Skip to main content

The Treatment of Advanced Prostate Cancer with Ketoconazole

Safety Issues

Drug Safety volume 20, pages 451–458 (1999)Cite this article

Abstract

The definition of hormone refractory prostate cancer is changing. It has become clear that patients with advanced prostate cancer whose disease has progressed following treatment with luteinising hormone releasing hormone agonists and antiandrogens can respond to additional hormonal manoeuvres. Ketoconazole is an imidazole antifungal and the antiandrogen effects of this agent have been known about for over 15 years. Initial concerns about the excessive adverse effects associated with this agent appear to have been overstated. Recent studies have demonstrated that treatment with ketoconazole can produce a significant response in a majority of patients with advanced prostate cancer and that the agent has a reasonable toxicity profile. The most common adverse effect is gastrointestinal intolerance, followed by fatigue, liver function abnormalities and skin changes; the agent is also associated with a variety of rarer adverse effects. The most serious potential adverse effects of the drug can be ameliorated by simple measures.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Trachtenberg J, Halpern N, Pont A. Ketoconazole: a novel and rapid treatment for advanced prostatic cancer. J Urol 1983; 130(1): 152–3

    PubMed  CAS  Google Scholar 

  2. Amery WK, De Coster R, Caers I. Ketoconazole: from an antimycotic to a drug for prostate cancer. Drug Dev Res 1986; 8: 299–307

    Article  Google Scholar 

  3. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet 1984; II(8400): 433–5

    Article  Google Scholar 

  4. Mahler C, Verhelst J, Denis L. Ketoconazole and liarozole in the treatment of advanced prostatic cancer. Cancer 1993; 71(3 Suppl.): 1068–73

    Article  PubMed  CAS  Google Scholar 

  5. 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(4): 1204–7

    Article  PubMed  CAS  Google Scholar 

  6. Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer 1997; 80(9): 1755–9

    Article  PubMed  CAS  Google Scholar 

  7. Rodriguez RJ, Acosta D, Jr. Comparison of ketoconazole- and fluconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology 1995; 96(2): 83–92

    Article  PubMed  CAS  Google Scholar 

  8. Van den Bossche H, Willemsens G, Cools W, et al. In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis. Antimicrob Agents Chemother 1980; 17: 922–8

    Article  PubMed  Google Scholar 

  9. Willemsens G, Cools W, Van den Bossche H. Effect of miconazole and ketoconazole on sterol synthesis in a subcellular fraction of yeast and mammalian cells. In: Van den Bossche H, editor. The host-invader interplay. New York: Elsevier North-Holland, 1980: 691–4

    Google Scholar 

  10. Geller J, de la Vega DJ, Albert JD, et al. Tissue dihydrotestosterone levels and clinical response to hormonal therapy in patients with advanced prostate cancer. J Clin Endocrinol Metab 1984; 58(1): 36–40

    Article  PubMed  CAS  Google Scholar 

  11. De Coster R, Wouters W, Bruynseels J. P450-dependent enzymes as targets for prostate cancer therapy. J Steroid Biochem Mol Biol 1996; 56(1–6 Spec No.): 133–43

    Article  PubMed  Google Scholar 

  12. Sarver RG, Dalkin BL, Ahmann FR. Ketoconazole-induced adrenal crisis in a patient with metastatic prostatic adenocarcinoma: case report and review of the literature. Urology 1997; 49(5): 781–5

    Article  PubMed  CAS  Google Scholar 

  13. Van Wauwe JP, Coene MC, Goossens J, et al. Ketoconazole inhibits the in vitro and in vivo metabolism of all-transretinoic acid. J Pharmacol Exp Ther 1988; 245: 718–22

    PubMed  Google Scholar 

  14. Williams G, Kerle DJ, Ware H, et al. Objective responses to ketoconazole therapy in patients with relapsed progressive prostatic cancer. Br J Urol 1986; 58(1): 45–51

    Article  PubMed  CAS  Google Scholar 

  15. Shaw MA, Nicholls PJ, Smith HJ. Aminoglutethimide and ketoconazole: historical perspectives and future prospects. J Steroid Biochem 1988; 31(1): 137–46

    Article  PubMed  CAS  Google Scholar 

  16. Muscato JJ, Ahmann TA, Johnson KM, et al. Optimal dosing of ketoconazole and hydrocortisone leads to long responses in hormone refractory prostate cancer [abstract]. Proceedings of the American Society of Clinical Oncology: 1994 May 14–17: Dallas. J Clin Oncol 1994; 13: 229

    Google Scholar 

  17. Trump DL, Havlin KH, Messing EM, et al. High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects. J Clin Oncol 1989; 7: 1093–8

    PubMed  CAS  Google Scholar 

  18. Jubelirer SJ, Hogan T. High dose ketoconazole for the treatment of hormone refractory metastatic prostate carcinoma: 16 cases and review of the literature. J Urol 1989; 142(1): 89–91

    PubMed  CAS  Google Scholar 

  19. Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with ketoconazole in the United Kingdom. BMJ (Clin Res ed.) 1987; 294(6569): 419–22

    Article  CAS  Google Scholar 

  20. Hay RJ. Ketoconazole in the treatment of fungal infection: clinical and laboratory studies. Am J Med 1983; 74(1B): 16–9

    Article  PubMed  CAS  Google Scholar 

  21. Janssen PA, Symoens JE. Hepatic reactions during ketoconazole treatment. Am J Med 1983; 74(1B): 80–5

    Article  PubMed  CAS  Google Scholar 

  22. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317(13): 812–8

    Article  PubMed  CAS  Google Scholar 

  23. Bercoff E, Bernuau J, Degott C, et al. Ketoconazole-induced fulminant hepatitis. Gut 1985; 26(6): 636–8

    Article  PubMed  CAS  Google Scholar 

  24. Stricker BH, Blok AP, Bronkhorst FB, et al. Ketoconazole-associated hepatic injury: a clinicopathological study of 55 cases. J Hepatol 1986; 3(3): 399–406

    Article  PubMed  CAS  Google Scholar 

  25. Benson GD, Anderson PK, Combes B, et al. Prolonged jaundice following ketoconazole-induced hepatic injury. Dig Dis Sci 1988; 33(2): 240–6

    Article  PubMed  CAS  Google Scholar 

  26. Rodriguez RJ, Acosta D, Jr. N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology 1997; 117(2–3): 123–31

    Article  PubMed  CAS  Google Scholar 

  27. Polsen JA, Cohen PR, Sella A. Acquired cutaneous adherence in patients with androgen-independent prostate cancer receiving ketoconazole and doxorubicin: medication-induced sticky skin. J Am Acad Dermatol 1995; 32(4): 571–5

    Article  PubMed  CAS  Google Scholar 

  28. Sella A, Kilbourn R, Amato R, et al. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer. J Clin Oncol 1994; 12(4): 683–8

    PubMed  CAS  Google Scholar 

  29. Aabo K, De Coster R. Hypertension during high-dose ketoconazole treatment: a probable mineralocorticosteroid effect [letter]. Lancet 1987; II(8559): 637–8

    Article  Google Scholar 

  30. Gylling H, Vanhanen H, Miettinen TA. Effects of ketoconazole on cholesterol precursors and low density lipoprotein kinetics in hypercholesterolemia. J Lipid Res 1993; 34(1): 59–67

    PubMed  CAS  Google Scholar 

  31. Kraemer FB, Pont A. Inhibition of cholesterol synthesis by ketoconazole. Am J Med 1986; 80(4): 616–22

    Article  PubMed  CAS  Google Scholar 

  32. Pont A, Williams PL, Loose DS, et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982; 97(3): 370–2

    PubMed  CAS  Google Scholar 

  33. Trachtenberg J. The effects of ketoconazole on testosterone production and normal and malignant androgen dependent tissues of the adult rat. J Urol 1984; 132(3): 599–601

    PubMed  CAS  Google Scholar 

  34. White MC, Kendall-Taylor P. Adrenal hypofunction in patients taking ketoconazole [letter]. Lancet 1985; I(8419): 44–5

    Article  Google Scholar 

  35. Tucker Jr WS, Snell BB, Island DP, et al. Reversible adrenal insufficiency induced by ketoconazole. J Am Med Assoc 1985; 253(16): 2413–4

    Article  Google Scholar 

  36. Best TR, Jenkins JK, Murphy FY, et al. Persistent adrenal insufficiency secondary to low-dose ketoconazole therapy. Am J Med 1987; 82(3 Spec No.): 676–80

    Article  PubMed  CAS  Google Scholar 

  37. De Felice R, Johnson DG, Galgiani JN. Gynaecomastia with ketoconazole. Antimicrob Agents Chemother 1981; 19(6): 1073–4

    Article  Google Scholar 

  38. Novack GD. Ocular toxicology. Curr Opin Ophthalmol 1994; 5(6): 110–4

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, 2356 Sutter Street, 5th Floor San Francisco, San Francisco, California, 94143, USA

    Robert A. Bok &  Eric J. Small

Authors
  1. Robert A. Bok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric J. Small
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bok, R.A., Small, E.J. The Treatment of Advanced Prostate Cancer with Ketoconazole. Drug-Safety 20, 451–458 (1999). https://doi.org/10.2165/00002018-199920050-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199920050-00005

Keywords

  • Prostate Cancer
  • Adis International Limited
  • Ketoconazole
  • Azole
  • DHEA