Androgen Deprivation May Improve Outcomes in Locally Advanced Prostate Cancer

Laurie Barclay, MD
January 2, 2008 — The addition of 4 months of androgen deprivation therapy (ADT) to external beam radiotherapy (EBRT) seems to have a dramatic impact on clinically meaningful endpoints in men with locally advanced prostate cancer without significantly increasing the risk for fatal cardiac events, according to the results of the Radiation Therapy Oncology Group (RTOG) 8610 study reported in the January 2 Early Release issue and will appear in the February 1 print issue of the Journal of Clinical Oncology.
"RTOG 8610 was the first major, phase III randomized trial to test the hypothesis that short-term neoadjuvant ADT combined with EBRT would improve treatment outcomes compared with EBRT alone," write Mack Roach III, MD, from the University of California San Francisco, and colleagues. "With relatively short follow-up, the addition of ADT was associated with an improvement in local control, a reduction in distant metastases, and cause-specific mortality. Herein, we update the long-term results of RTOG 8610 and confirm the important clinical benefits of adding short-term ADT to EBRT in patients with high-risk, locally advanced disease."
RTOG 8610 enrolled 456 assessable patients between 1987 and 1991. Median age was 70 years. Inclusion criteria, based on the 1988 American Joint Committee on Cancer Tumor, Node, Metastasis (TNM) staging system, were bulky (5 x 5 cm) tumors, stage T2-4, with or without pelvic lymph node involvement.
Patients were randomized to receive EBRT alone or with combined ADT, which consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg 3 times daily for 2 months before and during EBRT. The main outcome measures were overall survival, disease-specific mortality, distant metastases, disease-free survival, and biochemical failure.
At 10 years, estimates of overall survival (43% vs 34%) and median survival (8.7 vs 7.3 years) favored the combination of ADT plus EBRT vs EBRT alone. However, these differences were not statistically significant (P = .12). With the addition of ADT, improvements were observed in 10-year disease-specific mortality (23% vs 36%; P = .01), distant metastases (35% vs 47%; P = .006), disease-free survival (11% vs 3%; P < .0001), and biochemical failure (65% vs 80%; P < .0001).
The risk for fatal cardiac events was similar in both groups.
"The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events," the study authors write. "These updated findings of RTOG 8610 suggest that patients with high-risk, locally advanced disease who decline or who, for medical reasons, are not considered candidates for long-term ADT should be offered short-term neoadjuvant and concurrent ADT in combination with EBRT. The biologic rationale for using ADT with EBRT includes a reduction in the tumor volume and enhanced biologic effects."
The National Cancer Institute supported this study. Two of the study authors have disclosed various financial relationships with Astra-Zeneca.
J Clin Oncol. Published on January 2, 2008.2008;26:1-7.

DOD Prostate: Hitting Advanced Prostate Gently May Improve Quality of Life

ATLANTA, Sept. 17 -- Attacking locally advanced prostate cancer with intermittent androgen treatment may improve quality of life while maintaining the historical survival of more aggressive therapy. So reported Nicholas Bruchovsky, M.D., Ph.D., of Vancouver General Hospital and the University of British Columbia. He maintains that the intermittent regimen appears to delay progression from treatable androgen-dependent cancer to untreatable androgen-independent disease.
"We like to say that we are hitting the cancer with a flyswatter rather than using a sledgehammer," he said at the Department of Defense Prostate Cancer Research conference here.
In his single-arm treatment trial that included 103 eligible men, the observed survival after six years is about 80%, he said. The expected survival is about 70%, he added.
Dr. Bruchovsky recruited men who had undergone external beam radiation for treatment of prostate cancer, but whose rising PSA indicated a recurrence of the disease. The men were treated with androgen suppression until the PSA normalized at about 4 mcg/L. He then followed the men and when PSA again rose about 10 mcg/L, the patients underwent further treatment with cyproterone acetate or leuprolide acetate until the PSA dropped again.
"Biochemical recurrence after irradiation of localized prostate cancer proved amenable to cyclic androgen suppression with a high response rate," Dr. Bruchovsky said. "About 95% of the patients in the study did respond." The average age of the men in the study at the time of enrollment was about 73 years.
"I have treated men with this regimen who remain alive and will functioning 15 to 20 years later," he said.
The time between treatments -- after suppressing PSA below 4 mcg/L -- lasted as long as 75 weeks following the first treatment. The time off-treatment before PSA rebound generally was shorter. For example, after the second treatment period, the off-treatment interval was about 60 weeks. After the third treatment, the off-treatment interval was about 39 weeks.
Dr. Bruchovsky noted that the lower the PSA went down, the shorter the interval between treatments. "Nadir PSA was a powerful predictor of early progression to androgen independence," he said.
During the study, the researchers also measured multiple factors involving quality of life and particularly sexual quality of life. "Quality of life scales improved in the off-treatment interval," Dr. Bruchovsky said.
While on treatment, impotence dropped from 30% of patients at baseline to 11.5%, a significant difference (P=0.003); but rebounded while off treatment to 15.1% (P=0.1).
Sex in the last month decreased from baseline of 32.1% of the men to 8.2% during treatment (P=0.0009) and then rebounded to 24.6% (P=0.6) of the men when treatment stopped.
Sexual functioning decreased from 20.7% of the men at baseline to 9% during treatment (P<0.0001) and then rebounded to 16.7% (P=0.03) after treatments stopped.
While not endorsing the regimen outlined by Dr. Bruchovsky, Capt. E. Melissa Kaine, M.D., of U.S. Navy Medical Corps, deputy director of the Congressionally Directed Medical Research Program, commented, "It is important to look at the problem broadly and to consider these various research projects carefully."
She noted that in the Bruchovsky study the outcomes appeared similar to historical results and the quality of life was improved indicating that a further review of the program was warranted.
Dr. Bruchovsky and Capt. Kaine had no disclosures. Primary source: Innovative Minds in Prostate Cancer Today, Proceedings, Sept. 5-8. 2007Source reference: Nicholas Bruchovsky, et al "Locally Advanced Prostate Cancer -- Results from a Prospective Phase II Trial of Intermittent Androgen Suppression for Men with Evidence of PSA Relapse after Radiotherapy" Innovative Minds in Prostate Cancer Today, Proceedings, Sept. 5-8. 2007, Abstract P33-7, p. TK