• Vol. 36 No. 10, 811–814
  • 15 October 2007

Efficacy of Low-dose Ketoconazole in Hormone Refractory Prostate Cancer Patients at the National Cancer Centre and The Cancer Institute, Singapore



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Introduction: The advent of prostate specific antigen (PSA) has resulted in an increased incidence of early detection of prostate cancer recurrence. Patients treated with androgen deprivation therapy (ADT) become hormone-resistant after 18 to 24 months. In patients with biochemical failure, where there is a rise in PSA but no objective evidence of metastases, or in whom there are small volume metastases but who are asymptomatic, there is no standard of care after ADT. Ketoconazole, an antimycotic which affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer cell lines in in-vitro studies. This study describes our experience with ketoconazole treatment for hormone refractory prostate cancer (HRPC). Materials and Methods: A retrospective study of HRPC patients given ketoconazole at the National Cancer Centre and The Cancer Institute from 2004 to 2005 was performed. All eligible patients had histologically proven adenocarcinoma of the prostate and a rising PSA level despite ADT with orchidectomy or luteinising hormone-releasing hormone (LHRH) agonist therapy. All patients received 200 mg of ketoconazole thrice daily. Response was defined as a decline in PSA of at least 50% from the pre-treatment level and confirmed by a second PSA value 4 or more weeks later. The endpoints evaluated were the presence and duration of a response and the toxicity profile of the treatment. Results: A total of 32 patients with HRPC were treated with ketoconazole. Twelve (38%) of the 32 patients had a greater than 50% decrease in their PSA values. The median duration of response was 6.75 months. The median time to reach PSA nadir was 3.5 months. Five patients continue to exhibit progression-free response at the time of writing. Ketoconazole was generally well tolerated. Eighteen (56%) patients recorded mild toxicities related to ketoconazole. There were no grade 3 or 4 toxicities. Conclusions: Low-dose ketoconazole bridges the gap in the continuum of treatment for patients who have failed ADT and in whom cytotoxic chemotherapy would have a significant impact on the quality of life. Its good toxicity profile, low cost and ease of administration makes it a viable option for this group of patients.

Prostate cancer is the fifth most frequent malignancy among Singapore males, with the incidence rising steadily over the years.1 With the advent of prostate specific antigen (PSA), the incidence of prostate cancer is not only on the rise, but disease recurrence can also be detected earlier. PSA detects a subset of patients with biochemical failure, defined as a rising PSA without objective evidence of metastasis after treatment for localised disease. Although some of these patients are treated conservatively, others are started early on androgen deprivation therapy (ADT) due to the presence of poor prognostic factors or due to patients’ or even physicians’ psychological inability to accept a conservative approach. Despite ADT’s high response rate of 80% to 90%, these patients will eventually become hormone resistant, with a progression-free duration of 18 to 24 months. Docetaxel-based chemotherapy is effective in hormone refractory prostate cancer (HRPC) with a survival advantage when used as a first-line treatment. It is now considered the standard of care in metastatic HRPC.2,3

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