Adding short-term androgen-deprivation therapy (ADT) to radiation therapy (RT) for early-stage prostate cancer improves long-term survival for men at intermediate risk, according to trial results from the Radiation Therapy Oncology Group (RTOG) published in the July 14 New England Journal of Medicine.
The outcome of this clinical trial establishes the combined treatment as the new standard of care for men with intermediate-risk prostate cancer, according to the principal investigators. However, current irradiation methods that deliver higher doses of radiation more precisely may have already rendered the addition of hormone therapy obsolete, the authors also wrote (NEJM, July 14, 2011, Vol. 365:2, pp. 107-118).
The study of nearly 2,000 men with low- and intermediate-risk prostate cancer revealed that 10 years following treatment, those with intermediate-risk prostate cancer who had the combined therapy were 2.5 times less likely to die from the disease than those treated with radiation alone. However, men with low-risk prostate cancer did not experience the same benefits.
Co-principal investigator and lead author Dr. Christopher Jones, a radiation oncologist at Radiological Associates of Sacramento, and colleagues reported that by adding four months of ADT, 10-year disease-specific mortality decreased from 8% to 4%. Overall survival 10 years following treatment was 62% for the combined therapy group, compared with 57% for the RT-only group. Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at two years were also significantly improved with the combined treatment.
The Radiation Therapy Oncology Group 94-08 phase III trial began enrolling patients in 1994. Patients with histologically confirmed stage T1B-C or stage T2A-B prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng/mL or less were eligible to participate. The patient cohort included 1,979 men who received treatment at 212 cancer treatment centers in the U.S. and Canada. These patients were further stratified into groups based on low (35%), intermediate (54%), and high (11%) risk.
All patients received daily radiation therapy in 1.8-Gy fractions, for a 46.8-Gy radiation dose delivered to the pelvis and 19.8 Gy delivered to the prostate. Patients assigned to the short-term ADT group had this therapy first, followed by the radiation therapy treatment 60 days later. The men were followed for a median of 9.1 years.
A total of 95 patients died of prostate cancer, 31 from the combined treatment group and 64 from the RT-only group. The reduction in disease-specific deaths was mostly accounted for by the intermediate-risk patients who had the combined therapy -- a particularly important finding. This subgroup showed an increase in the 10-year rate of overall survival, from 54% to 61%, and a reduction in 10-year disease-specific mortality, from 10% to 3%.
The low-risk patients, however, had only a marginal increase in the 10-year rate of overall survival, from 64% to 67%, along with a 1% to 3% increase in 10-year disease-specific mortality.
"The results suggest a biological interaction between the two therapies, given that several randomized trials of surgery and short-course androgen-deprivation therapy did not show a benefit in outcome," commented Dr. Howard Sandler, RTOG Genitourinary Cancer Committee chair and a study co-author. Sandler is also chairman of the department of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute of Cedars-Sinai Medical Center.
Both ADT subgroups experienced the same levels of toxicities, which included an increase in erectile dysfunction after treatment, from 52% before treatment to 79% one year later. Hot flashes were experienced by more than half of the patients, and 3% developed rashes.
The finding that men with low-risk prostate cancer who received RT only had 4% disease-specific mortality, compared with an 8% rate for the combined group, does not support the addition of short-course ADT, the authors wrote. By eliminating this treatment, this subgroup of patients will experience fewer toxicities and have a better quality of life, in addition to reducing treatment costs.
In an accompanying editorial, Dr. Anthony D'Amico, PhD, professor of radiation oncology at Harvard Medical School, pointed out that the U.S. Food and Drug Administration (FDA) added warning labels in October 2010 to gonadotropin-releasing hormone agonists; one of the ADT drugs administered to some patients in the trial falls into this category.
According to the warnings, men receiving this hormonal therapy were at a small but increased risk for diabetes, heart attack, stroke, and sudden death. D'Amico also agreed that if hormone therapy showed no significant benefit for low-risk patients, it should not be prescribed.
