Safety of Extreme Hypofractionation Reassuring in Intermediate-Risk Prostate Cancer

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Randomized trials have confirmed the value of radiation dose escalation for prostate tumors, and the potential benefits of larger radiation doses in fewer fractions are expected to increase the therapeutic efficacy for men with prostate cancer.
— Anders Widmark, MD

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Giving patients larger fractions of radiation over shorter periods (ie, hypofractionation) is gaining ground in several types of cancers. This approach is attractive for patients’ convenience, shortening treatment and travel times, and also for resource utilization.

Several studies have shown that moderate hypofractionation given over 4 to 5 weeks is as effective and safe as conventional fractionation given over 8 weeks in men with prostate cancer. A new study, presented at the 58th Annual Meeting of the American Society for Radiation Oncology ­(ASTRO), is the first randomized trial to show that extreme hypofractionation given over 2.5 weeks does not increase long-term toxicity over 2 years compared with conventional fractionation in patients with intermediate-risk prostate cancer.1 Data are not yet available on whether the two techniques are similarly effective in reducing the rate of relapse.

“Randomized trials have confirmed the value of radiation dose escalation for prostate tumors, and the potential benefits of larger radiation doses in fewer fractions are expected to increase the therapeutic efficacy for men with prostate cancer,” said lead author of the study Anders Widmark, MD, of Umeå University, Sweden. “Most of the existing data on hypofractionation, however, draw on cases of moderately accelerated radiation treatment of the prostate, in contrast with our study using more extreme hypofractionation. Our trial shows that patients experience similar side effects at 2 years with highly accelerated extreme hypofractionation.”

Dr. Widmark explained that prostate cancer has sensitivity to high fractionation, suggesting a potential therapeutic benefit for hypofractionation in this cancer.

Study Details

The Scandinavian HYPO-RT-PC noninferiority trial enrolled 1,200 men with intermediate-risk prostate cancer between 2005 and 2015. Intermediate risk was defined as stages T1c to T3a, prostate-specific antigen (PSA) levels of 20 ng/mL or below, and one of three risk factors: stage T3a, Gleason score of 7 or higher, or PSA level > 10 ng/ mL. No androgen-deprivation therapy was allowed.

Extreme Hypofractionation in Prostate Cancer

  • The first randomized phase III trials of extreme hypofractionation showed encouraging safety data compared with conventional fractionation in men with intermediate-risk prostate cancer.
  • Both physician-reported and patient-reported outcomes showed a low incidence of side effects with extreme hypofractionation at 2 years.
  • Longer-term efficacy studies are needed to change management strategies.

Patients were randomized to receive extreme hypofractionation (42.7 Gy in 7 treatments of 6.1 Gy each over 2.5 weeks, treated every second day) or conventional fractionation (78 Gy in 39 treatments of 2 Gy each over 8 weeks). All patients received image-guided radiation therapy to the prostate. Dr. Widmark said that in this population (866 patients), 90% were treated with three-dimensional (3D) conformal radiation therapy, and 10% were treated with the more modern technique using volumetric arc therapy. In the total population (1,200 patients), the figures were 80% and 20%, respectively.

Primary outcome measures included both physician-reported side effects, measured with a modified Radiation Therapy Oncology Group (RTOG) scale, and patient-reported outcomes of urinary, bowel, and sexual function, measured with the Prostate Cancer Symptom Scale (PCSS) questionnaire. Median follow-up time for this analysis was 4.2 years from baseline, and results were based on 866 patients who reached the 2-year mark of follow-up as of May 2016.

Toxicity Findings

Side effects were similar at 2 years, approximately 5% in urinary toxicity and 3% in bowel toxicity in both the extreme hypofractionation and conventional fractionation arms. As might be expected because of the higher radiation dose in a shorter period, bowel toxicities were significantly higher with extreme hypofractionation at the end of radiotherapy. The higher level of urinary toxicity at 3 months in the conventional arm is probably due to the shorter time from the end of radiotherapy until measurement, 1 month, whereas the extreme hypofractionation arm had 2.5 months until a 3-month measurement, All time points were measured from the start of radiotherapy. However, by 2 years, rates of grade 2 and higher urinary and bowel toxicities were similar, according to both physicians’ and patients’ evaluations.

At 2 years, physician-reported grade 2 or higher urinary toxicity rates were 5.4% for extreme hypofractionation vs 4.6% for conventional fractionation; bowel side effects at 2 years were reported in 2.2% and 3.7% of patients, respectively. Physicians reported impotence in 34% of both groups at 2 years, compared with 16% at baseline among all participants.

Patient-reported outcomes were similar in both groups at 2 years. Four of 14 urinary symptoms (urinations per day; pain when urinating; urgency; and hurry to the bathroom when you have urgency) were significantly higher at 1 year in the extreme hypofractionation arm. Six of 10 measured bowel symptoms, were significantly higher at the end of radiotherapy.

Additional Commentary

George Rodrigues, MD

George Rodrigues, MD

“This is a timely study, with several ongoing trials looking at different fractionation schedules,” said session moderator George Rodrigues, MD, of the London Health Sciences Center, Western University in London, Ontario, Canada. “This short-term 2-year data on toxicity show that extreme hypofractionation has similar safety to conventional fractionation.”

He continued: “Research is a high priority for our patients to show that hypofractionation can be used without sacrificing efficacy. Longer-term data are needed to show that these are equivalent techniques and to change management.” ■

Disclosure: Drs. Widmark and Rodrigues reported no potential conflicts of interest.


1. Widmark A, Gunnlaugsson A, Beckman L, et al: Extreme hypofractionation vs conventionally fractionated radiotherapy for intermediate-risk prostate cancer: Early toxicity results from the Scandinavian randomized phase III trial “HYPO-RT-PC.” 2016 ASTRO Annual Meeting. Abstract LBA-5. Presented September 26, 2016.