Hypofractionation for prostate cancer

Abstract

Hypofractionation for prostate cancer was originally carried out in the pursuit of efficiency and convenience but has now attracted greatly renewed interest based upon a hypothesis that prostate cancers have a higher sensitivity to fraction size, reflected in a low alpha/beta ratio, than do late responding organs at risk such as the rectum or bladder. Tumor control and acceptable toxicity outcomes from several hypofractionation or brachytherapy analyses do in fact support an alpha/beta ratio for prostate cancer that is low, perhaps even lower that that for the normal organs that ordinarily constrain the delivery of radiation therapy. However, many of these studies lack sufficient patient numbers and follow-up, are clouded by dose inhomogeneity issues in the case of brachytherapy, or delivered effective doses that were too low by contemporary standards. Thus, the clinical efficacy of the approach has yet to be fully validated. However, a number of newer prospective trials, some randomized, are underway or have reached accrual but await sufficient follow-up for analysis. These studies, which cover a wide range of doses per fraction, should ultimately be capable of validating the utility of prostate hypofractionation and the models that predict its effects. With hypofractionation's significant potential for therapeutic gain, cost savings, and improved patient convenience, the future management of localized prostate cancer could be profoundly altered in the process.

Figure 1. Increasing therapeutic advantage with increasing hypofractionation

The equivalent total doses if delivered in 2 Gy fractions for prostate tumor (α/β = 1.5) and normal tissue late effects (α/β = 3) are shown versus fraction size-number combinations that preserve similar late effect levels, as would be predicted by the linear quadratic model. A reduction in total dose is required with increasing hypofractionation to maintain similar predicted late effects. The difference between the solid lines and dotted extensions on the right indicate in non-quantitative fashion a potential, over-prediction of biological effect by the linear quadratic model for very large fraction sizes.

Figure 2

Biochemical disease-free survival (bDFS) rates versus equivalent doses from six hypofractionation studies identified in Table 1 (for intermediate risk prostate cancer, when separately reported in the publications). Shown are 3-5 year actuarial bDFS rates using the ASTRO definition, which was the only method consistently available for all reports. The solid line dose response curve for radiation delivered in 2 Gy fractions is adapted from Fowler et al and is based upon 3-5 year biochemical control data for intermediate risk patients from 5 conventionally fractionated prostate cancer trials. Biochemical control points from the hypofractionation trials are plotted relative to their equivalent dose for an assumed prostate cancer α/β ratio of 1.5. Legend: NCIC: Hypofx □, Standard ■; Edinburgh: ▲; Adelaid: Hypofrx △, Standard ▷; Manchester: ▽; Princess Margaret: ○; Cleveland Clinic: ●; Chiba: △.