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Antiandrogen therapy may improve recurrent prostate cancer survival
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The addition of 24 months of antiandrogen therapy with bicalutamide to radiation therapy improved OS among patients with prostate cancer who have evidence of disease recurrence following radical prostatectomy, according to a double blind, placebo-controlled trial published in The New England Journal of Medicine.
“Surgery is a very common treatment for men with localized prostate cancer, but more than 30% of them will have recurrent disease,” William U. Shipley, MD, professor of radiation oncology at Harvard Medical School, said in a press release. “So, we specialists in genitourinary oncology have been working to address this problem for a long time. 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.”
Researchers of the study — conducted between 1998 and 2003 — enrolled 760 men (median age, 65 years) who had undergone prostatectomy with a lymphadenectomy and had disease with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with a histologic extension beyond the prostatic capsule). Patients had no nodal involvement and a median PSA level at trial entry of 0.6 ng/mL.
In total, 384 patients received antiandrogen therapy with 150 mg daily bicalutamide for 24 months plus radiation therapy. The other 376 patients received placebo plus radiation.
OS served as the primary endpoint.
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.
Median follow-up among surviving patients was 13 years.
The rate of OS at 12 years was 76.3% in the bicalutamide group, compared with 71.3% in the placebo group (HR = 0.77; 95% CI, 0.59-0.99).
Further, at 12 years, fewer men in the bicalutamide group had died of prostate cancer (5.8% vs. 13.4%; P < 0.001) or developed metastatic disease (14.5% vs. 23%; P = 0.005).
The incidence of late adverse events associated with radiation therapy was similar in the two groups.
However, gynecomastia occurred in 69.7% of the patients in the bicalutamide group compared with 10.9% of the placebo group (P = 0.001).
“Although the rate of gynecomastia was significantly higher in the bicalutamide group than the placebo group, this finding was not significantly linked as an explanation in patients taking less than the full course of oral tablets,” the researchers wrote.
Researchers noted that the survival gains reported in both groups were achieved without exacerbation of early or late bladder, bowel, hematologic or hepatic effects, and that bicalutamide was not associated with a significantly higher risk for cardiac death or serious hepatotoxic effects.
Recently, bicalutamide has been replaced by GnRH agonist drugs like leuprolide, which are being studied together with radiation in prostate cancer patients in two major clinical trials, Shipley said.
“Those trials started about 5 years ago, so it will take some time to get their results,” he said. “But, since both approaches act by lowering the supply of testosterone to the tumor itself, there isn’t any reason to expect the results to be different.”
Androgen deprivation therapy in combination with radiation is “worth serious consideration” in high-risk patients with high PSA recurrence, Ian M. Thompson, Jr., MD, president of Christus Santa Rosa Hospital, wrote in an accompanying editorial. The ongoing Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer trial, or RADICALS, will help address two critical questions, he added.
“With evidence that adjuvant radiation therapy significantly reduces the risk for disease recurrence and, in the NCI clinical trial, reduced the risk for metastases and prolonged survival, the RADICALS trial is comparing adjuvant radiation therapy (in high-risk patients after surgery) with salvage radiation therapy (at the time of PSA recurrence),” Thompson wrote.
“The other question that is addressed is the duration of the ADT: none, 6 months or 24 months,” he added. “A recent secondary analysis of a randomized trial of ADT showed that the benefit of 6 months of ADT added to radiation therapy was seen only in men with no or minimal coexisting conditions. Given the range of side effects in androgen deprivation in older men with coexisting conditions, especially in those with early cognitive decline or with the metabolic syndrome, the use of antiandrogen therapy in lieu of luteinizing hormone–releasing hormone–based therapies or the omission of hormonal therapy entirely may be considered.” – by Chuck Gormley
Disclosure: NCI and AstraZeneca funded the study. Shipley reports previous stock ownership in PFS Genomics. Please see the full study for a list of all other researchers’ relevant financial disclosures. Thompson reports no relevant financial disclosures.
Perspective
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The use of androgen deprivation therapy in combination with external beam radiation therapy for men with PSA recurrences became clearer and less controversial with the publication of RTOG 96-01 in this study published in The New England Journal of Medicine. Men were randomly assigned to receive postoperative radiation therapy with or without bicalutamide 150 mg for 2 years. These data needed almost 15 years to mature, but results demonstrated a survival benefit for the patients who received the bicalutamide with radiation — 12 years’ actuarial rate of OS was 76.3% in the bicalutamide group, compared with 71.3% in the placebo group (P = .04). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, compared with 13.4% in the placebo group (P < .001). The addition of the bicalutamide also reduced the cumulative incidence of metastatic prostate cancer at 12 years to 14.5% compared to 23% in the placebo group (P = .005).
On subgroup analysis, the patients with Gleason score 7, positive surgical margins and preradiation PSA levels greater than 0.7 ng/mL had the biggest survival advantage.
RTOG 96-01 demonstrates that some, but not all, men benefit from ADT combined with radiation therapy in the salvage radiation therapy setting. The men who most likely benefit include those with Gleason score 7 disease and positive surgical margins. Younger men will also benefit more than older men.
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