Timing of Androgen Deprivation May Affect Prostate Cancer

ANAHEIM, California—The timing of androgen deprivation therapy for prostate cancer may well affect disease-specific survival, according to two studies presented at the American Urological Association annual meeting.

Androgen deprivation therapy is the main treatment for recurrent and metastatic prostate cancer. After an initial high response rate to the therapy, most patients progress to androgen independence. A study from Wayne State University, Detroit (abstract 692), found that intermittent androgen deprivation may delay the time to androgen-independent status.

Emad Youssef, MD, and his colleagues treated 74 patients intermittently with luteinizing hormone-releasing hormone (LHRH) agonists with or without oral antiandrogens between January 1993 and March 2000. The indications were rising PSA level after local treatment (n = 41), bone metastases (n = 9), local recurrence (n = 16), and lymphadenopathy (n = 8).

Patients were treated with intermittent androgen deprivation for 1 to 6 cycles for a median of 21 months (range, 1 to 85 months) and were followed for a median of 60 months.

The study evaluated the pattern of PSA changes with each cycle, the length of each cycle, and the time interval between successive cycles. The time to androgen-independent status and the androgen-independent progression rate and its relation to the initial cause of treatment were quantified.

The main result was a progressive rise in PSA nadir with a progressive decrease in the time between treatment cycles, Dr. Youssef reported. Median PSA before the first cycle was 11.4 ng/mL. Median PSA nadir after each cycle increased progressively: from 0.1 ng/mL after the first cycle to 3.3 ng/mL after the fifth cycle.

The time interval between cycles also decreased progressively, from 9.5 months between the first and second cycles to 6 months between the third and fourth cycles. The median time to androgen-independent status has not been reached, he said, except for patients treated for bone metastases, where it was 18 months.

"Patients with biochemical failure benefited the most from intermittent androgen deprivation," he noted. "Median time to androgen-independent status was more than 5 years for that group, whereas patients with bone metastases progressed more rapidly."

The 4-year actuarial androgen-independent progression-free survival for the whole group was 71%. The 4-year actuarial androgen-independent progression-free survival rates were 80%, 67%, and 45% for patients treated for biochemical failure, locoregional recurrence, and distant metastases, respectively.

Canadian Study

Earlier initiation of hormonal therapy might also be beneficial, Canadian investigators found. The results support similar findings from several randomized trials, said Yves Fradet, MD, professor of surgery and urology, Laval University, Quebec.

This population-based study (abstract 694) included 8,535 men, aged 65 to 84 years, diagnosed with prostate cancer in the province of Quebec from 1984 to 1989 and followed until 1998, for a median of 7 years.

Their medical records were linked to the provincial mortality file to ascertain date and cause of death. Data on hormonal medications and surgery were obtained through record linkage with the provincial medical insurance files.

Interestingly, the study noted a 23% decline in prostate cancer mortality from 1992 to 1997, which the investigators could not attribute to PSA screening and earlier diagnosis. This study questioned whether the timing of hormonal therapy might be a factor in the decline in prostate cancer mortality.

During the follow-up period, 2,813 men died of prostate cancer, and 2,803 received androgen deprivation therapy. After adjusting for androgen deprivation, year of diagnosis, radical prostatectomy, and age, a 1-year delay in the initiation of androgen deprivation therapy was associated with a 19% increased risk of dying of prostate cancer. The hazard ratio was 1.19 (95% confidence interval, 1.16-1.22).

Subjects who received hormonal therapy for palliative reasons had a hazard ratio for dying of prostate cancer of 6.39, indicating that this form of therapy was mainly given to patients with advanced disease, he said. Men receiving radical prostatectomy had a hazard ratio of 0.48.

A smaller study of 384 patients treated between 1990 and 1992, and followed until 1997, confirmed the findings. This study showed a hazard ratio for dying of prostate cancer of 2.80 for all hormonal therapy recipients and 1.46 for patients whose therapy was delayed for 1 year.

"These findings from both a population-based study and a cohort study suggest there is a 20% increased risk of prostate cancer mortality with a 1-year delay in giving hormonal therapy," Dr. Fradet said. "This suggests that hormonal therapy may have an impact on reducing prostate cancer mortality."