Landmark Study on Hormone Therapy in Low-Risk Prostate Cancer: Results Now In

Nick Mulcahy

November 03, 2009

November 3, 2009 (Chicago, Illinois) — The practice of administering short-term hormone therapy to men with low-risk prostate cancer who undergo radiation therapy is not necessary.

The treatment does not improve survival in these men, according to the "greatly anticipated results" of a new study presented here during the plenary session of the American Society for Radiation Oncology (ASTRO) 51st Annual Meeting.

This definitively establishes no benefit in men with low-risk disease.

"This is a landmark, practice-changing study," said Matthew Smith, MD, who acted as a study discussant. Dr. Smith, who is from Harvard Medical School in Boston, Massachusetts, suggested that the broad use and uncertain benefits of short-term androgen deprivation fueled the anticipation about results.

Dr. Christopher U. Jones (Courtesy of ASTRO)

"This definitively establishes no benefit in men with low-risk disease," he continued. "Unquestionably, this is a setting where less is more," he said, after detailing the therapy's adverse effects.

However, short-term hormone therapy benefited men undergoing radiation for intermediate-risk prostate cancer, said Christopher U. Jones, MD, who presented the results on behalf of the Radiation Therapy Oncology Group (RTOG) 94-08 and is from Radiological Associates of Sacramento in California.

"The study is the first compelling evidence of survival benefit in men with intermediate risk," agreed Dr. Smith.

Despite these enthusiasms, both Dr. Jones and Dr. Smith explained that the new study is not the final word on short-term hormone therapy in intermediate-risk patients.

The radiation doses and techniques used in the current study, which started enrolling patients in 1994, are now dated, Dr. Jones said at a meeting press conference.

The study is the first compelling evidence of survival benefit in men with intermediate risk.

"In current practice, these intermediate-risk patients get a higher dose of radiation," he said, suggesting that modern radiation might eliminate the need for androgen deprivation in these patients.

Another RTOG study (08-15) is underway to evaluate more modern high-dose radiation methods and hormone therapy in these intermediate-risk patients, both he and Dr. Smith pointed out.

Comparable Outcomes in Low-Risk Patients

The landmark study presented at the meeting, with 1979 participants, is the largest prostate cancer study to date, and is still ongoing, Dr. Jones noted.

Originally, the study was designed to evaluate the treatment of men with low-risk prostate cancer only, but the definition of low risk evolved as the study got underway, Dr. Jones explained

"When we started this study in 1994, all of these patients were considered low risk," he said. As prostate-specific antigen (PSA) testing matured as a tool, it became clear that the study group could be further defined. "With the advent of PSA screening, we were able to further refine low- and intermediate-risk patients," he said.

Study participants were randomized to short-term androgen-deprivation therapy (2 months before and 2 months during radiation) plus radiation, or radiation therapy alone.

About a third of the patients were low risk (n = 685), which was defined as a Gleason score of 6 or less with a PSA level of 10 ng/mL or less and a tumor stage of T2a or less.

About one half of the patients were intermediate risk (n = 1068), which was defined as a Gleason score of 7, a Gleason score of 6 or less and a PSA of 10 to 20 ng/mL, or a Gleason score of 6 or less and stage T2b disease.

The remaining patients were high risk (n = 226), with Gleason scores of 8 to 10.

At 8 years, the overall and disease-specific survival rates were comparable in low-risk patients treated with hormones and radiation therapy than in those treated with radiation therapy alone.

"The combination of these 2 survival indicators suggests no need for hormone therapy in low-risk patients," Dr. Jones remarked.

Specifically, the overall survival rate at 8 years for patients treated with hormones and radiation therapy was 76%, compared with 73% for those treated with radiation therapy alone (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.83 - 1.39).

Low-risk patients do not need to undergo the toxicities of hormone therapy.

The disease-specific survival rate at 8 years for patients treated with hormones and radiation therapy was 98%, compared with 99% for those treated with radiation therapy alone (HR, 1.07; 95% CI, 0.83 - 1.39).

"Low-risk patients do not need to undergo the toxicities of hormone therapy," said Dr. Jones at a press conference, referring to hot flashes, loss of sexual function, liver toxicities, and other adverse effects.

Effective Therapy for Intermediate-Risk Patients

In the study, total androgen suppression was achieved with flutamide 250 mg twice daily and either goserelin 3.6 mg once a month or leuprolide 7.5 mg once a month.

The hormone therapy apparently benefited men with intermediate-risk disease.

At 8 years, the overall and disease-specific survival rates were favorable in intermediate-risk patients treated with hormones and radiation therapy, compared with those treated with radiation therapy alone.

Specifically, the overall survival rate at 8 years for patients treated with hormones and radiation therapy was 72%, compared with 66% for those treated with radiation therapy alone (HR, 1.23; 95% CI, 1.02 - 1.49).

"Among the intermediate-risk patients, there was a 23% greater chance of dying each year for patients treated with radiation alone," said Dr. Jones.

The disease-specific survival rate at 8 years for patients treated with hormones and radiation therapy was 98%, compared with 92% for those treated with radiation therapy alone (HR, 2.44; 95% CI, 1.47 - 4.04). "Patients treated with radiation alone were nearly 2 and a half times more likely to die from prostate cancer," said Dr. Jones.

The outcomes for the patients with high-risk disease were not as impressive as those for intermediate-risk disease, which probably reflects the fact that high-risk disease requires longer-term hormone therapy, Dr. Smith told the plenary audience.

Meaningful Results

"We wanted to know who needed short-term hormone therapy," said incoming ASTRO president Anthony Zietman, MD, about the original impetus behind the new study.

Although Dr. Jones's presentation emphasized 8-year data, the median follow-up time in the trial is a little more than 9 years, which approaches the length of time needed for meaningful results in prostate cancer, Dr. Zietman, who is from Harvard Medical School in Boston, told Medscape Oncology in an earlier interview. "Results need to be at least 10 years out to be meaningful."

He explained that the use of short-term androgen deprivation is not as widespread now as it has been in the past.

The use of short-term hormone therapy, especially leuprolide (Lupron), in low-risk prostate cancer patients undergoing radiation therapy jumped from about 10% of all such patients to about 50% during the mid- to late-1990s. "This almost became the norm with urologists," said Dr. Zietman.

The use tailed off somewhat when financial incentives to use the therapy ended, he said.

Although leuprolide use in low-risk patients was partly fueled by financial considerations, it was also probably spurred on by clinicians not sticking to evidence-based medicine, Dr. Zietman explained. "Clinicians took the evidence too far," he noted, referring to studies such as RTOG 86-10, in which the short-term therapy provided a number of benefits to men with locally advanced prostate cancer.

The new results provide some direction for clinicians, suggested Dr. Jones. "The study provides strong scientific evidence that shows us when to deliver hormone therapy with radiation in patients with localized prostate cancer," he said in a press statement.

American Society for Radiation Oncology (ASTRO) 51st Annual Meeting: Latebreaker. Presented November 2, 2009.

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