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Key Studies at ASTRO Annual Meeting Reinforce Importance of Phase III Trials: Short-Term Androgen Suppression as Good and Longer-Term; Sulfasalazine Found to Cause Rather than Prevent Diarrhea

Carlson, Robert H.

doi: 10.1097/01.COT.0000437206.74988.6b


ATLANTA—The phrase “contrary to popular belief” always draws attention, and deservedly so in the case of two trials presented by Mayo Clinic researchers here at the American Society for Radiation Oncology Annual Meeting.

A trial of neoadjuvant androgen suppression with radiotherapy showed that “more is not better,” when an eight-week course of total androgen suppression produced almost identical, excellent outcomes as those for a 28-week course.

The other study showed that giving sulfasalazine to prevent diarrhea due to pelvic radiation actually did more harm than good.

Both reports pointed to the importance of conducting Phase III trials to prove or disprove a hypothesis.

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RTOG 9910

In the prostate cancer study, Radiation Therapy Oncology Group (RTOG) 9910, a short-term total neoadjuvant androgen-suppression regimen of eight weeks was found to be virtually equal to 28 weeks in all outcome measures in men with intermediate-risk prostate cancer (Abstract 1).

“These were not the outcomes we expected,” said the study's principal investigator, Thomas M. Pisansky, MD, Professor of Oncology and Radiation Oncology. “We expected that with longer pre-radiotherapy androgen suppression there would be a reduction in prostate cancer death and a reduction in cancer regrowth—something that a fair amount of preclinical research has shown.

“The lesson here is that even though there was overwhelming [earlier] evidence for people to extrapolate and say that more is better, the results of this study should give us all some pause, that however strongly you may feel that something is better than something else, you always have to put it to this rigorous a scientific test.”

The Phase III plenary study compared extended-duration neoadjuvant total androgen suppression followed by external radiotherapy and concurrent total androgen suppression with standard-duration neoadjuvant total androgen suppression and radiation therapy in men with intermediate-risk prostate cancer.

Patients with intermediate prostate cancer were randomly assigned to receive eight weeks (752 patients) or 28 weeks (738 patients) of neoadjuvant total androgen suppression. That was followed in each arm by external-beam radiotherapy along with an additional eight weeks of androgen suppression.

The median follow-up was nine years, and patients' median age was 71 at the time of accrual. The five-year locoregional tumor control rate was 96 percent with the short-term androgen suppression regimen vs. 98 percent with the longer term. Ten-year rates were 94 and 96 percent, respectively.

In metastasis-free survival, the five-year rate for the short-term regimen was 97 percent for both regiments; the 10-year rates were also identical for each duration— 94 percent. These results are reproducible, “so men with intermediate-risk prostate cancer know what to expect with this treatment,” Pisansky said.

He added that while RTOG 9910 could be considered a negative study, it is positive in the sense that “disease-specific survival with 10 years of follow up is extraordinarily high for whichever treatment the men underwent.”

In time to biochemical failure the outcomes were again favorable and comparable, at 192 weeks for the eight-week course and 185 weeks for the 28-week course.

The 28-week group did have more side effects—mainly erectile dysfunction and hot flashes. “It is quite clear that the neoadjuvant total androgen suppression need last no longer than eight weeks, and androgen suppression before and during radiotherapy need last no longer than 16 weeks.”

Pisansky offered a positive take-home message from the study, noting that the rates of disease recurrence with either the long or short regimen were very, very low, and the chance of dying of prostate cancer in the decade after treatment for these patients is only five percent.

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‘Time to Shift Research Focus’

Further studies trying to reduce the risk of prostate cancer mortality will be difficult, he said, “because there is very little room for improvement and it will be hard for any further studies to prove further benefit.”

More fruitful areas of research would be finding ways to decrease biochemical failure that would lead to a decrease in secondary therapy, and decreasing side effects using intensity modulation and image guidance. “As with some other types of cancers—breast cancer in particular—it is time to shift our focus of research from survival endpoints, which are excellent, to other endpoints of improving quality of life and reducing side effects.”



The moderator of an ASTRO news conference that featured this and other plenary studies, ASTRO President-Elect Bruce G. Haffty, MD, Professor and Chairman of the Department of Radiation Oncology at Robert Wood Johnson Medical School, commented that the study could have a potentially important impact on quality of life: “I can tell you from personal experience that when you shorten treatment, patients perceive that their quality of life has improved,” he said. “And just as a shorter duration showed that clinical outcomes were the same, it may have also reduced the toxicity of treatment.”

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The Discussant for the study, Daniel A. Hamstra, MD, Assistant Professor in the Department of Radiation Oncology at the University of Michigan, first reviewed an earlier study, RTOG 9408, which had shown a five-percent improvement in 10-year overall survival with the use of 16 weeks of total androgen suppression starting eight weeks before radiotherapy for intermediate-risk prostate cancer (Jones et al: NEJM 2011; 365:107-118).

RTOG 9910 now shows that 28 weeks of neoadjuvant androgen deprivation is not superior to eight weeks, he said: “This negative study fundamentally changes how we will use hormonal therapy in intermediate prostate cancer.”

The National Comprehensive Cancer Network's 2013 guidelines recommend treatment for intermediate-risk disease of radiation therapy with dose escalation, with or without short-term hormonal therapy, and with or without brachytherapy, for a recommended hormone duration of four to six months. But, he noted, of the six randomized trials that have addressed the duration of short-term hormonal therapy in localized prostate cancer, ranging in size from 161 patients in a Montreal study to the almost 1,600 patients in RTOG 9910, five showed no difference in any endpoint for the longer duration of hormonal therapy.

“And with twice as many intermediate-risk patients on this one trial as on the other five trials combined, 9910 really is the defining study,” Hamstra said.

A question yet to be answered is whether hormonal therapy is still needed if the radiation dose is escalated, he said, noting that the RTOG 0815 study is now investigating that question.

Meanwhile, for intermediate-risk patients treated with 70 Gy of external-beam radiation, four months of short-term hormonal therapy—four weeks neoadjuvant and four weeks concurrent with radiotherapy—should be considered the standard of care, he said.



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Sulfasalazine Does Not Reduce Diarrhea in Preventing Enteritis during Pelvic RT

Another key study at the meeting found that patients receiving sulfasalazine to prevent enteritis during pelvic radiation actually had significantly more diarrhea than patients taking placebo (Abstract LBA2).

The lead author, Robert C. Miller, MD, Professor of Radiation Oncology at Mayo, noted that the drug had been reported in a previous Phase III trial to decrease enteritis during pelvic radiotherapy and has been recommended in European guidelines as prophylaxis to reduce diarrhea.

This new Phase III N08C9 trial, from the Alliance for Clinical Trials in Oncology, showed that the agent does not appear to reduce the risk of enteritis and may be associated with a higher risk of adverse event than placebo. He noted that the Data Safety and Monitoring Board halted the trial before recruitment was completed when 29 percent of the 35 patients receiving sulfasalazine experienced severe or life-threatening diarrhea vs. 11 percent of the 38 in the placebo arm.

“Sulfasalazine's inclusion in clinical guidelines for radiotherapy-enteritis prophylaxis should be reconsidered,” he and his co-researchers concluded.

Miller said the trial emphasizes once again the need for blinded, placebo-controlled trials: “This was an agent with little evidence to suggest it would be detrimental to our patients.”

Miller's research specialty in the Mayo Cancer Prevention and Control Program is testing existing medications to determine if they can be used to reduce the negative symptoms associated with radiotherapy. “These results [of N08C9] themselves are not all that surprising,” he said. “This type of finding has been a regular occurrence in the Prevention and Control Program as we have tested a series of agents that appeared promising in early reports only to prove harmful in controlled trials.”

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Abstracts Links

The abstracts for both studies (Abstracts 1 and LBA2) can be accessed via:

© 2013 by Lippincott Williams & Wilkins, Inc.
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