1. Goodwin, Peter M.

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BARCELONA-Ultrahypofractionated (U-HF) radiation delivered in only seven fractions (each triple the usual dose) in 2.5 weeks was just as effective for treating intermediate-risk prostate cancer-with no greater toxicity-as a standard protocol with 39 fractions over 8 weeks in findings from the phase III Scandinavian HYPO-RT-PC study reported at the 2018 European Society For Radiotherapy and Oncology (ESTRO 37) annual conference (Abstract OC-0599).


Anders Widmark, MD, PhD, Professor of Oncology and Senior Consultant in the Department of Radiation Oncology and the Umea University Hospital Cancer Centre in Umea, North Sweden, told Oncology Times they undertook their study because they had already improved outcomes-lowering rates of PSA relapse-by escalating doses, "moving up" from 32 fractions of radiotherapy (RT) to 39, but this brought a penalty. "That meant patients had to be there for 8 weeks," he said. "And we also wanted to increase the dose over time."


While the U-HF protocol offered potential for reducing treatment times, Widmark said they also predicted a clinical advantage from delivering radiation over a shorter period of time. "Prostate cancer cells are often dividing slowly. And that is a positive [reason] for using hypofractionation (HF) to get good results," he said.


Study Details

The primary outcome measures-toxicity and efficacy-of the Scandinavian HYPO-RT-PC study (conducted at 10 hospitals in Sweden and two in Denmark) were the first data from a large prospective randomized trial of U-HF compared with conventional fractionation (CF).


A total of 602 patients with intermediate (around 90% of the cohort) or high-risk (the remaining 10%) prostate cancer were randomized to CF with 39 daily fractions of 2.0 Gray (Gy) per fraction (total dose of 78.0 Gy) over 8 consecutive weeks and compared with 598 matched patients treated with U-HF in seven fractions of 6.1 Gy per fraction (total dose 42.7 Gy) given over 2.5 weeks. Androgen deprivation therapy was not permitted and treatment schedules were designed to be "equi-effective" for "late normal tissue complication probability." Image-guided RT was delivered to the prostate only.


For the efficacy endpoint (time to biochemical or clinical failure), a critical hazard ratio (HR) of 1.338 was pre-specified as the criterion for non-inferiority.


"That has been the big challenge: To really dare to do it. We were a bit scared in the beginning that we could get side effects, but our side effects today seem to be working out quite nicely," said Widmark.


The total number of events during the follow-up period was 102 in patients receiving CF and 100 in the U-HF group. 83.8 percent of patients in the CF arm and 83.7 percent in the U-HF arm were free of PSA or clinical failure at 5 years. U-HF was concluded to be non-inferior to CF with HR of 0.992.


There were no significant differences between the two arms in terms of physician-reported late grade 2 (or higher) toxicities from 4-6 years after treatment.


"There is one significant difference: More toxicity in the hypofractionated arm at the end of radiotherapy," Widmark said. This was due to the fact that the same intensity of photons was given in 2.5 weeks compared to 8 weeks, he explained. "That's probably the reason you get what's called an 'acute effect'-a bit more urinary toxicity and some worsening bowel toxicity. But that disappeared within 3-6 months."


When asked about the implications of the finding that the U-HF protocol was non-inferior, he said these were quite clear. "For patients, it's more or less a revolution. Instead of 8 weeks at the department, you have to be there for only 2.5 weeks-or just seven times instead of 39," he said.


"For the radiation departments, it has really increased their possibility to give other patients treatment in the time that prostate cancer patients have taken before. So it's really a benefit for the patient, for society, and for financial reasons, too," said Widmark.


The clinical implications, he said, were that it's going to be faster for patients to get their treatment. "But if you get money for each fraction you're in trouble. It might be a problem in a country where you are paid by the fraction.


"This is the first large patient trial of this kind and it shows that ultrahypofractionated radiotherapy is just as effective as standard radiotherapy at stopping prostate cancer from returning," said Widmark. "Importantly it also shows that patients treated in this way do not suffer any more side effects than those treated with conventional radiotherapy."


The researchers plan to continue to study patients in the trial to check whether there are differences in their survival or in longer-term side effects.



President of ESTRO Yolande Lievens, MD, PhD, Head of the Department of Radiation Oncology at Ghent University Hospital, Belgium, said: "Advances in radiotherapy mean that we are better able to locate and target tumors while minimizing damage to nearby organs. In prostate cancer, this can mean men retaining urinary and sexual function. This also means that we can consider giving higher individual doses over a shorter time, as in this study."


She said results of this trial suggested that U-HF radiotherapy was equal to conventional radiotherapy. "For patients, that could mean they have to spend much less time travelling to and from hospital for treatment. For health services, this could help them save resources and get more patients treated sooner.


"I think it's extremely important that by using the better technologies that we have now we can shorten treatment times very dramatically, which means that not only the outcome of the patient remains the same-in terms of survival or toxicity-but travel to the hospital has been shortened dramatically. This is very important for the patient," said Lievens.


Peter M. Goodwin is a contributing writer.


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