"Toxicity was moderate. The most common toxicity was
gastrointestinal upset and more specifically, nausea. Grade 1 or 2
nausea occurred in 10.4%."
Other toxicities listed are:
Grade 1 or 2
fatigue in 6.25%,
Edema in 6.25%,
Hepatotoxicity
in 4.2% (2 of 48 men),
Rash in 4.2%,
Anorexia in 2%.
Reference (2) is a trial on LDK. The table of toxicity
is on page 544, nausea is at the top, dry skin, fatigue, bruising and
then
Liver (AST, ALT elevation) - Grade 1 - none; grade 2, 1
patient(4%), Grade 3, 1 patient((4%). 28 patients in this study. 200mg
tid and hc. The grade 3 liver toxicity resulted in removal from the
trial. The grade 2 guy continued on trial.
-- PSA RR (drop of PSA by more than 50%) was 46%.
Reference (3) is a trial of IDK (Intermediate-Dose Ketoconazole) and Hydrocortisone. In this paper, using 300mg
ketoconazole tid and hydrocortisone (20mg plus 10mg), they state..."well
tolerated with only 15% ceasing treatment due to unacceptable side
effects." No other details are given.
A phenomenon called, "Sticky Skin" (4) seems to affect
some people. Reference (4) reports this side effect in a study of HDK
and doxorubicin. Eight of 28 patients reported sticky skin(29%). They
postulated that sticky skin might be related to therapy-induced
elevation of endogenous retinoids.
References (side effects).
1. Small EJ, et al, "Ketoconazole Retains Activity in
Advanced Prostate Cancer Patients with Progression Despite Flutamide
Withdrawal," The Journal of Urology, Vol. 157, 1204-1207, April 1997.
2. Harris, KA et al, "Low Dose Ketoconazole with
Replacement Doses of hydrocortisone in patients with Progressive
androgen Independent Prostate Cancer, ", The Journal of Urology, Vol
168, 542-545, August 2002.
3. Wilkinson S and Chodak G., An Evaluation of
Intermediate-Dose Ketoconazole in Hormone Refractory Prostate Cancer,
European Urology 45, (2004), 581-585.
4. 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 Apr;32(4):571-5.
There are some measures that might prevent liver
damage from ketoconazole: Silibinin(a milk thistle derivative) or a drug
called Ursodiol. Another supplement, N-Acetylcysteine(NAC), might also improve liver
enzymes. Discuss any of these with your doctor before taking any
of them.
Ketoconazole with Chemotherapy.
Ketoconazole has been combined with taxotere and mitoxantrone in studies
with hrpca patients. It has also been combined with adriamycin, but with
considerable toxicity.
Ketoconazole with Taxotere.
There are two studies that have been published so far on
combining ketoconazole with taxotere(docetaxel). Both were phase I
trials to evaluate the maximum tolerated dose (MTD). There is a potential drug
interaction due to both taxotere (docetaxel) and ketoconazole being
metabolized hepatically by the cytochrome p450 system (CYP3A4). Thus a
phase I dose escalation trial was warranted.
In (1), Figg et al used 400mg tid with
hydrocortisone (20mg morning + 10 mg evening) plus 3 out of 4 week taxotere at escalating dosages. They found a MTD of only 5 mg/m2
taxotere. at 10mg/m2 taxotere, there were grade 3 hepatic
toxicities, while at 5mg/m2 there were only grade 1-2 hepatic
toxicities. The PSA response rate (>50% PSA decline) was 50% (5 of 10
patients). They stated their plans are to reduce the ketoconazole dose
and escalate the taxotere dose. They are also trying to explain
the large amount of hepatic toxicity.
In reference (2), Van Veldhuizen et al, used
taxotere at a dose of 55mg/m2 given every 3 weeks. The ketoconazole dose
was escalated with small groups of patients. They found the maximum
tolerated dose of ketoconazole was 400mg twice a day with taxotere (docetaxel)
limited to 55mg/m2 (vs the standard q 3 week dosing of 60-70mg/m2).
A PSA RR of 7/12 patients (58%). Ketoconazole alone has provided
as high a RR in at least one trial. Dose-limiting toxicities included neutropenia and fatigue.
No hepatic toxicity was seen for this group of patients. Ketoconazole did not cause
a consistent effect on docetaxel pharmacokinetics, although there was
significant intrapatient and interpatient variability in serum levels.
References for ketoconazole and taxotere.
(1) W. D. Figg, Y. Liu, M. R. Acharya, J. L. Gulley, P.
M. Arlen, M. Lewis, H. L. Parnes, C. C. Chen, E. Jones, W. L. Dahut, A
phase I trial of high dose ketoconazole plus weekly docetaxel in
metastatic androgen independent prostate cancer. ASCO 2003, abstract
number 1731.
(2) Van Veldhuizen PJ, Reed G, Aggarwal A, Baranda J,
Zulfiqar M, Williamson S., Docetaxel and ketoconazole in advanced
hormone-refractory prostate carcinoma: a phase I and pharmacokinetic
study, Cancer. 2003 Nov 1;98(9):1855-62.
