Howard Sandler, MD
In the multicenter trial—which initially enrolled 760 men with biochemical recurrence after radical prostatectomy—patients were randomly assigned to treatment with bicalutamide or placebo for 2 years, along with 6.5 weeks of radiation therapy.
After a median follow-up of 13 years, the actuarial rate of overall survival (OS) at 12 years was 76.3% for patients treated with bicalutamide, compared with 71.3% for patients in the placebo group (HR, 0.77; 95% CI, 0.59-0.99; P = .04). The 12-year incidence of death from prostate cancer was 5.8% versus 13.4%, respectively (HR, 0.49; 95% CI, 0.32-0.74; P <.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group and 23.0% in the placebo group (HR, 0.63; 95% CI, 0.46-0.87; P = .005).
“Our study indicates that hormonal treatments should be incorporated into the management of men who need radiation therapy after surgery for prostate cancer," senior author Howard Sandler, MD, chair of the Department of Radiation Oncology at the Samuel Oschin Comprehensive Cancer Institute at Cedar's Sinai, said in a statement.
The double-blind, placebo-controlled trial was conducted between 1998 and 2003 and enrolled patients who had had their prostate gland removed for localized disease. Patients’ disease was originally assessed, on the basis of pathological testing, as tumor stage T2 or T3 without nodal involvement.
Eligible patients were also required to have a detectable PSA level of 0.2 to 4.0 ng/ml at least 8 weeks after surgery. Additionally, patients could not participate in the study if they had previously received chemotherapy, radiation therapy, or hormone therapy (other than preoperative short-term hormonal therapy for 2-6 months in some patients [6.4% of those enrolled]) for prostate cancer.
Salvage radiation therapy began within 12 weeks after randomization. A total dose of 64.8 Gy was administered in 36 daily fractions of 1.8 Gy at a rate of 5 sessions per week. Beginning at the initiation of radiation therapy, patients were given, on a daily schedule, either 150 mg of bicalutamide or 1 placebo tablet. Patients received their respective treatments for 24 months.
At the beginning and end of radiation therapy, the researchers evaluated patients’ clinical history, physical examination, Karnofsky performance status score, complete blood count, PSA level, serum alanine aminotransferase level, bilirubin level, and reports of any treatment-related adverse events. Subsequent follow-up evaluations were done every 3 months for 2 years, then every 6 months for 3 years, and then on a yearly basis. Bone and CT scans were performed at subsequent biochemical recurrence. Maximum androgen blockade was recommended if metastatic disease was present or if the serum PSA level rose to over 4.0 ng/ml.
The 2 groups of patients were well balanced in terms of demographic and tumor-related characteristics. The median age of patients was 65 years, and the median PSA level at study entry was 0.6 ng/ml. The median interval between surgery and the first detectable PSA level was 1.4 years, and the median interval between surgery and trial entry was 2.1 years.
The primary endpoint was the rate of OS. Prespecified secondary endpoints included disease-specific death, distant metastases, local disease progression, non–disease-specific death, any disease progression including a second biochemical recurrence, and adverse events.
A total of 21 patients treated with bicalutamide died from prostate cancer, compared with 46 patients in the placebo group. The cumulative incidence of a second biochemical recurrence at 12 years was 44.0% in the bicalutamide group, compared with 67.9% in the placebo group (HR, 0.48; 95% CI, 0.40-0.58; P <.001).
In terms of toxicity, the incidence of late adverse events associated with radiation therapy was similar between the 2 treatment arms. Gynecomastia was observed in 69.7% of the patients in the bicalutamide group, compared with 10.9% of patients in the placebo group (P <.001).
"This study's findings—that adding antiandrogen therapy to the radiation typically used against recurrence reduces the incidence of metastasis, death from prostate cancer and overall deaths - will change the standard of care for patients experiencing a postoperative recurrence," study author William U. Shipley, MD, Massachusetts General Hospital Department of Radiation Oncology, said in a statement.
Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017;376(5):417-428.