Hypofractionation in prostate cancer radiotherapy

Animal and clinical experiments in France in the 1920’s suggested that radiotherapy delivered in a number of daily dose fractions, spread out over a period of several weeks, resulted in better tumor control for a given level of normal tissue toxicity than the application of the radiation in a single large dose. In the 1980’s it was shown that there is a systematic difference in the fractionation dependence of late responding normal tissues and early responding tissues both normal and malignant, probably due to a difference in the proportion of dividing cells. In 1999, it was pointed out that, while this was true of most tumors, it was generally not the case for prostate cancer because it is particularly slow growing. Using data from both external beam radiotherapy and brachytherapy it was shown that prostate cancer responds to fractionation in a manner more similar to a late responding tissue than an early responding tissue. This led to the conclusion that much smaller numbers of fractions than usually used (with an appropriately reduced total dose) should be equally effective in treating prostate cancer, but with the associated advantages in cost, logistics and patient convenience. Many large scale randomized clinical trials have been completed in the past 18 years to test this concept, the conclusion being that that moderate hypofractionation, typically involving 15 to 25 fractions with doses per fraction of 2.5 to 3.5 Gy, is not inferior to conventional fractionation patterns involving 40 to 45 fractions with doses per fraction around 2 Gy. More recently extreme hypofractionation is being investigated, typically involving 4 to 7 fractions with much higher doses per fraction. It is too early to draw conclusions about extreme hypofractionation, but early toxicity results raise concerns.