Toward optimal external-beam fractionation for prostate cancer.

As an increasing number of men are undergoing radiotherapy for prostate cancer, and at younger ages, it is becoming more and more important to define optimal radiotherapeutic regimens to treat the disease. A great deal of effort has rightly been put into improving dose distributions, through three-dimensional conformal radiotherapy and intensitymodulated radiotherapy (1), as well as through brachytherapy (2). Less attention has, however, been paid to fraction size. By and large, most protocols for external-beam treatment of prostate cancer have adhered to 1.8 –2 Gy fractions, although results with hyperfractionation (3) and hypofractionation (4) have recently been reported. In part, this lack of attention to fraction size can be attributed to the comparatively slow-growing nature of prostate tumors (5), implying that overall treatment time is unlikely to be a critical factor. Fractionation plays another key role in radiotherapy, however, typically providing a therapeutic advantage between tumor control and late sequelae. Generally speaking, this therapeutic advantage comes by fractionating as much as possible, in that fractionation spares late-responding normal tissues more than tumors, because tumors normally respond as early-responding tissue (6)—in the language of the linear–quadratic model, fractionation spares tissues with a low a/b ratio (late-responding tissues) more than it does tissues with a high a/b ratio (early-responding tissues typical of most tumors). As we have known for many years, however, prostate tumors are highly atypical of most malignancies. Most prostate tumors consist of an extremely low proportion of cycling cells (5, 7), but with many dormant cells waiting to be recruited into cycle if stimulated. So, from the perspective of radiation sterilization, our major task is probably to sterilize noncycling, as well as cycling, prostate cells. In such a situation, the prostate would be expected to respond to changes in fractionation as a late-responding tissue, in which case the rationale for increased fractionation would disappear. In fact, a recent editorial by Duchesne and Peters (8) suggested just this in the context of brachytherapy—that high-dose-rate (HDR) brachytherapy of the prostate might be as efficacious as low-dose-rate, because the tumor and the surrounding late-responding tissue would respond in the same way to changes in fractionation. These concepts have recently been quantified by estimating an average a/b value for prostate tumors directly from clinical data, and the value obtained was indeed typical of a late-responding tissue, about 1.5 Gy (9, 10). The same conclusion can be drawn from a recent report by Martinez et al. (11) on HDR brachytherapy boosts after external-beam treatment for unfavorable prostate cancers. HDR brachytherapy was given either as three 6-Gy treatments or two 9-Gy treatments. An a/b value of 10 Gy for the prostate tumors would result in essentially identical tumor control for these two treatments, whereas an a/b value of 1.5 Gy would result in significantly increased tumor control for the 2 3 9 Gy compared to the 3 3 6 Gy boost. In fact, a significantly increased tumor control was seen with the 2 3 9 Gy boost (96% vs. 70% at 3 years, p 5 0.002), consistent with a low a/b value. What does this mean for external-beam radiotherapy of the prostate? Essentially what we have is a late-responding target tissue (the prostate tumor), adjacent to which are the bladder and rectum, both of which can exhibit early and late morbidity. Thus, moving to a smaller number of larger fractions (hypofractionation) should affect tumor control and late morbidity in the same way, so, assuming the prescribed dose is decreased appropriately, no change in tumor control or late sequelae rates would be expected. In other word, more convenient schedules, consisting of fewer larger fractions, should achieve equal tumor control with no increase in late effects. As an added bonus, because early sequelae are less responsive to changes in fractionation, for a given level of tumor control and late sequelae, one would expect less early morbidity from a hypofractionated regimen. Although early sequelae are not generally dose limiting, a