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Intermediate-dose Ketoconazole Promising in Reducing Prostate Specific Antigen Levels in Hormone-Refractory Prostate Cancer

Ketoconazole, in intermediate doses, is well-tolerated and effective in reducing prostate specific antigen (PSA) levels in a subgroup of patients who have failed standard hormone therapy, say researchers.

Ketoconazole inhibits testicular and adrenal androgen synthesis but is limited in use because of its toxicity at high doses. Simon Wilkinson, MD, and Gerald Chodak, MD, at the Midwest Prostate and Urology Health Center, Weiss Memorial Hospital, Chicago, Illinois, United States, undertook a retrospective study investigating the effectiveness of ketoconazole in patients with advanced hormone refractory prostate cancer.

The 38 patients evaluated in this retrospective study, median age 66 years (range 46-91 years), had failed second-line therapy with androgen blockade and evidenced progressive disease. The median interval between diagnosis and initiation of ketoconazole was 5 years (range 1-21 years).

Thirty patients were being treated with LHRH analogues, while the remaining 8 patients had undergone bilateral orchidectomy. When ketoconazole was initiated, the median PSA was 37 ng/mL (range 2.7-794). Bone scintigraphy demonstrated established metastatic disease in 73.4% of the 38 patients. Of the 10 patients with normal bone scans, 6 had histologically proven involvement of iliac lymph nodes.

In earlier studies, subjects received 400 mg, 3 times a day. In this study, the patients received ketoconazole 300 mg 3 times daily, as well as daily oral hydrocortisone replacement, 20 mg in the morning and 10 mg at night.

Principal end point was PSA response defined according to Prostate Specific Antigen Working Group guidelines. PSA levels and liver function were evaluated 1 month after study start and every 3 months thereafter. Therapy was terminated if there was no PSA decrease within 3 months, or if side effects and/or toxicity were intolerable.

The researchers found that 55.3% of the patients achieved a decrease in PSA of more than 50% while on ketoconazole. Median time to progression was 5 months (range 0-27 months) and median survival was 12 months (range 3-48 months), but with no apparent survival benefit, according to the authors.

Considering the 34 patients with established metastases, a PSA reduction of more than 50% was seen in 21 patients (61.8%). The median survival time for these patients was 24 months vs. 9 months for the non-responders (P = .0089).

There was no significant association between the response to ketoconazole and patient's age, Gleason score, bone scan results, lymph node involvement, PSA at initiation of ketoconazole, or duration of hormonal ablation, according to univariate or multivariate analyses.

Overall, 31.6% of patients reported ketoconazole-related toxicity, chiefly nausea (13.2%), fatigue (10.6%), diarrhoea (2.6%), and visual disturbance (2.6%). Six patients (15.8%) discontinued ketoconazole due to intolerable side effects. Liver function tests were abnormal in 2.6%.

The authors point out that hydrocortisone therapy itself has been associated with response rates of 14% to 22%. However, "our response rate was 55.3%," they say, and which they attribute chiefly to ketoconazole. They add, "this rate compares favourably to that reported with high-dose ketoconazole, 400 mg 3 times daily."

"In the absence of studies demonstrating better survival with chemotherapy in prostate cancer, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy," Dr. Wilkinson, Dr. Gerald Chodak advise.




Eur Urol 2004 May;45:5:581-5 "An evaluation of intermediate-dose ketoconazole in hormone refractory prostate cancer"

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