Author:
Howard Hansen
Date: 9
April 2008
Definitions
Glucocorticoids. The glucocorticoids
get their name from their effect of raising the level of blood sugar
(glucose). Cortisol(hydrocortisone) is the most
abundant glucocorticoid. These have anti-inflammatory properties and
also cause a depression of immune response. See
http://en.wikipedia.org/wiki/Glucocorticoid for more information.
Mineralocorticoids. The mineralocorticoids get their name from
their effect on mineral metabolism. The most important of them is the
steroid aldosterone which acts on the kidney promoting the reabsorption
of sodium ions (Na+) into the blood. Water follows the salt
and this helps maintain normal blood pressure. See
http://en.wikipedia.org/wiki/Mineralocorticoid for additional
information.
Adrenal Androgen Pre-cursors. These are dehydroepiandrosterone (DHEA),
DHEA sulfate, and androstenedione which may be converted to
testosterone.
Triamcinolone - a synthetic glucocorticoid. Triamcinolone is 5x
more potent than hydrocortisone. It has a duration of action (t1/2
in hours) of 12-36 hrs vs 8 hrs for hydrocortisone.
Up to Date for Patients has a
graphic of the endocrine pathways associated with the above.
Introduction
Triamcinolone (Aristocort) is a glucocorticoid in pill form. It is not
generally available as a pharmacy drug but can be made up at a
compounding pharmacy. Aristocort is one brand name associated with triamcinolone. Another form of triamcinolone is as a cream for
topical use on the skin. There are at least two mutant androgen
receptors (AR) that are commonly found in HRPC disease (or AIPC) -- the
T877A AR (estimated to occur in 25-33% of AIPC) and the ARccr
are the ones relevant to triamcinolone. ARccr is the
cortisol/cortisone-responsive AR and the T877A AR allows various
nonandrogenic steriod hormones and the AR antagonist flutamide to bind
to the AR and act as agonists, thereby driving the growth of prostate
cancer cells which have this mutation. Furthermore, the adrenally
derived steriods such as deoxycorticosterone, corticosterone, cortisol
and cortisone all can stimulate the T877A AR. Another estimate of the
frequency of point mutations in the AR gives 10-40%. Triamcinolone does
not stimulate these androgen receptors and therefore would not promote
cancer growth.
The net of the above is that if the
tumor does have these mutant ARs, triamcinolone will not activate them
and stimulate prostate cancer growth and the action of triamcinolone on
the adrenal axis will suppress cortisol and cortisone that would
stimulate these ARs. Additionally, if the tumor does not have these mutant ARs, then there is the additional action that glucocorticoids have of
inhibiting prostate cancer cell growth even if the AR is not mutated.
Clinical Trials Using Triamcinolone in HRPC Patients
So far, only one phase II study has been run with
triamcinolone in HRPC patients (1). It was used as a monotherapy.
The table 1 summarizes the results.
|
Table 1.
Clinical Trials for HRPC disease |
| Study |
Triamcinolone |
Other Drug(s) |
PSA RR (≥ 50% decrease in PSA) |
Measurable Disease RR |
Progression Free Survival |
Overall Survival |
| Srinivas et al (1) Urology 2006.
Phase II, 24 patients(a). |
4mg 2x/day. |
None. |
29% had ≥ 50% decrease in PSA.
21% had stable disease. |
No responses were seen on BS or CT.
(b) |
Median time to progression was 7.5 mo.
|
- |
(a) Chemo-naive. 13 patients had failed prior ketoconazole. Patients had
normal cortisol levels at study entry. There were no grade 3
or 4 toxicities.
(b) 20 of 24 patients had bone mets. Study was likely too short to see
any response on bone mets.
Discussion
Triamcinolone might be used as a monotherapy as was done in the Srinivas
study (1). This might be in the context of another "2nd line hormonal"
therapy prior to starting chemotherapy. One could also use triamcinolone along with ketoconazole (again, no data exists for this
use as far as this author is knows.) Additionally, although no
data exists for this use either, it could be used during a treatment holiday
after starting chemotherapy. Reference (2) suggests that the combination
of triamcinolone with casodex might be an effective treatment.
This study did not determine whether or not the
patients had the T877A or AR(ccr) mutant ARs, but did measure (serum
draw in the morning) their cortisol levels. Overall, 14 patients
(58%) had suppressed cortisol levels. No dose escalation was done.
The authors further questioned whether or not a higher dose might have
resulted in more responses by further suppressing cortisol levels
(defined as ≤ 5ng/mL) as the response rate was reduced in patients
without cortisol suppression.
Lastly, Shah RB et al (4), using warm autopsies, found that metastatic
disease was very heterogeneous, even within different metastatic samples
from the same site. Thus, in patients with heterogeneous PCa cells, some
of which exhibit AR mutations, one would expect to see partial
responses.
Anecdotal Reports
None. Anecdotal reports are not meant to provide proof that something will be
effective in any particular person. They do, however, indicate
that at least some patient has had some success.
References
1. Srinivas S, Krishnan AV, Colocci N,
Feldman D, Phase II study evaluating oral triamcinolone in patients with
androgen-independent prostate cancer,
Urology. 2006 May;67(5):1001-6.
(4) Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, Macvicar
GR, Varambally S, Harwood J, Bismar TA, Kim R, Rubin MA, Pienta KJ,
Androgen-independent prostate cancer is a heterogeneous group of
diseases: lessons from a rapid autopsy program.
Cancer Res. 2004 Dec 15;64(24):9209-16.
