A Prospective Phase III Randomized Trial of Hypofractionation Versus Conventional Fractionation in Patients With High-Risk Prostate Cancer

Purpose

To compare the toxicity and efficacy of hypofractionated (62 Gy/20 fractions/5 weeks, 4 fractions per week) vs. conventional fractionation radiotherapy (80 Gy/40 fractions/8 weeks) in patients with high-risk prostate cancer.

Methods and Materials

From January 2003 to December 2007, 168 patients were randomized to receive either hypofractionated or conventional fractionated schedules of three-dimensional conformal radiotherapy to the prostate and seminal vesicles. All patients received a 9-month course of total androgen deprivation (TAD), and radiotherapy started 2 months thereafter.

Results

The median (range) follow-up was 32 (8–66) and 35 (7–64) months in the hypofractionation and conventional fractionation arms, respectively. No difference was found for late toxicity between the two treatment groups, with 3-year Grade 2 rates of 17% and 16% for gastrointestinal and 14% and 11% for genitourinary in the hypofractionation and conventional fractionation groups, respectively. The 3-year freedom from biochemical failure (FFBF) rates were 87% and 79% in the hypofractionation and conventional fractionation groups, respectively (p = 0.035). The 3-year FFBF rates in patients at a very high risk (i.e., pretreatment prostate-specific antigen (iPSA) >20 ng/mL, Gleason score ≥8, or T ≥2c), were 88% and 76% (p = 0.014) in the former and latter arm, respectively. The multivariate Cox analysis confirmed fractionation, iPSA, and Gleason score as significant prognostic factors.

Conclusions

Our findings suggest that late toxicity is equivalent between the two treatment groups and that the hypofractionated schedule used in this trial is superior to the conventional fractionation in terms of FFBF.

Introduction

A number of randomized studies have recently provided evidence of improved biochemical control with higher cumulative doses of radiation in prostate cancer 1, 2. By using a conventional fractionation regimen, dose escalation is obtained by increasing the number of daily treatments to as much as 40–45 sessions with an overall time of 8–9 weeks. The delivery of such a high number of sessions requires increased access to radiotherapy departments for patients and can generate some distress in the elderly population with prostate cancer, especially those living at a distance from radiotherapy centers. Quicker treatment, such as radical prostatectomy or even a nondefinitive approach such as total androgen deprivation (TAD), can be an attractive or necessary option for these patients. A reduced number of higher-dose fractions to a biologically equivalent total dose (hypofractionation) should be less distressing for these cancer patients and should also result in reduced treatment costs and shorter waiting periods for patients who need to initiate radiotherapy as soon as possible. Such an alternative approach is based on the assumption that, similar to late-reacting normal tissue, prostate cancer is highly responsive to fraction size (has a low α/β ratio). Recent analyses and reviews of tumor control in prostate cancer 3, 4, 5 have suggested an α/β value on the order of 1 to 3 Gy for prostate cancer, which is somewhat lower than the value typically ascribed to the adjacent organs at risk, such as bladder and rectum (6). If this is indeed the case, it would offer a unique opportunity to improve the therapeutic ratio by using a hypofractionation approach. Fewer but larger-than-conventional fractions for a lesser total dose should achieve efficacy equivalent to higher doses delivered with conventional fraction sizes.

There is little experience with hypofractionation delivered to high total equivalent doses 7, 8, 9. These regimens appear to be associated with excellent results and with acute and late toxicity that is similar to that observed with the conventional fractionation. However, the still-short follow-up and the single-arm nature of these reports do not allow for meaningful comparisons with the conventional regimens. At present, only two randomized studies 10, 11 comparing radiation schedules with different fraction sizes in patients with prostate cancer have been published. Both these trials were designed and performed before the studies suggesting a low α/β for prostate cancer (with no attempt to make the arms isoeffective) and did not provide conclusive evidence with regard to either outcomes or toxicity.

This study was designed to ascertain whether a hypofractionation regimen, designed to be equivalent to a conventional fractionation scheme with regard to tumor control, can result in decreased late toxicity without decreasing freedom from biochemical failure (FFBF). This is the first report describing the outcomes and late toxicity for all randomized patients.