Sensitizers and radiation dose fractionation: results and interpretations

Misonidazole is generally regarded as having been a clinical failure as a radiation sensitizer. It is hoped that the newer sensitizers SR-2508 and Ro 03-8799 will give better results because single dose studies with animal tumors have indicated that these two drugs give higher enhancement ratios than misonidazole at clinically tolerated doses. Other factors may also have influenced the clinical efficacy of misonidazole, however, particularly reoxygenation during the course of the fractionated treatments. In this paper reoxygenation in animal tumors and experimental studies in which fractionated radiation doses have been combined with sensitizers are reviewed. It is concluded that, even for dose fractions of 2 Gy, reoxygenation may not completely eliminate the influence of hypoxic cells on tumor response, when large total doses are given. Problems associated with tumor heterogeneity are also discussed to highlight the desirability of selecting the most suitable patients for clinical studies. Poorly reoxygenating tumors, rapidly growing tumors and tumors in patients in whom oxygen delivery to tissue is compromised are those whose control is most likely to be improved by combining radiation sensitizers with conventional treatment. However effective sensitizers should also allow fractionation schedules to be modified, to achieve a therapeutic gain, by taking advantage of differences in repair or repopulation between the tumor and critical normal tissue, without having to consider possible detrimental effects on reoxygenation.