LOS ANGELES--Early use of combination chemotherapy may have a role in
the treatment of poor-prognosis, androgen-dependent prostate cancer,
as well as androgen-independent patients, preliminary results from an
ongoing study suggest. Evidence of anticancer activity has been seen
in several patients treated with the combination of paclitaxel
(Taxol), estramustine (Emcyt), and carboplatin (Paraplatin), William
Kelly, DO, reported at the ASCO meeting.
"We have yet to find an effective chemotherapy regimen for
refractory prostate cancer," said Dr. Kelly, a medical
oncologist at Memorial Sloan-Kettering Cancer Center. "A major
point of this study is that were changing the treatment
paradigm. Were moving chemotherapy up front, using it earlier
in patients who have locally aggressive or metastatic disease."
Dr. Kelly said the study derived from clinical trial data, presented
at ASCO in 1995, indicating that estramustine combined with a
platinum-based compound has activity in patients with
aggressive-phenotype prostate cancer.
Additionally, estramustine and pac-litaxel have been shown to have
synergistic activity, and estramustine is known to increase drug
retention. The combination has demonstrated efficacy in
androgen-independent prostate cancer patients (J Clin Oncol
Attempt to Inhibit Drug Resistance
"We hypothesized that giving chemotherapy that includes
estramustine might inhibit drug resistance prior to or during
androgen deprivation and enhance tumor cell kill," Dr. Kelly said.
The investigators evaluated a three-drug combination in 21 patients
with androgen-independent prostate cancer (who had progressed on
primary hormonal therapy) and 19 with poor-prognosis
androgen-dependent cancer, classified as poor risk on the basis of
tumor stage, Gleason grade, PSA level, and metastatic pattern.
For both groups of patients, chemotherapy consisted of weekly doses
of paclitaxel (60 to 100 mg/m²); estra-mustine at a dose of 10
mg/kg 5 days a week; and carboplatin every 4 weeks at a dosage
resulting in an AUC of 6.
For most of the androgen-dependent group, follow-up is too short to
draw conclusions about the effect of therapy, Dr. Kelly said. In the
androgen-independent cohort, 13 of 17 patients evaluable for response
had PSA declines of 50% or greater. Four of eight patients with soft
tissue disease had partial responses lasting 4 to 7 months; three
others had disease stabilization. The remaining patients have been
followed for too brief a time to evaluate.
Notable toxicities in the androgen-dependent group were one case of
cardiac ischemia and one deep-vein thrombosis. In the
androgen-independent group, single episodes of grade 3 cardiac
arrhyth-mia, deep-vein thrombosis, pulmonary embolism, and
thrombophlebitis have been seen.
A majority of patients in both groups experienced anemia and
thrombocyto-penia, but most cases were grade 1 or 2. Mild or moderate
diarrhea, nausea, vomiting, and dyspnea occurred in about 20% to 45%
of patients in each group.
"Our results show that this combination regimen can be
administered safely and that it has activity in androgen-independent
prostate cancer," Dr. Kelly said. "However, we need to
strive to make this regimen more tolerable if it is going to be successful."