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Alternatives To LHRH
Agonists As Adjuvant Regimens After Primary Treatment For Prostate Cancer
“Because
of increased awareness of prostate cancer and improved detection methods,
patients are presenting with earlier-staged disease and at a younger age
than before. Drug therapy for prostate cancer therefore needs to consider
patients’ QOL as well as survival endpoints.”
This quote comes in the conclusion of the
excellent review “An Evaluation of Bicalutamide in the Treatment of
Prostate Cancer” by Schellhammer and Davis, Clinical Prostate Cancer,
March 2004. Bicalutamide - “Casodex” - is being extensively studied as
adjuvant therapy in stages T1-T2 and locally advanced PC in the 8113 man
Early Prostate Cancer (EPC) trial, a composite of separate trials in the
USA, and Scandinavia, and collectively in Europe, Israel, South Africa,
Mexico, and Australia.
The schema for these trials is the
comparison of Casodex 150 mg/day with a placebo. The USA trial continued
treatment for 2 years, and the others for > 5 years. “The
primary endpoints of the trial are time to objective
progression and overall survival.” Since the PSA values for the placebo
group would be expected to rise, PSA progression was not an
endpoint in itself, but time to PSA doubling over baseline was noted. 55%
of participants had undergone radical prostatectomy. The patients “were
scheduled to have bone scans at two years, or earlier if clinically
indicated”. Although survival data is immature, 3 year follow-up data
(Iverson, J UROL Dec. 2003) found that 150 mg Casodex was associated with
a superior outcome compared to placebo in the following categories.
1) Casodex reduced the overall risk of
objective disease progression by 42%. Data from the USA trial is still
immature since determining the outcome of its relatively better stage
patients, who mostly had cT1c-T2a and pathologic T2 disease, will require
longer follow-up. The risk reduction at 3 years for localized prostate
cancer was 28%, and for locally advanced PC, 54%. For men with Gleason
scores 5-6 the reduction was 47%, and for those with Gleason 7-10, 43%.
Risk reduction occurred irrespective of nodal status. In node positive
patients the reduction was 71% and in node negative men, 41%, and in NX,
40% (UROL, May 2004)- i.e., the greatest benefit was seen in the patients
with the poorest prognosis.
2) Casodex reduced the risk of time to PSA
doubling from baseline by 59%.
3) At 48 weeks some sexual function was
retained in 75% of men in the Casodex arm versus 85%, placebo; and sexual
frequency was retained in 63.5% vs.78% for the placebo arm.
4) The EPC trial reported that Casodex was
associated with gynecomastia in 66% of men and breast pain in 73%,
although these events were mild to moderate in > 90% of patients. Other
studies have shown that 1 or 2 prophylactic electron beam treatments prior
to starting Casodex reduces gynecomastia by 33%. In Casodex patients hot
flashes occurred in 13%, impotence in 9% and physical capacity was better
maintained. [Note: Casodex accentuates the action of Coumadin]
Two large earlier studies compared 150
mg/day Casodex to castration or a LHRH agoinst in 480 men with locally
advanced M0 disease. With a median follow-up of 6.3 years, these studies
established there was no significant difference in outcome between the two
treatments in M0 disease. The median survival was approximately 5 3/4
years for both arms. In M1 disease survival in the castration arm was
superior only by a median of 42 days.
Casodex, a nonsteroidal antiandrogen, blocks
access of testosterone to the androgen receptor thus decreasing
proliferative stimulation of cancer cells, but serum testosterone levels
are maintained, unlike the fall to castrate levels of testosterone which
follows Lupron, for example. This biologic difference explains the
important contrasting side effect profiles between the two medications. In
these two Casodex vs. castration trials bone density in the lumbar spine,
evaluated at two years, increased by 2.4% in the Casodex arm but decreased
by 5.4% in patients undergoing medical castration.
A 12 month study of 51 men with M0 disease
evaluating Casodex (C) vs. Lupron (L) (Smith, JCO July 1, 2004) with
respect to changes in bone mineral density and body composition reported
results in the following categories:
1) trabecular bone mineral density in the
lumber spine, C = +4.7%, L = -7.6%;
2) lower extremity strength, C = +3.7%, L =
-1.2%;
3) fat mass, C = +2.4%, L = +3.6%;
4) breast enlargement/breast tenderness C =
100%/100%, L = 54%/ 8%
5)
loss of sexual interest, C = 40%, L = 81%.
Dr. Iverson (J UROL, Dec. 2003) in the
discussion portion of the article pointed out that “there is a growing
amount of experience from previous bicalutamide trials that from 30% to
50% of patients [who fail 150 mg Casodex] will respond favorably to second
line LHRH or castration.” This contention is strengthened by a recent
article from the Dana-Farber Cancer Institute, Boston, (Annals of Oncology
15, 974-978, 2004): “Finasteride [5 mg/day] and bicalutamide [150
mg/day] as primary hormonal therapy in patients with advanced
adenocarcinoma of the prostate”. These patients had metastatic disease.
The relevant point to be made apropos of the issue of subsequent salvage
by Lupron is that of 14 patients who experienced PSA failure during the
course of the Casodex regimen 12 responded again to medical castration for
a median of an additional 9.8 months until further PSA progression.
A strategy could be emerging of exploiting
the QOL advantages of adjuvant Casodex as initial therapy, while reserving
Lupron for salvage when, and if, needed.
The application for approval of use of the
150 mg dose of Casodex in the USA was denied by the FDA in 2002. However,
much new favorable data has accumulated since that time and one might
expect an approval on the next application.
Bottom Line: Data is accumulating
establishing the efficacy of 150 mg/day of Casodex as adjuvant therapy
following primary treatment for men with higher-risk prostate cancer.
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