SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Hypofractionated radiation therapy, which delivers fewer, larger fractions relative to conventional radiation therapy, can be considered a new standard of care for localized prostate cancer, according to a pair of phase III noninferiority randomized trials reported at the Genitourinary Cancers Symposium.

The Radiation Therapy Oncology Group’s 0415 trial, conducted among men with low-risk disease, found that the 5-year rate of disease-free survival with a 70-Gy hypofractionated regimen was noninferior to that with a conventional regimen (86% vs. 85%). And a trial conducted by the U.K. CHHiP Trial Management Group among men with mainly intermediate-risk disease found that the 5-year rate of freedom from biochemical failure or prostate cancer recurrence with a 60-Gy hypofractionated regimen was noninferior to that with a conventional regimen (90.6% vs. 88.3%).

The trade-offs were small increases in the rates of some gastrointestinal and genitourinary toxicities with the hypofractionated regimens.

“Both of these trials now clearly establish that modest hypofractionated regimens are noninferior for biochemical failure, with modest to no change in toxicity. This is probably ready for prime time,” contended invited discussant Dr. Daniel A. Hamstra , a radiation oncologist with Texas Oncology in Irving. “Hypofractionation provides a cost- and resource-effective treatment that is easier and more convenient for patients.”

Among the points yet to be ironed out are identification of the optimal regimen and implementation of hypofractionation in the United States, he noted; uptake of hypofractionated radiation therapy in breast cancer has been slow, even though research there is about 5 to 10 years ahead of that in prostate cancer. “It will be intriguing to see what happens in the United States, whether or not this type of modest hypofractionation takes off,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

RTOG 0415 trial

In the first trial, NRG Oncology’s RTOG 0415 , investigators led by Dr. W. Robert Lee , a radiation oncologist at Duke University, Durham, N.C., randomized 1,115 men with low-risk prostate cancer to a conventional regimen (73.8 Gy given in 41 fractions over 8.2 weeks) or a hypofractionated regimen (70 Gy given in 28 fractions over 5.6 weeks). None received androgen suppression.

With a median follow-up of 5.8 years, the 5-year rate of disease-free survival (the trial’s primary endpoint) was 85% with conventional radiation therapy and 86% with hypofractionated radiation therapy. The absolute difference of 1% and the hazard ratio of 0.85 in favor of hypofractionation fell well within the predefined noninferiority margins of 7.65%, and 1.52, respectively.

The 5-year rates of biochemical recurrence were 8% with conventional radiation and 6% with hypofractionated radiation (hazard ratio, 0.77).

The two regimens did not differ significantly with respect to the rates of grade 3 or 4 early gastrointestinal and genitourinary adverse events. The hypofractionated regimen was associated with a higher rate of late gastrointestinal adverse events (P = .002), driven by more grade 2 events (18.3% vs. 11.4%), and a trend toward a higher rate of late genitourinary adverse events (P = .06), also driven mainly by more grade 2 events (26.2% vs. 20.5%).

“In men with low-risk prostate cancer, 70 Gy in 28 fractions is not inferior to 73.8 Gy in 41 fractions, albeit with a slight increase in grade 2 GI or GU toxicity,” Dr. Lee concluded. “It will be of great interest to determine if the small increase in grade 2 toxicity is manifest in patient-reported quality of life.”

When asked by an attendee whether the evidence from the two trials is sufficient to make hypofractionation standard of care, he said, “If you have a regimen that has been demonstrated in multiple phase III studies to be better or equivalent, then that can be considered a standard of care.”

Dr. Lee speculated that concerns that 5 years is not a sufficient follow-up may stem from past events in the field. “It’s perhaps related to the worry that radiation oncology really deservedly has about large dose per fraction given our history in the ‘70s and ‘80s when we tried to do things quicker. But if you remember, those toxicities were seen very early,” he elaborated.

“And my question back is, how many patients for how long do you need?” he said, given the more than 4,000 patients with 5-year follow-up in the two trials reported, plus an additional 1,700 expected from a similar Canadian study shortly. “How many patients are enough? Do you need 10,000 patients for 15 years?”

CHHiP trial

In the second trial – Conventional or Hypofractionated High-Dose, Intensity-Modulated Radiotherapy for Prostate Cancer ( CHHiP ) – Dr. David P. Dearnaley , leader of the Clinical Academic Radiotherapy Team at the Institute of Cancer Research, London, and his colleagues studied 3,216 men who predominantly had intermediate-risk disease, most of whom first received hormone treatment.

They were randomized evenly to three radiation therapy regimens: a conventional regimen of 74 Gy in 37 fractions over 7.4 weeks, a hypofractionated regimen of 60 Gy in 20 fractions over 4 weeks, or a hypofractionated regimen of 57 Gy in 19 fractions over 3.8 weeks.

With a median follow-up of 62 months, the 5-year rate of freedom from biochemical failure or prostate cancer recurrence was 88.3% with the conventional regimen, 90.6% with the 60-Gy hypofractionated regimen, and 85.9% with the 57-Gy hypofractionated regimen.

Compared with the conventional regimen, the 60-Gy hypofractionated schedule yielded a hazard ratio of 0.84, which fell well within the predefined hazard ratio of 1.208 for noninferiority (P = .004). In contrast, the 57-Gy hypofractionated schedule yielded a hazard ratio of 1.20, which was inconclusive.

When the two hypofractionated regimens were compared with each other, the 57-Gy one was inferior to the 60-Gy one, yielding a higher risk of biochemical failure or prostate cancer recurrence (HR, 1.44; P = .003).

Results for prostate cancer mortality and all-cause mortality did not differ significantly, but numbers of events were fairly small, so “we’ll have to wait and see,” Dr. Dearnaley said.

The three regimens yielded similar rates of acute bladder toxicity of various grades, but the timing of the peak rate was earlier with hypofractionation. In contrast, acute bowel toxicity occurred not only earlier, but also at higher rates (P less than .001) with the hypofractionated regimens.

At 5 years, late bowel toxicity with the hypofractionated regimens did not differ from that with the conventional regimen; however, comparing the hypofractionation regimens, the 60-Gy one yielded a higher rate than the 57-Gy one. Similarly, for late bladder toxicity, the rate of grade 2 or worse events was higher with 60 Gy.

The trial population was somewhat heterogeneous, Dr. Dearnaley acknowledged. “We will be doing a multivariate analysis to look at all of these very detailed histopathological features, in addition to a translational study where we want to look at molecular characterization of these patients. We’ve got biopsies on most of them for that.”

“We believe that modest hypofractionation using 60 Gy in 20 fractions delivered with high-quality radiotherapy techniques can now be recommended as a new standard of care in patients with this type of intermediate- and low- and high-risk cancer,” he concluded.

“As we move toward image-guided radiotherapy – and I don’t mean just by using fiducials, I mean by using the MR scans – we can start to boost dominant lesions. And I think the effectiveness of 57 Gy in treating lower amounts of volume of cancer within the prostate may mean that we can get the best therapeutic ratio by lowering the dose a little bit to 57 Gy, but boosting our dominant lesions,” Dr. Dearnaley added.

He agreed with Dr. Lee that collectively, the findings at 5 years of follow-up are sufficient to propel hypofractionation into standard of care, noting that trials of dose escalation show that the hazard ratio for biochemical control remains stable between 5 and 10 years. Additionally, in his opinion, survival is not the right endpoint when it comes to investigating fractionation.

“So because the [prostate-specific antigen] data is robust and I don’t think that’s going to change, the critical issue is actually that of side effects. You can get late, late side effects, and I do think we have to be a little bit cautious about those,” Dr. Dearnaley said, although data from the first patients enrolled in CHHiP in 2001 have not raised any concerns.

“My view is the evidence is sufficiently robust in that large number of patients to change practice now,” he concluded.


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