Patients on androgen deprivation therapy (ADT) for prostate cancer (CaP) eventually progress with a rising PSA. Definitions of androgen-independence vary, but usually include a documented castrate level of testosterone and failure of second-line hormonal therapy. One second-line therapy is ketoconazole, a broad-spectrum azole anti-fungal drug that inhibits gonadal and adrenal steroid synthesis. High dose ketoconazole (HDK) is historically thought to achieve the best suppression of testosterone synthesis, but low dose ketoconazole (LDK) offers a more favorable toxicity profile. In the online version of Cancer, Dr. Nakabayashi and associates from the Dana-Farber Cancer Center report a retrospective analysis of LDK in patients with AICaP. It appears as effective as HDK.

Analysis included 138 patients who had median follow-up of 27.6 months. All participants were initially treated with LDK (200mg 3 times daily, and increased to HDK (400mg 3 times daily) for a rising PSA. Corticosteroids were given to some patients. The primary study endpoint was to define the percentage of patients who achieved a clinically significant decline in PSA after initiation of Ketoconazole, defined as a >50% decrease.

Regarding PSA response, 39 of 138 patients (28.3%) demonstrated PSA declines >50% when on LDK. The median duration of LDK therapy was longer in patients who responded than non-responders (10 vs. 2.5 months). A greater PSA level at time of ketoconazole initiation was associated with a greater response rate. Only 55 of 138 patients (40%) had dose escalation to HDK. Median duration of LDK was 3.6 months in the dose escalation group and 3.0 months in the non-dose escalation group. After dose escalation, 7 of 55 patients (12.7%) had a subsequent decline in PSA >50% and 13 (24%) had a PSA decline >25%.

Overall, 65% of patients' experienced PSA and/or disease progression on LDK and 11 patients stopped ketoconazole due to side effects before progression. The most common side effect on LDK was fatigue, 13.5%. The median survival was 37.2 months in LDK responders and 35.4 months in LDK non-responders. These data suggest that LDK has comparable efficacy but less toxicity than HDK as secondary hormonal therapy in patients with AICaP.

By Christopher P. Evans, M.D.

Cancer 2006
Volume 107, Issue 5 , Pages 975 - 981
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