6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients With Clinically Localized Prostate Cancer

A Randomized Controlled Trial

Anthony V. D'Amico   JAMA. 2004;292:821-827.

Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events.

Between December 1, 1995, and April 15, 2001, 206 patients from the Harvard outreach and central hospitals with 1992 American Joint Commission on Cancer7 category T1b to T2b, NX, M0 centrally reviewed adenocarcinoma of the prostate8 were randomized to receive 70 Gy 3D-CRT alone or in combination with 2 months each of neoadjuvant, concurrent, and adjuvant AST. Eligible patients included those patients with a PSA of at least 10 ng/mL (maximum, 40 ng/mL) or a Gleason score of at least 7 (range, 5-10). Low-risk patients were ineligible unless they had radiographic evidence using endorectal coil magnetic resonance imaging (MRI) of extracapsular extension or seminal vesicle invasion. Patients were also considered ineligible if they had a prior history of malignancy except for nonmelanoma skin cancer or any history of hormone therapy use.

All patients were required to have a negative bone scan and pelvic lymph node assessment using MRI or computed tomography (CT) within 6 months of randomization. Eligible patients also needed to have an Eastern Cooperative Oncology Group performance status of 0 or 1 (range, 0-4), white blood cell count of at least 3000/µL, hematocrit of more than 30%, platelet count of more than 100 x 103/µL, and a life expectancy of at least 10 years, excluding death related to prostate cancer at study entry. Main Outcome Measures Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival.

Treatment

Radiation Therapy. Photons of 10 MV or more were used. Patients were treated once daily and 5 days per week. The daily dose was 1.8 Gy for the initial 25 treatments, totaling 45 Gy, and 2.0 Gy for the final 11 treatments, totaling 22 Gy. Therefore, patients received a total dose of 70.35 Gy (67 Gy normalized to 95%) to the prostate plus a 1.5-cm margin using a 4-field 3D-CRT technique, which involved CT-based treatment planning and shaped conformal cerrobend blocks or a multileaf collimator. The prostate and the seminal vesicles were included in the initial radiation field using a 1.5-cm margin. Patients were simulated (radiation field mapped) before the start of neoadjuvant hormone therapy.

Hormone Therapy. AST consisted of a combination of a luteinizing hormone–releasing hormone (LHRH) agonist (leuprolide acetate) or goserelin and a nonsteroidal anti-androgen (flutamide). Leuprolide acetate (n = 88) was delivered intramuscularly each month at a dose of 7.5 mg or 22.5 mg every 3 months. Goserelin (n = 10) was administered subcutaneously each month at a dose of 3.6 mg or 10.8 mg every 3 months. Both LHRH agonists were permitted because they have been shown to have equivalent efficacy in the treatment of prostate cancer.9 Flutamide (n = 98) was taken orally at a dose of 250 mg every 8 hours and starting 1 to 3 days before the LHRH agonist to block the transient increase in testosterone caused by the LHRH agonist. Treating physicians and patients were not blinded to treatment groups because the institutional review boards did not believe sham injections were justified.

Results After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P = .04), lower prostate cancer–specific mortality (P = .02), and higher survival free of salvage AST (P = .002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group.

Conclusion The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.