SHORT TERM ADT BEFORE RADIOTHERAPY IMPROVES PROSTATE CANCER SURVIVAL IN INTERMEDIATE RISK PATIENTS

July 15, 2011 — The addition of short-term androgen-deprivation therapy (ADT) to conventional radiotherapy was associated with a survival benefit for men with localized prostate cancer, according to a study published in the July 14 issue of the New England Journal of Medicine.
The 10-year overall survival rate was 62% among men who received radiotherapy plus short-term ADT compared with 57% among men who received radiotherapy alone. Adding ADT also decreased the 10-year disease-specific mortality rate from 8% to 4%.
However, when the authors reanalyzed the data according to risk subgroups, they found that the improvements in overall survival and reductions in disease-specific mortality were primarily limited to patients in the intermediate-risk subgroup.
The authors note that they also saw reductions in the secondary endpoints of biochemical failure, distant metastases, and the rate of positive findings on repeat biopsies at 2 years.
"For men with high-risk prostate cancer, previous studies have shown us that adding short-term ADT to radiation therapy is not enough," said lead author Christopher U. Jones, MD, from Radiological Associates of Sacramento in California. "We need to add long-term ADT to radiation therapy for maximum benefit for these patients."
The data from this study support these previous findings, he added.
"But for men with intermediate-risk prostate cancer, treated with conventional doses of radiation, the standard of care now should be to add short-term ADT to the radiation therapy," Dr. Jones told Medscape Medical News.
However, the authors point out that despite the favorable results seen in their study, the adoption of new and advanced modalities in radiotherapy may put the value of adding short-term ADT in patients treated with these new radiation therapy techniques in doubt.
"What complicates the issue is that most men are now treated with modern techniques, which allows considerably higher doses of radiation to be administered safely and with improved efficacy against prostate cancer," Dr. Jones explained. "We do not know if the addition of short-term ADT will still be needed for patients treated with these higher doses of radiation."
He added that the Radiation Therapy Oncology Group (RTOG) has opened a new clinical trial, RTOG 0815, to answer this question.
Further Studies Needed
Even though combination therapy appears to be indicated in men with intermediate risk for prostate cancer, it is unclear whether a radiation dose larger than 66.6 Gy or longer durations of hormonal therapy can further reduce mortality, commented Anthony V. D'Amico, MD, PhD, chair, Division of Genitourinary Radiation Oncology, Dana-Farber Cancer Institute in Boston, Massachusetts.
He points out in an accompanying editorial that 2 previous randomized trials (MRC RT018 and DFCI 950964) have provided evidence that these interventions may further increase survival in this subgroup of men.
Another randomized trial, ICORG 97-0110, which evaluated a 70-Gy radiation dose to the prostate and 8 vs 4 months of hormonal therapy, showed no difference in outcome. However, only 16% of the study cohort had intermediate-risk disease, "which was not sufficient to address the question of the duration of hormonal therapy in these men," Dr. D'Amico writes.
"Therefore, radiation therapy and 4 or 6 months of hormonal therapy remain treatment options for men with intermediate-risk disease," he concludes. "Whether 4 or 6 months of hormonal therapy for intermediate-risk disease is best requires further study."
Improvements Seen in Combined-Therapy Group
In the current study, Dr. Jones and colleagues randomly assigned 1979 patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen level of 20 ng/mL or less to receive radiotherapy alone (n = 992) or radiotherapy plus 4 months of ADT (n = 987).
The total dose of radiation was 66.6 Gy, and patients assigned to receive short-term ADT received both flutamide 250 mg orally 3 times a day and either monthly subcutaneous goserelin (3.6 mg) or intramuscular leuprolide (7.5 mg) for 4 months. Radiotherapy began 2 months after ADT. The median follow-up period was 9.1 years.
Combination therapy conferred a modest but significant increase in the 10-year rate of overall survival (hazard ratio for death with radiotherapy alone, 1.17; P = .03). There also was a significant reduction in 10-year disease-specific mortality (hazard ratio for radiotherapy alone, 1.87; P = .001).
Secondary endpoints were also improved in patients receiving combination therapy. The 10-year rate of biochemical failure was 41% among patients who received radiation therapy alone compared with 26% in the combined-therapy group (hazard ratio, 1.74; P < .001). The 10-year cumulative incidence of distant metastases was 8% in the radiotherapy-alone group and 6% in the combined-therapy group (hazard ratio, 1.45; P = .04), whereas the 10-year cumulative incidence of death from causes other than prostate cancer was 37% among those receiving radiotherapy alone vs 34% in the combined-therapy group (P = .56).
Within the cohort, 439 patients in the combined-therapy group (44%) and 404 patients in the radiotherapy-alone group (41%) underwent a repeat prostate biopsy at 2 years. Persistent cancer was detected in 20% of specimens in the combined-therapy group compared with 39% in the radiotherapy-alone group (P < .001).
On multivariate analysis, the authors found that a Gleason score of 7 or higher was a negative prognostic factor for several endpoints including overall survival, disease-specific mortality, distant metastases, and biochemical failure. Other negative prognostic factors were older age and nonwhite race or ethnic group for overall survival, clinical T2 lesions for disease specific mortality, and a prostate-specific antigen level of 4 ng/mL or higher for biochemical failure.
In the combined-therapy group, 55% of patients experienced hot flashes, 3% had rash, 16% had hepatic toxic effects, 16% had decreased hemoglobin levels, and 4% had elevated white cell counts, all grade 1. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%.
The study was supported by grants from the National Cancer Institute. Coauthor Michael Chetner, MD, reports receiving lecture fees from and serving on the advisory boards of Amgen, Ferring, GlaxoSmithKline, and Eli Lilly and receiving fees for the development of educational presentations from Amgen and GlaxoSmithKline. Coauthor Howard Sandler, MD, received consulting fees from Calypso Medical and Varian.
N Engl J Med. 2011;365:107-118, 169-171. Article summary, Editorial extract