Using Ketoconazole, Its Timing and Its Effects on Delaying Prostate Cancer Progression
ByKetoconazole (Keto) is commonly used as a secondary hormonal therapy in men with castration-resistant prostate cancer (CRPC). Keto is known to be a much rougher drug than the first level ADT drugs to tolerate. Keto can have significant toxicity, especially to the liver, so its use needs to be carefully evaluated.
Usually, Keto is used after the first line androgen therapy (ADT) drugs have stopped controlling prostate-specific antigen (PSA) levels, prior to the administration of docetaxel-based chemotherapy.
At the Lank Center for Genitourinary Oncology, Department of Medical Oncology, and Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, a recent retrospective study was performed using Keto after chemotherapy instead of prior to its administration.
This very small study identified 34 men with CRPC who were treated with ketoconazole as a secondary hormonal therapy after being treated with docetaxel-based chemotherapy. The treatment consisted of ketoconazole 200-400 mg three times daily with or without hydrocortisone. Men with prior exposure to ketoconazole were excluded from the study. Additionally, half the men had received estramustine as part of their chemotherapy regimen.
The primary endpoint of the study was the proportion of patients with a decline of >/=50% in their PSA level. The PSA Working Group 1 Criteria defined PSA progression.
Eight of the 32 evaluable patients (25%) had a PSA decline of >/=50%. The median time to progression (TTP) was 3 months (95% confidence interval, 1.2-5.4). A history of previous response to taxane-based chemotherapy was not associated with the response to ketoconazole.
However, previous use of oestrogens (diethylstilboestrol) for CRPC was significantly associated with a shorter TTP on ketoconazole (1.5 vs 10.2 months; P = 0.03).
The study concluded that Keto has moderate activity as a secondary hormonal therapy in men with CRPC previously treated with taxane-based chemotherapy, although the TTP was short. Previous treatment with oestrogenic therapy is associated with a shorter TTP.
This study leads me to ask a number of questions, all pertaining to the scheduling of treatments for advanced prostate cancer.
1- Is here an effect on TTP (time to progression) when Keto is administered before or after chemotherapy? If there is, then changing “the order” of drug administration might extend life.
2- What is the effectiveness of oestrogenic drugs vs. Keto? Should oestrogenic drugs be considered if Keto is in the possible mix? Which provide the bigger potential to delay TTP?
3- Can oestrogenic drugs be effective post chemotherapy and Keto administration in order to benefit with a longer TTP from the Keto?
Reference:
BJU Int. 2009 Oct 23. Epub ahead of print.
doi:10.1111/j.1464-410X.2009.08971.x, Nakabayashi M, Oh WK, Jacobus S, Regan MM, Taplin ME, Kantoff PW, Rosenberg JE.
PubMed Abstract
PMID:19863532
Joel T Nowak, MA, MSW
I was under the understanding that liver, rather than kidney, damage was the concern. See
http://www.prostate-cancer.org/education/andeprv/Lam_HDK.html
And as an anecdotal side note, for me KET resulted in a >97% (0.42 to <0.02 PSA) drop in PSA sustained for at least 18 months (hopefully more!). Minimal side effects.
I wanted to recount my experience with ketoconazole. When I first went on Zoladex (first line ADT), my PSA dropped from 51.1 to 1.1 in one month. However, my PSA immediately started going up and was almost doubling every month, so I started keto at 200mg 3 times a day (low dose keto) plus prednisone. My PSA dropped to <0.1 and has remained there for about 9 months. I have tolerated it extremely well with no toxicity or side effects.
Thank you Corey, you are correct.