Massive Trial in Prostate Cancer Supports Accelerated Hypofractionated Radiotherapy

David Dearnaley, MD

David Dearnaley, MD

Accelerated hypofractionated radiotherapy using a schedule of 60 Gy in 20 fractions (60 Gy/20f) of 3 Gy delivered in 4 weeks was found to be comparable (ie, noninferior) to the conventional schedule of 74 Gy/37 of 2 GY delivered in 7.2 weeks in the 5-year analysis of the phase III CHHiP trial in patients with localized prostate cancer taking androgen deprivation therapy (ADT).

Progression-free survival (PFS) and rates of late adverse events (AEs) were comparable in the two arms. Other AEs were comparable between the two schedules, with the exception of higher rates of acute grade 2 bowel toxicity in the accelerated arm. A third arm in the trial using 57 Gy/19f did not perform as well as the 60 Gy/20f arm.

Lead investigator David Dearnaley, MD, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK,

reported these results at the 2015 European Cancer Congress.

Experts hope that this high-level phase III data will hasten this approach, which delivers a lower total dose in fewer larger daily doses over fewer weeks compared with conventional radiotherapy.

“The scarcity of long-term results from well-designed phase III randomized trials has so far prevented the general adoption of this approach,” explained John Yarnold, MD, also of The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, who was not involved in this trial.

Study Details

CHHiP enrolled 3163 patients from 71 different centers in the UK, Ireland, New Zealand, and Switzerland. Study subjects were randomized in a 1:1:1 ratio to conventional radiotherapy (74 Gy/37f) or two different hypofractionated schedules: 60 Gy/20f and 57 Gy/19f. All men in the trial had localized prostate cancer confined to the prostate gland and started androgen deprivation therapy 3 months prior to radiation and continued hormonal treatment throughout the trial for a median of 5.6 months.

“This was the largest trial ever undertaken in prostate cancer,” Dearnaley told listeners. “Radiation technique is important. Our study had mandatory dose restraints.”

Baseline characteristics were well balanced in all three treatment arms. Median age was 69 years, and median prehormone therapy PSA was 10.1 ng/mL; 15% were low risk, 73% were intermediate risk, and 12% were high risk according to NCCN criteria. The primary endpoint of the trial was biochemical failure according to PSA level.

5-year progression-free survival rates were: 88.3% for conventional radiotherapy, 90.6% for 60 Gy/20f, and 85.9% for 57 Gy/19f.

“This demonstrated that 60 Gy/20f is non-inferior to 74 Gy/37f,” he stated.

Acute grade 2 bowel toxicity was higher in the 60-Gy/20f arm compared with conventional radiotherapy: 90.6% for 60Gy-arm, and 88.3% for the conventional arm, with no significant differences between arms in acute bladder toxicity.

“Bowel toxicity in the hypofractionated arm disappeared by 18 weeks,” Dearnaley said.

At 5 years, late bowel toxicity was 2% in all three groups, and bladder toxicity was similar, ranging from 11% to 13%. Sexual dysfunction was similar in all three arms.

“Patients had fewer symptoms at 5 years than before they had treatment. There was no significant cumulative toxicity out to 5 years,” he said

Quality of life related to bowel and/or bladder symptoms was similar for all three groups and improved over pretreatment levels.

Expert Comment

Philip Poortmans, MD, PhD, who discussed these results at the

Congress’ Presidential Session, was enthusiastic about the results but injected a note of caution about the uptake of hypofractionation.

“I congratulate the authors for presenting results of the CHHiP trial,” he said. “The fact that there were only a few prostate cancer-specific deaths in the trial highlights the efficacy of current treatments of prostate cancer.”

“Hormone therapy can maintain remission for a number of years.

Recurrence does not mean progression to death within a couple of months, so it is important to look at side effects of these treatments,” noting that there were very few differences in this trial in acute and long-term side effects.

Data from other trials suggests that some patients have more acute toxicity. The FLAME study and the HYPO-FLAME study—currently ongoing—will provide more data.

“We can trust in hypofractionation, but only with high-quality treatment techniques, including appropriate image guiding for patient positioning. For now, the fraction size should be limited to 3 Gy. For higher sizes, we need to wait for results of other trials,” Poortmans stated.

Poortmans is President of ESTRO and head of the Department of Radiation Oncology at Radboud University, Nijmegen area, The Netherlands.

Reference

Dearnaley D, Syndikus I, Mossop H, et al. 5 year outcomes of a phase III randomised trial of conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): report from the CHHiP Trial Investigators Group. Presented at European Cancer Congress 2015. Septembre 28, 2015. Abstract 8LBA.