Is There Any Benefit From Hypofractionation in External-Beam Irradiation for Prostate Cancer?

To the Editor:

Pollack et al¹ recently reported the results of a large randomized trial of hypofractionated external-beam irradiation for prostate cancer; the article was accompanied by an editorial by Lee.² In the study, more than 300 men with favorable- to high-risk prostate cancer were randomly assigned to receive either conventionally fractionated intensity-modulated radiation therapy (IMRT; 38 fractions of 2.0 Gy each to a cumulative dose of 76 Gy), or a higher, biologically equivalent dose by hypofractionated IMRT (26 fractions of 2.7 Gy each to a cumulative dose of 70.2 Gy). The study's goals were to compare the relative efficacy of the two regimens in preventing biochemical (ie, prostate-specific antigen [PSA]) and/or clinical failure (biochemical and/or clinical disease failure [BCDF]), and to compare their relative toxicities—specifically, to assess the theoretical superiority of hypofractionation over standard fractionation. The results of that study showed no significant difference in disease-free survival between the two arms at a median follow-up of over 5.5 years, and although overall toxicity of the two regimens was also comparable, men whose baseline urinary function was already compromised before treatment had significantly worse obstructive symptoms after receiving the hypofractionated regimen. The authors concluded that the primary advantage of the hypofractionated regimen lies in its shorter time course (by 2.5 weeks), but that this benefit must be weighed against the increased risk of significant urinary toxicity. The study was powered to observe a 30% versus 15% BCDF at 4.0 years, but the control group's BCDF at 5.0 years was 21%, suggesting that the study was underpowered to test the authors' hypothesis. Additionally, as the authors state, the increased urinary toxicity with the hypofractionated regimen was derived from an unplanned subgroup analysis, but obviously it is of concern.

We do not dispute the results or the conclusions drawn from the study by Pollack et al,¹ but there are growing data for both modest hypofractionation (25 to 30 fractions) and accelerated hypofractionation (four to five fractions), the latter using stereotactic body radiotherapy (SBRT) techniques. The Radiation Therapy Oncology Group (RTOG) has recently completed accrual for a large prospective study of 1,115 patients randomly assigned to either 28- or 41-fraction regimens (RTOG 0415), and a randomized phase II trial comparing five- and 12-fraction accelerated hypofractionation is nearing accrual completion (RTOG 0938). Beginning approximately 10 years ago, radiation oncologists at several institutions began treating prostate cancer with accelerated SBRT using the CyberKnife—generally 36.25 Gy in five fractions—and the results have been favorable, both in terms of maintained biochemical response and in terms of toxicity, culminating in two major multi-institution studies being presented at the 2012 American Society for Therapeutic Radiology and Oncology conference. One was a pooled 5-year retrospective series of 1,100 patients treated at eight institutions, 60% with favorable-risk disease (Gleason grade < 6 and PSA < 10), 30% with intermediate-risk disease, and 10% with high-risk disease (Gleason grade 7 to 10 and PSA 10 to 20).³ At a median follow-up of 36 months, the 5-year biochemical relapse–free actuarial survival (bRFS) for all patients was 93%, and for the 335 patients with at least 4 years of follow-up, the bRFS was 97% for low risk and 89% for intermediate risk. The other study was a prospective multi-institution trial wherein 129 patents with intermediate-risk disease (Gleason grade 7 with PSA < 10, or Gleason grade 6 with PSA 10 to 20) received 40 Gy in five fractions (and 36.25 Gy to the seminal vesicles).⁴ At a median of 30 months of follow-up, the 3-year bRFS was 99.2%, and GI and urinary toxicities were minimal and in line with external-beam data, as was the preservation of sexual potency. Most recently, Katz et al⁵ presented their 6-year single-institution series of more than 300 patients, and the data are still holding up, both with regard to efficacy and toxicity.

We therefore believe that there are in fact good data to support the advantage of accelerated hypofractionated irradiation in the treatment of prostate cancer. In addition to making it feasible to administer an entire course of treatment in only five fractions—far less than the standard 8+ weeks, which is now the norm for IMRT, yet with both equal efficacy and morbidity—SBRT also carries with it the added benefit of substantially lower costs to both patients and insurers.

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Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Irving D. Kaplan, Accuray Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None