Prostate Cancer and the Hypofractionation Hypothesis

“Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished. They are indispensable for the workman; but you mustn’t mistake the scaffolding for the building.”—Goethe Nearly 15 years ago, Brenner and Hall authored a provocative paper that claimed that the fractionation sensitivity of prostate cancer was different from most tumors and, as a consequence, radiation oncologists should treat this cancer with hypofractionation (fewer, larger daily fractions). The optimal fractionation schedule for specific cancers has been the subject of argument for more than a century. In the first three decades of the 20th century, two methods of practice evolved. One method (popularized by Seitz and Wintz) involved large single-dose treatments. Advocates of this approach believed that fractionation of treatment would “favor the tumor.” The other method, advocated by Regaud and Coutard, called for treatment to be fractionated. By the late 1930s, the fractionated approach would be adopted by most radiotherapists. del Regato, in the Regaud lecture in 1968, would claim that this was “the last time in radiotherapy where consensus is reached.” As del Regato anticipated, the arguments about optimal fractionation continue to this day. As most readers will be unfamiliar with the underlying theory of fractionation, a brief primer is in order. Radiation-induced death for mammalian cells is classically described according to the linear quadratic equation. According to this formalism, the survival rate of a given cell will depend on the overall radiation dose, the dose per fraction, and the overall treatment time. In this model, the dose-response of tumors and normal tissues to fractionated irradiation can be described according to the alpha-beta ratio ( / ). The / parameter is an indication of the fractionation sensitivity of a particular cell type. In general the / is high ( 10) for early-responding normal tissues (skin, mucosa) and most tumors, and low ( 5) for later-responding normal tissues (spinal cord, bone). One implication of different / for tumor cells and normal tissue is that it may be possible to increase the therapeutic ratio by using unconventional fractionation schedules. The / estimate for prostate cancer provided in the 1999 paper by Brenner was 1.5; most tumors are reported to have an / of 10. Over the ensuing decade a number of retrospective analyses have been published and the majority of these papers, although not all, favor the low / hypothesis for prostate cancer. Indeed, some authors already accept the claim that the / is low, evidently viewing this as settled science and no longer a hypothesis. In the early 2000s clinical researchers in a number of centers used explicit / estimates to design clinical trials that would test this hypothesis, namely that the / of prostate cancer is low. In the article that accompanies this editorial, Pollack et al report the results of one of these studies. The purpose of this editorial is threefold: to define hypofractionation as it relates to prostate cancer, to review the design and results of Pollack et al’s clinical trial, and to discuss the use of superiority and noninferiority designs in trials of prostate cancer. At the end I will comment on whether moderate hypofractionation should become the standard of care. Voltaire instructs us to “define our terms” at the beginning of discourse. For the purposes of this editorial, conventional fractionation involves daily treatments of 1.8-2 Gy for 38 to 45 fractions. Hypofractionation is anything that uses fewer, larger fractions. Hypofractionation has been further subdivided into moderate hypofractionation (2.4 to 4 Gy/fraction for 15-30 fractions) and extreme hypofractionation (6.5 to 10 Gy/fraction for 4-7 fractions). Although brachytherapy can be used to deliver hypofractionated treatment this editorial will focus on the use of linear accelerators (teletherapy) to deliver moderate hypofractionation. There are a number of potential advantages to using fewer treatments. First, fewer treatments is more convenient for patients. Using conventional fractionation some patients are treated for 9 to 10 weeks and reducing this to 2 to 6 weeks is clearly an advantage. Second, in environments with a limited number of linear accelerators, fewer treatments allow more patients to be treated with the same number of linear accelerators. Finally, reducing the number of treatments will lower the costs of treatment, especially in health systems like the United States in which the fee-for-service model dominates and costs are directly tied to the number of treatments. As important as these considerations are, most of the enthusiasm for hypofractionation has been associated with the possibility of increasing the therapeutic ratio, which leads us to the Pollack et al trial. To begin, the Fox Chase investigators are to be commended for completing this study. It is a significant accomplishment to enroll more than 300 patients in less than 4 years at a single institution (only two patients were treated outside of Fox Chase). As such this is the largest, contemporary phase III study examining moderate hypofractionation in prostate cancer reported to date. The sample size was motivated by the hypothesis that dose escalation using hypofractionated intensity-modulated radiation therapy (HIMRT; 70.2 Gy in 26 fractions of 2.7 Gy) would reduce the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 31 NOVEMBER 1 2013