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Hypofractionated radiotherapy for prostate cancer fails to reduce long-term toxicity
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Hypofractionated radiotherapy did not reduce late toxicity or maintain efficacy compared with conventional fractionation among high-risk patients with organ-confined prostate cancer, according to final results of a phase 3 clinical study.
However, hypofractionation appeared to be a prognostic factor for freedom from biochemical failure and prostate cancer–specific survival.
Stefano Arcangeli, MD, from the department of radiation oncology at San Camillo-Forlanini Hospital in Rome, Italy, and colleagues randomly assigned 168 patients with high-risk organ-confined prostate cancer in a 1:1 ratio to conventional radiotherapy for 8 weeks (n = 85; 80 Gy in 40 fractions) or hypofractionated radiotherapy for 5 weeks (n = 83; 62 Gy in 20 fractions). Among the patients, 61% had a cancer stage less than T2c (n = 102) and 39% had a cancer stage of T2c or greater (n = 66).
Late toxicity served as the primary outcome measure. Additional outcomes included freedom from biochemical failure, prostate cancer–specific survival and OS evaluated on an intention-to-treat basis.
“We tested the hypothesis that hypofractionation would result in lower rates of late complications,” the researchers wrote.
Researchers previously reported preliminary data at 5 years; the current analysis included data after a median follow-up of 9 years (interquartile range, 7.5 to 10.1).
Patients in the hypofractionated radiotherapy group and conventional radiotherapy group experienced similar rates of freedom from late grade 2 or worse genitourinary toxicity (86% vs. 79%) and gastrointestinal toxicity (86.5% vs. 84.6%).
On actuarial freedom from biochemical failure curves, the 10-year freedom from biochemical failure rate was 72% among patients in the hypofractionation group and 65% among patients in the conventional group (HR = 1.62; 95% CI, 0.88-2.97).
Mean freedom from biochemical failure — using the flexible parametric model restricted to 10 years — was 8.7 years (standard error [SE], 0.29 years) in the hypofractionation group and 7.9 years (SE, 0.36 years) in the control arm. The benefit of 0.8 years in the experimental arm appeared significant (P < .001).
The 10-year OS rate was not significantly different between the arms (75% vs. 64%). However, the hypofractionation arm showed a trend toward improved 10-year prostate cancer–specific survival (95% vs. 88%; HR = 2.4; 95% CI, 0.77-6.84).
Multivariate analysis showed hypofractionation, pretreatment PSA level, Gleason score and clinical tumor stage were significant prognostic variables for freedom from biochemical failure, and hypofractionation and Gleason score were significant prognostic variables for prostate cancer–specific survival.
Although treatment-related toxicity was equivalent in both arms, it is important to note that the incidence of grade 2 or worse genitourinary toxicity increased from the earlier report, when the rates were 6% for conventional radiation and 8% for hypofractionated radiation at 3 years, James B. Yu, MD, MHS, director of the prostate and genitourinary cancer radiotherapy program at Yale School of Medicine, wrote in an editorial.
Further, the current analysis showed macroscopic hematuria occurred significantly more frequently in the hypofractionation arm (16.5% vs. 3.6%; P = .009), and the freedom from grade 2 or worse genitourinary toxicity curves seemed to separate after 6 years, Yu wrote.
“So where does this leave us?” he wrote. “With regard to efficacy, I would say that cancer control in terms of biochemical control can now be robustly determined to be equivalent for organ-confined–risk prostate cancer when compared with conventional and moderate hypofractionation at 5 years. Cancer control likely will be equivalent as well for a patient’s lifetime, although longer follow-up is needed before this statement is definitive.
“With regard to toxicity ... the Arcangeli et al data hint that perhaps more is to come on late genitourinary toxicity,” Yu added. “We should continue to be cautious about giving moderate hypofractionation to patients with significant preexisting urinary symptoms.” – by Melinda Stevens
Disclosure: The researchers report no relevant financial disclosures. Yu reports institutional research funding from 21st Century Oncology.
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