The phase III HYPRO study failed to prove the non-inferiority of using hypofractionated radiotherapy compared with fractionated radiotherapy for late genitourinary and gastrointestinal toxicity in men with intermediate- or high-risk prostate cancer.
“Moreover, the cumulative incidence of grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group,” Shafak Aluwini, MD, of Erasmus MC Cancer Institute, Rotterdam, Netherlands, and colleagues wrote in Lancet Oncology. “Together with previous findings that were unable to show non-inferiority of hypofractionation for both acute gastrointestinal and genitourinary toxicity, and the recorded significant increase in incidence of acute gastrointestinal toxicity, the findings of late toxicity question the added value of hypofractionation with a fraction dose higher than 3 Gy for all patients, and the need for patient selection—eg, based on baseline symptoms, which can reduce both genitourinary and gastrointestinal toxicity.”
The HYPRO study compared the use of standard fractionation with 39 fractions of 2 Gy for 8 weeks with hypofractionation with 19 fractions of 3.4 Gy for 6.5 weeks among 820 patients with intermediate- or high-risk prostate cancer. Data on acute toxicity was previously published. These updated results discussed late genitourinary and gastrointestinal adverse effects.
The researchers designed the trial to reject inferiority of hypofractionation for late genitourinary toxicity with a hazard ratio [HR] of less than 1.11, and for gastrointestinal toxicity with an HR of 1.13.
At 3 years, grade 2 or worse genitourinary effects were recorded in 39% of the patients assigned standard fractionation compared with 41.3% of patients assigned hypofractionation (HR, 1.16 [90% CI, 0.98–1.38]). In addition, cumulative grade 3 or worse genitourinary toxicity was significantly greater among patients assigned to hypofractionation (19% vs 12.9%; P = .021).
Similarly, grade 2 or worse gastrointestinal effects occurred in 17.7% of patients assigned standard fractionation compared with 21.9% of patients assigned hypofractionation (HR, 1.19 [90% CI, 0.93–1.52]). However, there was no statistical difference between the two groups for the cumulative stage 3 or worse late gastrointestinal toxicity (2.6% for standard vs 3.3% for hypofractionation).
In an editorial that accompanied the results, Alberto Bossi and Pierre Blanchard of Gustave Roussy Cancer Center, Villejuif, France, wrote that the results of this trial are important to the oncology community, but pointed out several issues with the trial including that toxicities results may be underestimated as they only included those patients that had no relapse, and that with five endpoints, interpretation of this trial can be difficult.
“Although we agree with the researchers that a long follow-up is needed when investigating efficacy of treatment for prostate cancer, readers should be aware that the efficacy results of this trial have been reported earlier in 2015 with the same follow-up as in the present report,” Bossi and Blanchard wrote. “Five-year biochemical relapse-free survival was 77% for conventional treatment and 80% for hypofractionated treatment (P = .36), with an adjusted HR of 0.86 (95% CI, 0.63–1.16).” When considering the overall results of this trial, the editorial authors noted, none of the five primary endpoints met its initial target and hypothesis.
“The HYPRO trial must be viewed as overall negative, and the definitive results of future trials, especially the large PROFIT (ISRCTN 43853433) and CHHiP trials (ISRCTN 97182923), are awaited before hypofractionation at 3 Gy or more per fraction can be safely be used for routine clinical care,” they wrote.