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Ketoconazole: Further thoughts
about this second-line hormone intervention (May 2003)
Ketoconazole is one of the triad of second-line hormone interventions to
be considered when the PSA rises after successful suppression by androgen
deprivation. An excellent summary of "Secondary Hormone Therapies in the
Treatment of Prostate Cancer" was presented by Wm. Oh in UROLOGY Vol.60,
Supplement to September 2002, p. 87. There continues to be a bit of a
mystery about how ketoconazole, customarily prescribed as an "anti-fungal"
agent, actually functions as a treatment for prostate cancer. However, the
most common inference is that, after being exposed for a time to the low
testosterone environment fostered by an LHRH agonist, the androgen
receptor responds by increasing its sensitivity to testosterone.
Ketoconazole is known to decrease the production of testosterone and
cortisol by the adrenal gland, which normally provides about 5% - 10% of
the total serum testosterone. The coupling of these two thoughts leads to
speculation that this additional lowering of serum testosterone by
ketoconazole may further inhibit signaling via the androgen receptor and
thereby slow the proliferation of cancer cells. New information, however,
suggests that this scenario may be too simplistic.
But first, what does the established record tell about the effectiveness
of this drug in "hormone refractory" PC ? Because, ketoconazole may lower
the adrenal's output of cortisol, replacement doses of prednisone or
hydrocortisone are customarily prescribed. But the companion use of a
cortisol introduces difficulty in identifying the specific independent
efficacy of ketoconazole, since prednisone or Decadron themselves have
significant efficacy in PC treatment.
Wm. Oh summarized the best current studies of ketoconazole and
hydrocortisone. When efficacy was judged by the criterion of achieving a
>50% decline of PSA, the studies, using the conventional dose of 400 mg
TID, showed responses of 27%, 40%, and 63%. An important article (to which
I will return) by Harris, "Low Dose Ketoconazole with Replacement doses of
Hydrocortisone [30 mg. / day] in Patients with Progressive Androgen
Independent Prostate Cancer" (J UROL. Aug. 2002, p. 542) very nicely
demonstrated that a dose of 200 mg. TID is equally efficacious, yielding a
response of 55% and 30 weeks median duration. The cost was less with fewer
side effects.(A 200 mg. pill costs about $3.10 = about $280-300/month.)
The duration of median response has generally been four to five months,
with some responses strikingly longer. In Harris' study, those men who did
not respond to the 200 mg. dose had no response to re-challenge with the
higher dose. Side effects from ketoconazole can be troublesome: nausea,
29%, fatigue, 14%, edema, rash, and heptotoxicity, and the drug can effect
a potentially dangerous rise in the blood levels of coumadin and the
statin drugs. The medication should be taken on an empty stomach.
The interpretation of efficacy and duration of response in all these prior
studies is made difficult because of the current tendency for clinicians
to intervene with secondary hormonal therapies at an earlier point in the
face of a rising PSA. Early therapeutic intervention is likely to
encounter a lower tumor burden against which treatment may be more
effective and can introduce "lead time bias" that can confound comparing
time to survival endpoints. These considerations are relevant since all
the quoted studies involved substantial numbers of men with well
established metastatic disease and high PSAs (median of 49 ng/ml, range
6.3 - 557.8, in the Harris study). Among the 28 men in that study only 8
men were treated for progression indicated only by PSA elevation, the rest
progressing with clinically evident bone and soft tissue disease. A PSA
response occurred in only 33% of men with bone and/or soft tissues
disease, whereas 75% (6 of 8)of men responded in the group treated for PSA
rise only. Harris also discusses the intrepretive difficulties resulting
from utilizing the combination of ketoconazole and cortisol. The reported
efficacy of corticosteroids alone in PC treatment is 16-29% for 30-40 mg.
of hydrocortisone. Nishimura (CANCER, Dec., 2000, p. 2570) reported a 62%
PSA response to Decadron at 0.5-2 mg/day.
The Harris study added information that confounds our current speculation
about the mode of ketoconazole's action. The output of adrenal androgens (androstenedione,
DHEA, and DHEAS) was significantly lowered by the drug, however,
"the degree of androgen suppression was not associated with response nor
was the degree of suppression predicted by response to low dose
ketoconazole." This finding points to alternative explanations for drug
mechanism of action.
The basis of the action of ketoconazole is interference with the function
of a very important family of enzymes, the Cytochrome P-450 enzymes. The
inhibition of one member of this family accounts for preventing the
conversion in the adrenal gland of cholesterol into the androgens and
cortisol. There is emerging evidence that the enzyme, Cyclooxygenase-2
(COX-2) - the target of the anti-arthritic drugs, Vioxx and Celebrex ,
stimulates cellular proliferation and likely is associated with initiation
or progression of cancer. A recent study shows that ketoconazole via a
complex feedback loop inhibits the production of this sometimes harmful
COX-2 enzyme. A study by Peehl (J UROL, Oct 2002) reported anti-proliferative
effects of ketoconaszole in tissue culture that resulted from interference
with P-450 enzymes. These findings are intriguing leads that may be
developed into new avenues of therapy for prostate cancer.
Bottom Line: Ketoconazole has moderate effectiveness as a second-line
treatment for PCa
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