CHICAGO—There is no significant advantage to administering short-term endocrine therapy to men with low-risk prostate cancer who are undergoing radiation treatment, according to the results of a landmark study presented at the plenary session here at the American Society for Radiation Oncology (ASTRO) Annual Meeting.
Adding a short course of hormone-blocking therapy to radiation treatment improved the survival rates of intermediate-risk prostate cancer patients, but did not extend the lives of low-risk patients, compared with radiation alone, the study showed.
“Our findings show that men with intermediate-risk disease, which is a significant minority of patients, gain a benefit in overall survival from the addition of four months of hormone therapy,” Christopher U. Jones, MD, a radiation oncologist at Radiological Associates of Sacramento, said during his late-breaking presentation. “But low-risk patients do not need to undergo the toxicities of hormone therapy,” which include hot flashes, impotence, and liver toxicities.
After studies in the 1990s showed that patients with advanced prostate cancer benefited from androgen-deprivation therapy, oncologists began offering it to lower-risk patients as well, explained ASTRO 2009–2010 President Anthony L. Zietman, MD, the Jenot W. and William U. Shipley Professor of Radiation Oncology at Harvard Medical School.
“The results were seized upon by radiation oncologists, who made the assumption that if it was good for nasty cancers, it was probably pretty good for low-risk patients too.”
By the mid- to late-1990s, about half of low-risk patients were being offered hormone-blocking drugs—“This almost became the norm, but it was not evidence-based medicine,” Dr. Zietman said.
The use in low-risk patients was further spurred by studies such as the Radiation Therapy Oncology Group (RTOG) 86-10 trial, which showed that a short course of androgen ablation administered before and during radiotherapy was associated with a significant improvement in local control, disease progression, and overall survival in patients with locally advanced carcinoma of the prostate—“Clinicians took the evidence too far,” he said, and soon some physicians began to question whether the benefits of the treatment outweighed the risk in lower-risk patients.
Enter RTOG 94-08
The new study, RTOG 94-08, was originally designed to clarify the benefits of androgen-deprivation therapy in men with low-risk prostate cancer, but the definition of low risk was refined after the study was under way, Dr. Jones explained.
“When we started this study in 1994, all of these patients were considered low risk. As PSA testing matured, we were able to further refine low- and intermediate-risk patients.”
In the study, which is still ongoing, 1,979 men were randomized to radiation plus neoadjuvant androgen-deprivation therapy, two months before and two months during radiation, or radiation therapy alone.
To be eligible, patients had to have biopsy-proven Stage T1b-T2b prostate cancer and a PSA level of 20 ng/mL or less.
Androgen deprivation therapy consisted of 250 mg of flutamide twice daily and either 3.6 mg of goserelin once a month or 7.5 mg of leuprolide once a month.
All patients received a total radiation dose of 66 Gy, consisting of 48.8 Gy to the regional lymph nodes, with a 19.8 Gy boost to the prostate. The primary endpoint of the study was the overall survival rate.
Low vs Intermediate Risk
A total of 685 of the men were classified as low risk, 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.
A total of 1,068 men were classified as intermediate risk, 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 226 patients were classified as high risk, with Gleason scores of 8 to 10.
No Benefit to Low-Risk Patients
At a median of eight years of followup, the overall survival rate for low-risk patients treated with endocrine and radiation therapy was 76%, compared with 73% for those treated with radiation therapy alone, a nonsignficant difference.
“The findings suggest there is no need for hormone therapy in low-risk patients,” Dr. Jones said.
Men with intermediate-risk disease, on the other hand, did benefit from androgen suppression: At eight years, the overall survival rate for intermediate-risk men treated with anti-hormone therapy and radiation therapy was 72%, compared with 66% for those treated with radiation therapy alone.
“This corresponded to a [significant] 23% greater chance of dying each year for patients treated with radiation alone,” Dr. Jones said.
The eight-year disease-specific survival rate for intermediate-risk patients treated with anti-hormone and radiation therapy was 98%, compared with 92% for those treated with radiation therapy alone.
The hazard ratio was 2.44, meaning that patients treated with radiation alone were nearly two and a half times more likely to die from prostate cancer, Dr. Jones said.
Patients with high-risk disease also benefited from the addition of androgen-deprivation therapy, although the results were not as striking as those for patients with intermediate-risk disease. The reason, Dr. Jones, suggested, is that high-risk patients require longer-term hormone therapy.
Study Discussant Matthew R. Smith, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Assistant in Hematology/Oncology at Massachusetts General Hospital, called the study landmark and practice-changing.
“This definitively establishes no benefit for endocrine therapy in men with low-risk disease,” he said.
As for intermediate-risk patients, “the study is the first compelling evidence of survival benefit,” Dr. Smith said.
ASTRO 2008–2009 President Tim R. Williams, MD, a private practitioner at Boca Raton Community Hospital, agreed, telling a news conference that “this is the best data we have and it really clarifies who does and who does not need hormone therapy after radiation.”
Nevertheless, all the physicians agreed that further study is needed to clarify the benefits of short-term androgen-deprivation therapy in intermediate-risk patients.
The reason, Dr. Jones explained, is many patients in the study received radiation protocols that are no longer used.
“The question now is, with modern radiation therapy, which is higher dose, will hormone therapy still benefit the intermediate risk patients?” he said.
Another RTOG study, 08–15, is currently under way to determine the benefits of hormone-blocking therapy in intermediate-risk patients treated with modern, high-dose radiation techniques, Dr. Jones said.