Misonidazole in fractionated radiotherapy: are many small fractions best?

Abstract

Computer simulations were made of 4 radiotherapy fractionation regimes in current use or proposed for clinical trials of misonidazole. A variety of cell-survival parameters and reoxygenation patterns were used. The models allowed assessment of the relative importance of repair capacity, reoxygenation rate and dose per fraction for these 4 schedules in the presence or absence of misonidazole. Unlike hyperbaric O2, the dose of misonidazole and the fractionation scheme used were critically interdependent, because the total drug dose was limited to 12 g/m2 by its neurotoxicity, regardless of the extent to which it was fractionated. The largest sensitizing effect was always demonstrated with 6 fractions, each given with 2 g/m2 of misonidazole. In the absence of reoxygenation, a sensitizer enhancement ratio of 1.7 was predicted, but this falls to 1.1-1.2 with extensive reoxygenation. Less sensitization occurred with 30 fractions, each with 0.4 g/m2 of drug. For clinical use, the important question is which treatment kills the maximum number of tumor cells. Many of the simulations predict a marked disadvantage of reducing the fraction number for only X-rays. The circumstances in which this disadvantage is offset by the large SER [X-ray dose without sensiter/X-ray dose with sensitizer to achieve equal cell kill for fully hypoxic cells] values with a 6-fraction schedule are few. The model calculations imply many small fractions, each with a low drug dose, are safest unless the clinician has some prior knowledge that a change in fraction number is not disadvantageous.