Right Dose per Fraction Key in Prostate Cancer Radiotherapy

Pam Harrison

July 11, 2016

Two trials comparing hypofractionated radiation with conventional radiation for localized prostate cancer have come to opposite conclusions. But the two studies used different schedules of hypofractionation, and it is the dose per fraction that is important, says an expert not involved in either study.

Both studies and an accompanying comment were published online June 20 in the Lancet Oncology.

Do fewer, larger daily fractions of external-beam radiotherapy provide equally effective disease control?

Yes, say British researchers reporting 5-year outcomes from the British Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.

The British team says the hypofractionated regimen used in their study should be considered the new standard of care for localized disease, offering patients a shorter and less costly course of treatment.

But the authors of the Dutch Hypofractionated Irradiation for Prostate cancer (HYPRO) study argue the opposite. They found that the hypofractionation regimen they used was not superior to conventional radiotherapy, and so they say it should not be regarded as the new standard of care for intermediate- or high-risk prostate cancer.

"It's the dose per fraction that is significant here," Robert Lee, MD, Duke University School of Medicine, Durham, North Carolina, explained to Medscape Medical News. He authored the editorial that accompanied the studies.

"The Dutch dose per fraction was higher [3.4 Gy] than the British dose [3 Gy]," he pointed out. If that higher dose "had proven to be more effective than conventional fractionation, you might argue that you could accept an increase in toxicity, but the dose the Dutch used clearly wasn't more effective, and given the increase in toxicity, I agree with the authors that the hypofractionation regimen as used in their study should not be adopted."

In his editorial, Dr Lee writes that the results of the British CHHiP study (and also the previously reported NRG Oncology RTOG 0415 trial) suggest that hypofractionation does not result in any loss of efficacy and could make treatment less expensive and more convenient for patients in comparison with conventionally fractionated radiotherapy.

In the CHHiP trial, no increase in toxic effects was recorded with 60.0 Gy in 20 fractions. "For practitioners interested in judicious use of resources and patients' convenience, this regimen can be presented confidently and discussed with patients as an alternative to conventional fractionation," Dr Lee writes.

However, he warns against a wholesale move from one technique to the other. "In view of these reports, should radiation oncologists routinely abandon conventional fractionation and move to hypofractionation? I do not think so."

Results From the British CHHiP Trial

The CHHiP trial randomly assigned 3216 men with localized (T1b-T3aN0M0) prostate cancer to one of three treatment arms.

Men assigned to the conventionally fractionated arm received 2 Gy a day from Monday to Friday for 7.4 weeks for a total of 74 Gy in 37 daily fractions.

Men assigned to one of the two experimental groups received fractions of 3 Gy daily for a total dose of either 60 Gy in 20 daily fractions over 4 weeks or a total dose of 57 Gy in 19 daily fractions over 3.8 weeks.

"Short-course androgen deprivation treatment was given for 3-6 months before and during radiotherapy; this was optional for patients with low-risk disease," lead author David Dearnaley, MD, the Institute of Cancer Research, and consultant, Royal Marsden Hospital, London, United Kingdom, notes.

The primary outcome of CHHiP was time to biochemical or clinical failure.

At a median follow-up of approximately 62 months, the proportion of patients who had not reached the primary endpoint of biochemical or clinical failure was 88.3% in the 74-Gy group, 90.6% in the 60-Gy group, and 85.9% in the 57-Gy group, Dr Dearnaley and colleagues report.

The investigators concluded that hypofractionated radiotherapy at a dose of 60 Gy in 20 fractions is noninferior to conventional fractionation. The same could not be said for the alternative hypofractionated protocol, in which men received 57 Gy in 19 fractions.

"Acute RTOG [Radiation Therapy Oncology Group] bowel and bladder symptoms peaked sooner in the hypofractionated schedules than in the control, at 4-5 weeks compared with 7-8 weeks," Dr Dearnaley and colleagues report.

However, by 18 weeks, rates of the occurrence of bowel and bladder toxicity of RTOG grade 2 or higher were low and were comparable across the three treatment arms.

Table. RTOG Grade 2 or Worse Bowel/Bladder Toxicity

  Conventional RT (74 Gy) Hypofractionated RT (60 Gy) Hypofractionated RT (57 Gy)
Bowel toxicity 3% 3% 3%
Bladder toxicity 6% 5% 5%

 

At study endpoint, rates of grade 2 bowel, bladder, and sexual toxicities were again similar across the three fractionation regimens tested.

Treatment Reduction

Dr Dearnaley points out that switching to a 20-fraction schedule could reduce the number of fractions required to treat localized prostate cancer in the United Kingdom by approximately 200,000 a year.

"For patients, this means fewer visits to hospital," he is quoted as saying in a science blog from Cancer Research UK.

 
Treatment is more convenient and finished sooner, allowing patients to go back to their normal lives. Dr David Dearnaley
 

"And treatment is more convenient and finished sooner, allowing patients to go back to their normal lives," he added.

Dr Dearnaley noted that this was as the largest trial ever conducted in localized prostate cancer. "High-dose modest hypofractionation using high-quality treatment methods such as those used in this trial should become a new standard of care for external-beam radiotherapy," he states.

Results of the Dutch HYPRO Trial

The Dutch HYPRO trial randomly assigned 804 men with T1b-T4NX-N0MX-M0 localized prostate cancer either to hypofractionated radiotherapy consisting of 19 fractions of 3.4 Gy of radiation given over 6.5 weeks (3 fractions per week) for a total dose of 64.6 Gy or to conventional fractionation consisting of 39 fractions of 2.0 Gy over 8 weeks (5 fractions a week), for a total dose of 78 Gy.

Almost all participants received intensity-modulated radiotherapy.

Two thirds of patients also received androgen deprivation therapy.

The primary endpoint of HYPRO was the proportion of men who were free from relapse at 5 years or initiation of hormone therapy. Relapse included biochemical and clinical relapse as well as locoregional or distant relapse.

At 5 years, 80.5% of men who received the hypofractionation regimen were relapse free, as were 77.1% of those assigned to the conventional treatment arm.

Treatment failure rates were virtually identical as well, at 20% for the hypofractionation arm and 22% for the conventional arm.

At 5 years, post hoc assessment of overall survival showed that survival rates were very similar, at 86.2% and 85.9% for the hypofractionation and conventional fractionation groups, respectively.

"Acute grade 2 or worse genitourinary toxic effects were comparable between treatment groups, whereas the cumulative incidence of acute grade 2 or worse gastrointestinal toxic effects was significantly higher after hypofractionation than conventional fractionation," write the researchers, with lead author Luca Incrocci, MD, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Although differences in acute toxicity lessened between the two treatment arms 12 weeks after radiotherapy, "findings of the HYPRO trial show that hypofractionated radiotherapy with 19 fractions of 3.4 Gy cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer," they conclude.

Noninferiority Again Shown

In his editorial, Dr Lee notes that the results now reported from the Britsih CHHiP study are similar to those that were reported recently from the NRG Oncology RTOG 0415 trial, which he led. For this study, the investigators used a slightly different hypofractionation schedule of 28 fractions of 2.5 Gy, with five fractions administered per week.

At a median follow-up of 5.8 years, the hypofractionation schedule proved to be noninferior to conventional fractionation (41 fractions of 1.8 Gy, five fractions a week) in terms of disease- free survival rates.

A third, as yet unpublished, noninferiority trial involving 1200 patients in Canada compared the same hypofractionation regimen that was declared noninferior to conventional fractionation in the CHHiP trial.

Although findings from the Canadian trial are pending publication, "I'm confident that 60 Gy in 20 fractions will become a standard of care at least in Canada sooner rather than later," Dr Lee observed.

The authors have disclosed no relevant financial relationships.

Lancet Oncol. Published online June 20, 2016. CHHiP study, full text; HYPRO study, abstract; Editorial

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