Adding short-term androgen-deprivation therapy before and during conventional radiotherapy for early localized prostate cancer confers a modest but significant increase in 10-year survival, according to a new report in the July 14 issue of the New England Journal of Medicine.

The strategy also halves disease-specific 10-year mortality, reduces the rate of biochemical failure (recurrence of elevated PSA), cuts the incidence of distant metastases, and decreases the rate of positive findings on repeat prostate biopsy after 2 years, said Dr. Christopher U. Jones of Radiological Associates of Sacramento and his associates in this Radiation Therapy Oncology Group (RTOG) phase III clinical trial.

These benefits were most pronounced for men deemed to be at intermediate risk at diagnosis, they noted.

The RTOG initiated the international randomized trial because little is known about the role of short-term androgen-deprivation therapy (ADT) for nonbulky localized tumors. Study subjects comprised 1,979 men with stage T1b, T1c, T2a, or T2b prostate adenocarcinomas and an initial PSA level of 20 ng per milliliter or lower.

Patients were randomly assigned to standard radiotherapy alone (992 subjects) or radiotherapy plus three-times-daily flutamide and either subcutaneous goserelin or intramuscular leuprolide beginning 2 months before initiation of radiotherapy and continuing through 2 months of radiotherapy (987 subjects).

The primary end point was overall survival after a sufficiently long interval had passed to allow for recurrence of this often indolent cancer. The 10-year overall survival was 62% with added ADT, compared with 57% with radiotherapy alone.

The 10-year disease-specific mortality was 4% with combined therapy and 8% with radiotherapy alone. The 10-year rate of biochemical failure was 26% with combined therapy and 41% with radiotherapy alone. The 10-year cumulative incidence of distant metastases was 6% with combined therapy and 8% with radiotherapy alone.

Approximately 45% of the study population underwent repeat prostate biopsy after 2 years. Persistent cancer was detected in 20% of the specimens from men who had received radiotherapy plus ADT, compared with 39% of the men who had received radiotherapy alone.

A subgroup analysis showed that adding ADT to radiotherapy was most beneficial for men who had been considered to be at intermediate risk at baseline; they comprised slightly more than half of the study subjects. In this subgroup of 524 men who received combination therapy, 10-year overall survival was 61% (vs. 54% in the 544 intermediate-risk men who received radiotherapy alone) and 10-year disease-specific mortality was 3% (vs. 10%).

Low-risk men did not show these benefits when ADT was added to radiotherapy, but ADT did significantly decrease the incidence of biochemical failure and the rate of positive results on repeat biopsy in low-risk men. "It is conceivable that in patients with indolent disease, longer follow-up is required to show a benefit with respect to the disease-specific mortality and overall survival rates," Dr. Jones and his colleagues said (N. Engl. J. Med. 2011;365:107-18).

For the small number of subjects (11% of both study groups) considered to be at high risk at baseline, adding short-term ADT to radiotherapy did not appear to be beneficial. This comparison, however, may have been underpowered. It also may be that, as previous clinical trials have suggested, more than 4 months of ADT is required for maximum benefit in this population, the investigators added.

In all, 395 of the study subjects were black, and black men showed similar benefits from short-term ADT as did white men. Adding ADT decreased the 10-year disease-specific mortality from 7% to 5% and cut the 10-year rate of biochemical failure from 40% to 19% in black men. Overall survival was worse among black men compared with white, but disease-specific mortality was similar.

Acute and late radiation-induced toxic effects were similar between subjects who received radiotherapy alone and those who received radiotherapy plus ADT. The rate of grade 3 or higher toxic effects related to ADT was less than 5%.

Given that the addition of ADT may not be as beneficial for low-risk patients, the treatment’s toxic effects, which do affect quality of life, may tip the balance against using this approach in low-risk men. Hot flashes and erectile dysfunction were more common with ADT, and previous studies have suggested that such erectile dysfunction may be less responsive to interventions than after radiotherapy alone. Moreover, other studies have reported that even short-term ADT can cause measurable muscle loss, fat accumulation, decreased insulin sensitivity, and increases in cholesterol and triglyceride levels, Dr. Jones and his associates said.

They noted that radiotherapy techniques have changed somewhat since this study was initiated, and intensity-modulated radiotherapy, low-dose-rate brachytherapy, and high-dose-rate brachytherapy now allow "the safe delivery of higher doses of radiation than was possible when this study was conducted." The value of adding short-term ADT to these techniques is not yet known but is currently being studied in another RTOG clinical trial, they said.

The study was supported by the National Cancer Institute and no commercial support was provided. Dr. Jones’ associates reported ties to Amgen, Ferring, GlaxoSmithKline, Eli Lilly, Calypso Medical, and Varian.

Short-Term ADT with Radiotherapy Ups Prostate Cancer Survival