little or no cell killing by heat alone. The increased radiation sensitivity is best modelled as a change in the single hit, alpha, parameter (with no significant effect on the two-hit parameter, beta) of the cell survival curve. The implications of heat-induced radiosensitization being mediated by a change in alpha on the traditional thermal enhancement ratio (for various radiation doses/fraction and alpha/beta) are reviewed. Response rates for a cohort of 60 patients enrolled on a prospective thermal dose escalation study are modelled assuming that the thermal dose dependence of heat-induced radiosensitization is modulated by a heat-induced delta alpha. The clinical data are fitted with delta alpha about 0.05-0.1 Gy-1. Randomized trials reported in the literature and the implication for the design of future prospective trials are reviewed in light of these observations.