Ketoconazole (Nizoral)
Plus Hydrocortisone
Note: It
can take up to three months to see a response to ketoconazole, i.e.,
your PSA can continue to rise for up to three months before starting a
downward trend. Often, however, the drop in PSA happens much
sooner. Here is a list of one patient's PSA levels while taking low dose
ketoconazole (600mg/day plus 5mg prednisone):
| Date |
PSA |
|
November |
55 |
| December |
71 |
| January |
68 |
|
February |
70 |
|
March |
56 |
| May |
32 |
| July |
20 |
| September |
24 |
| October |
19 |
| December |
17 |
Note that when taking HDK, it is
recommended that you remain on an LHRH agonist such as Lupron or Zoladex.
The reason is explained in a P2P post by Dr. Strum: "You do NOT want to
stop Lupron or any other LHRH agonist while going on HDK because: HDK
inhibits testosterone production by the testicles & adrenals & sends a
message to the brain to make more testosterone. In the absence of LHRH
inhibition of LH, the brain responds by making LHRH which will often
stimulate LH so much that it over-rides the effect of HDK on the
testicle.
High Dose
Ketoconazole(HDK)
In cases where prostate cancer (PCa) is not considered treatable with
a prostatectomy or radiation, or has returned/remained following one
of these treatments, the first line of treatment is hormone ablation
(also called combined hormone therapy—CHT—when multiple agents are used)
by a LHRH agonist (Lupron/Zoladex) and an antiandrogen (Casodex/Flutamide),
and possibly Proscar.
In
some patients CHT, clinically and statistically, has a finite life;
other patients successfully remain on CHT for many years. However, if
the CHT fails, the PSA begins to rise, possibly accompanied by other
symptoms reflecting tumor growth. The next mode of treatment is to stop
the antiandrogen (Casodex/Flutamide), hoping for a drop in PSA from
such withdrawal. But, this is effective only about 30% of the time and,
even if there is a drop, it lasts a mean of 3.5 months before the PSA
begins rising again.
Following
exhaustion of CHT, one option for additional hormonal manipulation is
HDK (high-dose ketoconazole) + HC (hydrocortisone). Ketoconazole is
a broad-spectrum antifungal type of antibiotic long used to treat fungal
infections. But, in its early use, doctors discovered that, in high
doses, it caused breast enlargement in men who were using it; thus,
it was determined that ketoconazole blocked testosterone made by the
testicles, as well as androgens made by the adrenal gland. Its early
use in PCa was for immediate crisis relief of acute spinal pain or cord
compression as it lowers testosterone levels to castrate stage within
48 hours. Because ketoconazole suppresses steroids normally produced
by the adrenal gland, it must be accompanied by a corticosteroid (HC).
An often
recommended amount of HC: Hydrocortisone 20-40mg a day - taken as
20 mg with breakfast and 10-20mg with dinner or later in evening with
food.
HDK
+ HC is an excellent treatment for both androgen-dependent PCa (ADPC)
and androgen-independent PCa (AIPC, or HRPC) and could be used as an
initial treatment, especially if the patient presents with spinal pain
or cord compression.
In
clinical trials, Nizoral has also proved to be symbiotic with various
chemotherapy agents as a cytotoxic combination.
The
normal dosage is 1,200 mg of Nizoral/day, 400 mg (2 tablets) every 8
hours. The 8 hour interval is due to the pharmacologic half life of
ketoconazole.
Take it on an empty stomach unless
you experience nausea. You might have to wait up to 2 hours after eating
before your stomach is really empty before taking ketoconazole. This
varies with the individual and the food ingested. Waiting to eat
for an 30-60 minutes afterwards allows full absorption of the dose of ketoconazole. Take the ketoconazole with an 'acidic' drink such as diet
or regular Coke, Pepsi, 7Up, orange juice, grape juice, apple juice, and
tomato juice are all possible drinks. Avoid grapefruit juice as this can
greatly increase blood levels of ketoconazole potentially leading to
serious complications.
An empty stomach and the acidic drink are necessary
for the most efficient absorption of the Nizoral. The HC is normally
dosed as 20 mg with breakfast and 20mg with dinner. Too much HC can
result in ankle edema or worsening diabetes and reducing the dose to 20
with breakfast and 10mg with dinner or even 10mg/10mg is then suggested.
Too little HC might show up as increasing fatigue.
If HDK is discontinued, then HC is tapered off over
2 weeks and not stopped abruptly.
Anti-acid medications
and H2 blockers must not be taken with Nizoral or else the acidic environment
will not be present for maximum absorption.
Clinical trials reflect that 70% of patients respond to HDK. Most can
expect a PSA decrease of 79-90%. The median duration of response was
3.5 months, with a range of 3.3 to 12.8 months in Small et al.
(J.Urol., 1997)(1). However, there are cases of responses lasting
in excess of 3 years.
Possible
side effects include nausea, body rashes, hair loss, headaches, weight
gain, and dizziness or disorientation. Ketoconazole in high doses creates
some risk of liver function damage and a complete blood analysis is
essential before embarking on HDK, and should be continued at regular
intervals while on the therapy.
Ketoconazole has good efficacy
in prostate cancer, but potential side effects and drug interactions
require close monitoring. For example, ketoconazole can actually
increase blood levels of chemotherapy (i.e., Taxotere) via the
Cytochrome p450 proteins.
In
summary, HDK + HC is a viable treatment for suppression of PSA and PCa
after CHT is no longer effective.
References
(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.
Bill
Aishman and Howard Hansen (update 4/23/05)
