Reasons for Concern
Despite the large body of data showing the potential biological and economic benefits of prostate hypofractionation, there are causes for concern. Although there are many researchers who feel that the α/β ratio for prostate cancer is low, there is no definitive conclusion as to exactly how the α/β ratio for prostate cancer compares to that of nearby late-responding normal tissues, such as the rectum and bladder. Additionally, those advocating the widespread adoption of hypofractionation have typically only relied on imprecise modeling assumptions and an imprecise biologically effective dose (BED) equation.
Most importantly, the exact therapeutic gain is not known. Although many trials report favorable outcomes for patients with prostate cancer who have undergone hypofractionation, there are a number of trials that report conflicting evidence. With regard to tumor control, a Canadian multicenter study found that the estimated 5-year biochemical or clinical failure rate was higher in the hypofractionated arm than in the standard treatment arm.
A number of trials have also reported negative acute toxicity outcomes associated with prostate hypofractionation, as noted previously. A Fox Chase Cancer Center randomized trial reported a small but significantly higher level of GI toxicity (grade ≥ 2) in the hypofractionated arm, but a lower grade of GU toxicity compared with the normofractionated arm. Canadian and Australian randomized trials found a significant increase in GI and GU toxicity in the hypofractionated group when comparing symptoms at the end of radiotherapy with patients’ baseline. These results, considered together with other studies showing no major differences in toxicity, suggest a relative lack of consensus regarding the risks and benefits of hypofractionated treatment. It is hoped that the controversies and questions regarding hypofractionated treatment for prostate cancer will be addressed by ongoing clinical trials.
Because there remains considerable debate regarding the therapeutic advantage of prostate hypofractionation, there is a strong need to assess the efficacy and safety of hypofractionation in future trials. Several recently closed and ongoing trials aim to provide information that will further inform the development of this treatment. A recently closed Radiation Therapy Oncology Group (RTOG) phase III randomized trial (0415) aims to compare the disease-free survival of patients with favorable-risk stage II prostate cancer treated with hypofractionated three-dimensional conformal radiotherapy (3D-CRT) or IMRT vs standard fractionated 3D-CRT or IMRT. The investigators also will determine whether the incremental gains in disease-free survival outweigh effects on such QOL domains as mobility, self-care, ability to perform usual activities, pain/discomfort, and anxiety/depression. This trial closed to accrual in 2009.
Following the close of RTOG 0415, the multicenter RTOG 0938 trial opened; RTOG 0938 seeks to demonstrate that 1-year health-related QOL for at least one hypofractionated arm (of two hypofractionated regimens being studied) is not significantly lower than baseline as measured by the bowel and urinary domains of the EPIC instrument. This trial will only include men with favorable-risk prostate cancer. Additionally, the Proton Collaborative Group has undertaken a phase III clinical trial comparing standard vs hypofractionated treatment with proton therapy in men with low-risk prostate adenocarcinoma. Because proton therapy is growing in popularity, the results of this trial will be instructive. All of the aforementioned trials will further illuminate the effectiveness of prostate hypofractionation and provide information that will potentially change the way in which clinicians treat prostate cancer.
Hypofractionation for the treatment of prostate cancer remains a growing area of research. Many trials illustrate the significant risks and benefits associated with this treatment modality. Because this treatment modality has the potential to lower overall treatment costs and increase patient convenience, prostate hypofractionation is of interest in a fiscally conservative health care system. Depending on the results of future trials, prostate hypofractionation could serve as a resource-efficient and well-tolerated treatment modality that will prove effective in the long-term management of prostate cancer worldwide.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.