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`Ketoconazole in Advanced Prostate Cancer: Have Tolerability
`Concerns Been Overstated?
`Drug Ther Perspect. 2000;15(4)
`Introduction
`Originally introduced into clinical practice over 20 years ago, ketoconazole†; is a broadspectrum imidazole antifungal
`agent that inhibits 14alphademethylase and thereby interrupts the synthesis of an essential fungal membrane sterol. As
`ketoconazole became widely used as an antifungal agent, it was noticed that a small number of male patients developed painful
`gynaecomastia; this led to the discovery of the inhibitory effects of the drug on gonadal and adrenal steroidogenesis.
`Ketoconazole has been shown to be a useful secondline treatment in patients with advanced prostate cancer, but its use has
`been limited by concerns over its adverse effects (notably those on the liver). Recent reevaluation of the literature has
`suggested, however, that these concerns have been overstated and that the most serious potential adverse effects of
`ketoconazole can be avoided in the majority of patients.
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`†; Ketoconazole is available in Spain, but is not approved for the treatment of advanced prostate cancer.
`
`Prostate Cancer: What Are the Risks?
`
`Prostate cancer is a common problem, as illustrated by figures from the US. In 1995, 244 000 men were diagnosed with the
`disease, and over 40 000 died. The high prevalence of prostate cancer is shown by autopsy evidence that approximately 30% of
`men aged over 50 years have signs of malignant tissue in the prostate gland. The lifetime risk in a 50yearold man is 42%, and
`the overall lifetime risk of invasive disease is 15%.[1]
`
`Treatment Depends on the Stage of Disease
`
`Early disease (not clinically detectable or confined to the prostate gland) is treated by radical prostatectomy or radiotherapy. No
`definitive action is taken in some patients with low prostatespecific antigen (PSA) levels, who remain under observation only.
`Locally advanced disease is primarily treated with radiation therapy. Advanced prostate cancer is managed primarily either by
`observation or with hormonal therapy. Bilateral orchiectomy or estrogen therapy are the 2 traditional treatments; others
`introduced more recently include the luteinising hormone releasing hormone (LHRH) agonists (e.g. leuprolide or goserelin) and
`the antiandrogens (steroidal and nonsteroidal).[2]
`
`Ketoconazole, together with aminoglutethimide (an inhibitor of adrenal steroid synthesis), is classified as a secondline hormonal
`treatment, recommended for patients who do not respond satisfactorily to LHRH agonists or antiandrogens.[3]
`
`Effects on Steroid Synthesis Are Useful
`
`Ketoconazole inhibits cytochrome P450 enzymes involved in the synthesis of androgens in the testes and the adrenal glands,
`especially 17,20lyase. This blocks the synthesis of the precursors (dehydroepiandrosterone and androstenedione) of
`testosterone. Because androgenic stimulation is necessary for prostatic growth, it is this property that has made the drug useful
`in patients with advanced prostate cancer.
`
`In humans, the adrenal glands secrete large quantities of precursor steroids that are converted into androgens. This contribution
`to the total androgen pool is blocked by ketoconazole but not by orchiectomy or oestrogen therapy, the traditional modes of
`treatment for advanced prostate cancer, and clinical studies have shown encouraging response rates and relief of metastatic
`bone pain in patients treated with ketoconazole.[4,5] Paradoxically, however, the enzymatic effects that confer antiandrogenic
`properties upon the drug are also responsible for some of the problems that have been associated with its use.
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`Early Enthusiasm Tempered...
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`Interest in the use of ketoconazole in eligible patients with advanced disease waned in the late 1980s and early 1990s, largely
`because of the introduction of the novel LHRH agonists and concern over reports of adverse effects with ketoconazole (see
`table 1).
`
`A knowledge of the synthetic pathways affected by ketoconazole gives a theoretical basis for some of the adverse effects.
`
`
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`Furthermore, ketoconazole has the potential to be involved in a variety of interactions with other drugs.[7] Most notably,
`ketoconazole inhibits the metabolism of both cisapride and terfenadine, which can result in hazardous heart arrhythmias. These
`drugs should not be administered concomitantly.[7]
`
`...But Initial Concerns Overstated?
`
`Attention has recently become focused once again on ketoconazole for its value as a secondary hormonal therapy in patients
`with prostate cancer. This has followed on from an improved understanding of the tolerability profile of the drug, and clarification
`of the significance of these events in relation to the clinical benefits of treatment.
`
`Good Response Rates With Acceptable Tolerability
`
`Ketoconazole therapy has produced significant and prolonged responses, with acceptable tolerability, in patients whose disease
`has not responded to traditional hormonal management.[6,8] One centre has reported a consistent PSA response rate of >60%
`in patients resistant to conservative androgen deprivation.[3] A median response duration of 5 to 6 months was reported, with
`responses of >2 years' duration in some patients.
`
`Putting Adverse Effects into Perspective
`
`The most common adverse effects of ketoconazole by far are gastrointestinal in nature (mainly nausea and anorexia). In the
`past, the incidence of these effects has been estimated at >30%, although more recent estimates put the proportion of patients
`affected at only 10%.[6,8] The incidence and severity of these effects are reduced by administration with milk or food (although
`an acidic environment aids absorption of ketoconazole), or by starting therapy with a reduced dosage.
`
`Acquired cutaneous adherence, or sticky skin syndrome, has been reported with patients receiving ketoconazole, but has never
`caused sufficient discomfort for therapy to be withdrawn. Rashes, nail dystrophy and desiccated mucosa[9] have also been
`observed. These cutaneous effects are thought to be related to the effect of ketoconazole on retinoic acid metabolism, and do
`not influence the course of therapy in most patients.
`
`A variety of cardiovascular effects have also been reported, but their frequency appears low.[3]
`
`Endocrine Effects Are Linked to Steroid Inhibition
`
`The theoretical risk of adrenal suppression with ketoconazole therapy has been appreciated for some time, but the first report of
`this in a patient with prostate cancer appeared only recently and was linked to frequent administration (4 rather than 3 times
`daily) of the drug.[10] Asthenia related to adrenal suppression is also seen, but may be alleviated by hydrocortisone.[3]
`
`Impotence is anticipated with ketoconazole therapy, but its clinical significance is limited by the likely preexistence of this
`condition because of previous primary hormonal therapy. At dosages used to block androgen production, the incidence of
`gynaecomastia with 'ketoconazole is 10 to 15%, although breast pain usually resolves after several weeks' treatment.[3]
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`Major Concerns Over Hepatic Effects Addressed
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`The mechanism of the hepatotoxicity of ketoconazole is not clear, but is probably idiosyncratic and thus doseindependent. The
`major metabolite of the drug, Ndeacetylketoconazole, undergoes further metabolism to a potentially toxic dialdehyde that may
`be involved in the hepatic damage.[11]
`
`As with gastrointestinal effects, hepatic effects vary in reported frequency. Scrutiny of the literature, however, reveals only a low
`incidence of clinically significant events. Despite the introduction of restrictions on the use of ketoconazole in the UK in 1981
`after reports of hepatic problems, by late 1982 it was clear that the incidence of symptomatic hepatotoxicity was 1 in 12 000
`courses of treatment, and over 50% of affected patients were found to have a history of hepatitis or idiosyncratic drug reactions.
`[12] Most patients in whom hepatotoxicity is noted with ketoconazole therapy recover uneventfully after withdrawal of the drug,
`and the majority of effects take the form of transient and asymptomatic increases in hepatic enzyme levels (see table 1).
`
`References
`
`1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995; 45: 830
`
`2. Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J HealthSyst Pharm 1996; 53: 38196
`
`3. Bok RA, Small EJ. The treatment of advanced prostate cancer with ketoconazole.
`
`4. Amery WK, De Coster R, Caers I. Ketoconazole: from an antimycotic to a drug for prostate cancer. Drug Dev Res 1986;
`8: 299307
`
`5. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet 1984; II (8400): 4335
`
`6. Small EJ, Baron AD, Fippin L, et al. Ketoconazole retains activity in advanced prostate cancer patients with progression
`despite flutamide withdrawal. J Urol 1997; 157: 12047
`
`7. British National Formulary. No. 38. London: The Pharmaceutical Press, 1999 Sep: 280, 5701
`
`8. Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in
`patients with advanced prostate carcinoma. cancer 1997; 80: 17559
`
`9. De Coster R, Wouters W, Bruynseels J. P450dependent enzymes as targets for prostate cancer therapy. J Steroid
`Biochem Mol Biol 1996; 56 (16 Spec. No.): 13343
`
`10. Sarver RG, Dalkin BL, Ahmann FR. Ketoconazoleinduced adrenal crisis in a patient with metastatic prostate
`adenocarcinoma: case report and review of the literature. Urology 1997; 49: 7815
`
`11. Rodriguez RJ, Acosta Jr D. Ndeacetyl ketoconazoleinduced hepatotoxicity in a primary culture system of rat
`hepatocytes. Toxicology 1997; 117: 12331
`
`12. lakeBakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with ketoconazole in the United Kingdom. BMJ
`(Clin Res Ed.) 1987; 294 (6569): 41922
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`Drug Ther Perspect. 2000;15(4) © 2000 Adis Data Information BV
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