Six-months of adjuvant androgen suppression plus 74 Gy or 78 Gy of concurrent external-beam radiation led to a statistically significant improvement in event-free survival and disease-free survival but failed to improve distant metastasis-free survival and overall survival vs external-beam radiation alone in patients with intermediate-risk prostate cancer.
Six-months of adjuvant androgen suppression plus 74 Gy or 78 Gy of concurrent external-beam radiation led to a statistically significant improvement in event-free survival (EFS) and disease-free survival (DFS) but failed to improve distant metastasis-free survival (DMFS) and overall survival (OS) vs external-beam radiation alone in patients with intermediate-risk prostate cancer, according to long-term findings from the phase 3 EORTC trial 22991 (NCT00021450) that were published in the Journal of Clinical Oncology.1
At a median follow-up of 12.2 years, external-beam radiation plus androgen suppression led to a 57% reduction in the risk of EFS events (HR, 0.53; 95% CI, 0.41-0.70; P < .001) and a 33% risk reduction in DFS events (HR, 0.67; 95% CI, 0.49-0.90; P = .008).
The 10-year EFS rate was 68.1% with radiation plus androgen suppression (95% CI, 61.6%-73.7%) vs 49.3% with radiation alone (95% CI, 42.4%-55.8%). The 10-year DFS rate was 76.2% (95% CI, 70.1%-81.3%) vs 66.0% (95% CI, 59.2%-71.9%), respectively.
The benefits in EFS vs DFS, respectively, were seen across age groups (< 70 vs ≥ 70 years; P = .646; P = .710) and were independent of radiation dose (74 Gy vs 78 Gy; P = .874; P = .571).
“Our findings in the intermediate-risk disease subgroup are in line with recent studies showing that DMFS is a strong surrogate for OS, but that EFS is not,”wrote lead study author Michel Bolla, MD, a professor of radiation oncology at Grenoble University Hospital, and coauthors in the study publication. “These are the most robust data from a randomized trial with long-term follow-up addressing this question. They shed light on the important clinical question of the value of androgen suppression in men treated with radiation if dose escalation is used.”
Primary findings from the EORTC trial 22991 showed that, with 7.2 years of median follow-up, 6 months of adjuvant androgen suppression led to an improvement in 5-year EFS and DFS in patients with intermediate- and high-risk localized prostate cancer who had been treated with 70 Gy to 78 Gy of concurrent external-beam radiation vs radiation alone.
However, current practice states that a minimum dose of 74 Gy should be administered to patients with intermediate- and high-risk localized prostate cancer. Moreover, modern standards indicate that high-risk patients should receive long-term androgen suppression vs the 6-month short course of androgen suppression.
As such, investigators evaluated the outcomes only of patients with intermediate-risk disease who had received a minimum dose of 74 Gy of radiation, a population which received the current standard of care.
A total of 819 patients were randomized to external-beam radiation plus androgen suppression (n = 410) or external-beam radiation alone (n = 409). Of those patients, 481 (58.7%) presented with intermediate-risk disease and were treated with 74 Gy or 78 Gy of radiation; 245 patients were randomized to radiation plus androgen suppression and 236 to radiation alone.
External-beam radiation was given as 5 daily fractions of 2 Gy a week at a dose of 46 Gy for planning target volume (PTV) I, which included prostate and seminal vesicles, 24 Gy for PTV II, which included prostate and the proximal part of the seminal vesicles, and 0 Gy, 4 Gy, or 8 Gy for PTV III, which included the prostate depending on center policy.
Pelvic lymph nodes were irradiated to 46 Gy when indicated.
Androgen suppression consisted of 2 subcutaneous injections of 3-monthly depot of the luteinizing hormone releasing hormone (LHRH) analog goserelin, which was given the first day of irradiation, then 3 months later. Flare protection consisted of 1 month of the antiandrogen bicalutamide (Casodex) at a dose of 50 mg daily, which was started 1 week prior to the first LHRH injection.
Of these patients, 481 had intermediate risk, defined by International Union Against Cancer TNM 1997 cT1b-c or T2a disease with a prostate-specific antigen (PSA) level of at least 10 ng/mL, or a Gleason score of 7 or less and a PSA level of 20 ng/mL or less, without nodal involvement or metastatic disease.
These patients received 74 Gy (n = 342; 71.1%) or 78 Gy (n = 139; 28.9%) of external-beam radiation.
EFS, DFS, DMFS, and OS were reported in the intention-to-treat population and stratified by external-beam radiation dose at a two-sided α of 5%.
Additional findings showed that 92 patients had EFS events in the external-beam radiation plus androgen suppression arm (n = 245) vs 132 patients in the external-beam radiation alone arm (n = 236); events primarily occurred because of PSA relapse (48.7%) or death (45.1%).
The 10-year DMFS rate was 79.3% (95% CI, 73.4%-84.0%) with external-beam radiation plus androgen suppression vs 72.7% (95% CI, 66.2%-78.2%) with external-beam radiation alone (HR, 0.74; 95% CI, 0.53-1.02; P = .065), failing to reach statistical significance.
The 10-year OS rate was 80.0% (95% CI, 74.1%-84.7%) with external-beam radiation plus androgen suppression vs 74.3% (95% CI, 67.8%-79.7%) with external-beam radiation alone; the difference between arms was not statistically significant (HR, 0.74; CI, 0.53-1.04; P = .082).
In terms of safety, more patients in the radiation/androgen suppression arm experienced late-onset grade 3 or greater genitourinary toxicities (7.4%) vs patients in the radiation-alone arm (4.3%; P = .174).
Similarly, more patients who received radiation/androgen suppression experienced late-onset severe impairment of sexual function (30.9%) vs patients who received radiation alone (22.1%; P = .038).
Additionally, 3 patients in each arm experienced late-onset grade 3 or greater gastrointestinal toxicities.