Minimal Toxicities Reported in Extreme Hypofractionated Comparison Trial in Prostate Cancer

Anders Widmark, MD

Men with intermediate prostate cancer who received extreme hypofractionated (E-HF) radiotherapy reported a low incidence of side effects, with no significant differences compared with a similar cohort of men who received conventional fractionation (CF), after 2 years of treatment. E-HF was delivered in 7 fractions across 2.5 weeks and the conventional therapy was delivered in 39 fractions across 8 weeks.

The Scandinavian study, called HYPO-RT-PC, was an open randomized phase III noninferiority trial that accrued 1200 men between July 2005 to November 2015. The primary endpoint was 5-year failure-free survival (FFS) with freedom from biochemical failure (PSA nadir + 2.0 ng/ml) or prostate cancer recurrence. The secondary endpoints included PSA response rate, cancer specific survival, overall survival (OS), and side effects and quality of life that focused on urinary, gastrointestinal morbidity, and sexual function.

“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 study author Anders Widmark, MD, a professor of Radiation Sciences at Umeå University in Umeå, Sweden. “Most of the existing data on hypofractionation, however, draws on cases of moderately accelerated radiation treatment of the prostate. Our trial shows that patients experience similar side effects at 2 years with highly accelerated extremely hypofractionation.”

Eligible patients presented with tumor stages of T1c to T3a, prostate-specific androgen (PSA) levels of 20 or below, and 1 or 2 of 3 risk factors: stage T3a, a Gleason tumor score of 7 or higher, or a PSA level greater than 10. Eighty percent of patients received three-dimensional conformal RT (3-D CRT), and the remaining patients received volumetric arc therapy (VMAT). Androgen-deprivation therapy was not allowed among study participants.

Urinary, gastrointestinal, and sexual function toxicity was evaluated using the physician’s evaluation (RTOG scale) and patient reported outcomes measurement (Prostate Cancer Symptom Scale questionnaire using a VAS scale from 0-10). Of the 1200 randomized men, 866 were eligible for evaluation at the 2-year analysis.

Side effects were measured prior to radiotherapy (RT) start (baseline), at the end of RT, and at 3, 6, 12, 18, and 24 months following completion of RT. Median follow-up time from randomization for the entire patient population was 4.2 years, and findings reflect the 866 patients who reached 2-year follow-up at the time of reporting in May 2016.

For the cohort who received E-HF, physician-reported grade 2 and higher toxicities did not differ significantly between the treatment arms. Widmark reported that 5.4% of E-HF patients and 4.6% of CF patients experienced urinary side effects (P = 0.59). Bowel side effects were reported in 2.2% of E-HF patients and 3.7% CF patients (P = .20).

“If we look at the bowel toxicity, we see no difference at 2 years,” said Widmark. “There is, however, a significant increase in toxicity in the extreme hypofractionated arm that we interpret as a higher, hotter, and shorter time given these treatments.”

Impotence at 2 years posttreatment was reported in 34% of both groups, compared with 16% among all participants at baseline. Patient-reported outcomes at 2 years following treatment also did not differ significantly between treatment groups for overall bother from urinary (P = .17), bowel (P = .12), or sexual function (P = .71) symptoms.

At 1-year post-treatment, patient-reported urinary function was significantly worse among E-HF patients for 4 of the 14 symptoms measured. “We have some symptoms on our scales that we found out had significant differences at 12 months, namely, urinations per day, pain when urinating, urgency, and hurry to the bathroom when you have urgency,” Widmark said.

Bowel symptoms included number of bowel movements in the past 24 hours, planning of toilet visits due to bowel problems, cramping associated with bowel movements, and the presence of mucous in stools.

Some modest but statistically significant differences emerged between the accelerated and conventional treatment arms in shorter-term bowel and urinary side effects. Acute urinary toxicity immediately following treatment was similar for both treatment groups (27.6% for E-HF vs 22.8% for C-HF; P = 0.11), although acute bowel toxicity at the end of RT was higher for the accelerated E-HF treatment than for CF (9.4% vs 5.3%; P = .023).

“The trial was designed to have equal late toxicity, so although there were some differences in shorter-term side effects, the results for long-term toxicity were precisely what we hoped to find,” said Widmark. “Our plan moving forward is to analyze primary endpoint data and present updated toxicity results approximately 1 year from now.”

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.” Presented at: 2016 ASTRO Annual Meeting; Boston, Massachusetts, September 25-28, 2016.