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Chemotherapy News From The June 2004 Asco Meeting: Results Of Two
Important Chemotherapy Trials In Men With Metastatic Hormone Refractory
Prostate Cancer (July 2004)
>> Oncologists
have been eagerly awaiting the report of "A multicenter phase III
comparison of docetaxol (D) [Taxotere] + prednisone (P) and
mitoxanthrone (MTZ) [Novantrone] + prednisone in patients with hormone-refractorty
prostate cancer (HRPC)." Mitoxantrone was the first chemotherapy drug
approved for use in HRPC based on the superior, but modest,
effectiveness of this combination in controlling pain from bone
metastases compared to prednisone alone. No survival difference,
however, was demonstrated between the two arms. Promising results of the
newer drug, Taxotere, had been recently demonstrated in several Phase II
trials and there was an emerging expectation that Taxotere might be a
superior drug for HRPC than Mitoxanthrone. In the reported Phase III
trial MTZ+P was administered to 337 men in standard fashion, 12 mg/M2 q
3 wk X 10 cycles with continuous P 5 mg BID. Taxotere was also combined
with P 5mg BID and given in tworegimens: D 75mg/M2 q 3 wk X 10 cycles
(335 men), or D 30mg/wk X 5 of6 wks X 5 cycles (334 men). The patients
had histologically proven metatatatic disease, and testosterone levels
were maintained at < 50 ng/ml. The study end points were survival, PSA
response, pain response and toxicity. Overall grade 3/4 toxicities were
greater in the two D arms versus MTX, 45%-43% for D and 34% for MTZ. The
weekly D arm showed only 1.5% high grade neutropenia, whereas D/q 3 wk
was 32% and MTZ was 22%. Results for median survival: D/q 3 wk - 18.9
mo.; D/q wk - 17.4 mo.; and MTZ - 16.5 mo. Results for a PSA decrease of
> 50% for at least 4 weeks: D/q 3 wk - 45%; D q wk - 48%; and MTZ-32%.
Pain response: D/q 3 wk - 35%; D/q wk - 31%; MTZ - 22%. Conclusion: D/q
3 wk + P showed improved overall survival and better PSA and pain
responses than MTZ+P. The abstract concludes "This is the first phase II
trial to show a significant survival benefit in HRPC."
Complementing the
above trial was the report of the SWOG trial 99-16, "Randomized phase
III trial of docetaxel (D)/estramustine (E) [EMCYT] versus mitoxantrone
(M)/prednisone (P) in men with androgen-independent prostate cancer",
which studied 770 men with progressive metastatic disease. EMCYT was
dosed at 280 mg PO D1-5 q 3 wks (332 men). The alternative arm was D
given at 60 mg/M2 on day 2 (after 60 mg premedication of Decadron on day
1) and repeated in 3 wks (334 men). D was increased to 70 mg/m2 and M to
14 mg/M2 if toxicity permitted. Results: median survival D/E - 18 mo;
M+P - 15 mo. (P =.008). Objective disease response for D/E was 17% and
for M+P 10%. Grade 3/4 toxicity overall in D/E was 54% versus 34% in M+P;
and this included high grade gastrointestinal toxicity of 18% in D/E
versus 6% in M+P and high grade cardiovascular toxicity of 14% in D/E
versus 6% in M+P, the higher toxicities in D/E likely due to side
effects from EMCYT. This trial could also claim a position as the first
trial to show a survival advantage in HRPC. For perspective in
evaluating these encouraging Taxotere results it can be cited that in
the earlier 1999 pivotal trial, "Hydrocortisone with or without
Mitoxanthrone in men with HRPC, results of the CALGB 9281 study" (Kantoff,P,
JCO 1999;17;2506), the median survival of M/H was 12.6 months versus
12.3 months for H alone and no significant difference in survival was
seen between the two study arms. It would be a fair statement (although
not strictly methodologically acceptable) in counseling patients who are
considering chemotherapy to use the12.3 months survival of
Hydrocortisone alone as a baseline comparison to the ~18 months median
survival of these two Taxotere studies, even though corticosteroids
alone have shown some small benefit in controlling prostate cancer
progression.
Bottom Line:
Survival advantage for Taxotere chemotherapy regimens in two Phase III
trials can has now been documented as compared to the prior standard of
Mitoxantrone/Prednisone. The Taxotere/Prednisone combinations yielded an
~18 month median survival comparable the Taxotere/Emcyt regimen, but did
so with lesser toxicity.
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