Rationale, conduct, and outcome using hypofractionated radiotherapy in prostate cancer

Hypofractionated radiation therapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic ratio with treatments delivered in larger-sized fractions. In addition, the associated reduction in fraction number produces attractive cost and patient convenience advantages as well. A still limited but growing number of hypofractionation trials have reported acceptable short-term levels of toxicity and biochemical control, but most have insufficient follow-up to ensure the long-term safety and efficacy of this approach. This situation will improve as many currently active trials mature, particularly several high-value randomized trials. In contrast, extreme hypofractionation, with schedules delivering only on the order of 5 fractions, is truly in its infancy for prostate cancer, with extremely limited tolerance and efficacy information currently available. Several uncertainties in the radiobiology of hypofractionation mitigate for an organized, cautious investigational approach. The fractionation response (alpha/beta ratio) of prostate cancers and, for that matter, late-responding normal tissues, has yet to be rigorously defined. Additionally, the linear-quadratic (LQ) model used in the design of hypofractionation schedules is subject to its own uncertainties, particularly with respect to the upper limit of fraction sizes for which it remains valid. Contemporary dose-escalated radiation therapy is already highly effective, making it imperative that ongoing and future studies of hypofractionation be performed in carefully designed, randomized clinical trials. Clinical validation permitting, the adaptation of hypofractionation as a standard of care could profoundly influence future management of localized prostate cancer.