Estramustine (Emcyt) is nornitrogen mustard linked to
estradiol. The original concept behind the design of the drug was that the estradiol
could be used as a vehicle to deliver the alkylator into tumor cells that
expressed estrogen receptors. It is now clear, however, that modified estrogens
such as estramustine exert very little alkylating activity, and
that they act primarily as antitubulins.
Estramustine binds to tubulin and to microtubule-associated
proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear
matrix.[2-4] Of uncertain clinical relevance, it is also an inhibitor of
p-glycoprotein, the multidrug resistance protein.
Estramustine has been most extensively studied as an oral agent.
While the half-life of the parent compound, estramustine phosphate, is
approximately 2 hours, the half-lives of the active metabolites estramustine and
estromustine range from 50 to 100 hours. The drug is usually administered in
split daily doses to minimize nausea.
Estramustine as Single Agent
As a single agent, estramustine was studied in a
placebo-controlled, double-blind, randomized study by the Danish Prostatic
Cancer Group. Of 131 patients with hormone-refractory prostate cancer, 129
were evaluable. Patients were randomized to receive oral estramustine phosphate
(n = 61), administered continuously at the dose of 280 mg bid, or placebo (n =
68) using the same schedule.
The most valuable results of this study lie in the
placebo-controlled evaluation of estramustine’s toxicity profile. Nausea and
vomiting were experienced by 26 out of 61 (43%) of the estramustine patients,
and considered severe in 8 out of 61 patients (13%). In the placebo group,
however, this toxicity was experienced by 21 out of 68 (31%) patients and was
severe in 9 out of 69 (13%). This suggests that a large proportion of the nausea
and vomiting seen with this agent at this dose is related to pill taking or is
The only other toxicity seen in more than 10% of patients was
breast tenderness or gynecomastia, which occurred in 25% of estramustine
patients and 1% of those receiving placebo. One patient in the estramustine
group had a pulmonary embolism, and no cases of deep vein thrombosis were
In terms of efficacy, this study reinforced the common wisdom
that prostate cancer is essentially chemoresistant. No objective responses
were observed and no differences in time to disease progression or survival were
seen between estramustine and placebo.
There was a suggestion of activity with estramustine using PSA
(prostate-specific antigen) criteria, however. Of 94 patients whose baseline PSA
was at least twice the normal level, 16 out of 43 (37%) in the estramustine
group had a ³ 50% reduction in PSA (PSA-50), while only 1 out of 51 (2%)
patients in the placebo group displayed such a response.
Taxanes as Single Agents
Like estramustine, the taxanes exert their antitumor effect by
targeting the microtubular apparatus. Paclitaxel (Taxol) and docetaxel
(Taxotere) polymerize the microtubules, but additionally inhibit Bcl-2 and
Bcl-xL by phosphorylation. These agents thus induce G2M arrest and apoptosis.
Studies have shown that paclitaxel as a single agent is
essentially ineffective against prostate cancer. In a phase II study performed
by the Eastern Cooperative Oncology Group (ECOG), 23 patients with
hormone-refractory prostate cancer received paclitaxel as a 24-hour infusion at
doses ranging from 135 to 170 mg/m2. One patient (4%) had an objective response,
and was the only one to have a response by PSA-50 criteria.
In contrast, docetaxel has modest activity as a single agent in
this disease. Preliminary results of two phase II studies of docetaxel at 75
mg/m2 given every 3 weeks in hormone-refractory prostate cancer have been
reported. In a study reported by Picus et al of 35 patients, 20% had an
objective response, and 46% had a response by PSA-50 criteria. Friedland et
al studied 21 patients, and reported a 5% objective response rate and PSA-50
responses in 33%.
Synergistic Action of Taxanes
and Estramustine Combined
The modest activity of the taxanes and of estramustine as single
agents in hormone-refractory prostate cancer clearly provides little rationale
for combining them for use in this disease. When combined in vitro, however, the
antitubulin activity of these agents is synergistic, with estramustine acting as
a modulator of the taxane.
Phase II studies of combined estramustine and paclitaxel (Table
1), [13,14] and combined estramustine and docetaxel (Table
2) [15-18] in
hormone-refractory prostate cancer have been reported. These combinations have
resulted in impressive objective (11%-27%) and PSA-50 (39%-82%) response rates
in this disease and warrant further investigation. Although these data are from
single-institution phase II studies, and the schedules of both estramustine and
the taxanes vary significantly, indirect comparison of these results with those
from single-agent studies suggests that the demonstrated in vitro synergism of
these agents may indeed be clinically relevant.
Two studies have assessed the role of estramustine in
combination with a taxane in metastatic breast cancer (Table
3). Garcia et al
reported a 20% response rate in 18 evaluable breast cancer patients entered in a
phase I study of paclitaxel and estramustine. All of the patients had
previously received paclitaxel. Talbot et al reported a 25% response rate in a
phase II study of combined docetaxel and estramustine in patients with
metastatic breast cancer. Interestingly, the same response rate was observed in
patients both with and without previous paclitaxel exposure. As in prostate
cancer, these data suggest that in breast cancer, estramustine is an effective
modulator of taxanes.
Thromboembolic events complicate the course of approximately 10%
of patients treated with combined estramustine and taxanes. Although not a
prominent toxicity in the single-agent estramustine studies, thromboembolic
events are more likely related to the estrogen moiety of the estramustine than
to any synergism between the two agents. This complication was documented in
studies of both prostate and breast cancer, and at all doses and schedules of
estramustine, with the exception of the study by Sinibaldi et al, in which
all patients received prophylactic warfarin (Coumadin) with excellent effect.
New strategies are required to improve the toxicity profile of
the estramustine/taxane combination if it is to become a part of routine
oncology practice. The most appealing option
to minimize toxicities is simply to reduce the dose. As estramustine is being
given as a modulator of taxanes rather than as an antineoplastic agent in its
own right, it may not be necessary to administer it at the maximum tolerated
dose to achieve the required biological effect. If lower doses can modulate the
taxanes as effectively as doses that have been studied to date (generally 600-840
mg/d in prostate cancer and approximately 1,500 mg/d in breast cancer), it may
to abrogate toxicities without further intervention.
The problem of nausea and vomiting is already being addressed.
An intravenous formulation of estramustine is now in clinical development. It
appears to be associated with less nausea than the oral formulation, and can be
administered once per cycle on the same day as the chemotherapy. Intravenous
estramustine is now being incorporated into combinations with taxanes and with
vinorelbine (Navelbine), and will probably eventually replace the oral
preparation in the clinic.
The study by Sinibaldi et al demonstrates that thromboembolic
complications can be minimized with the use of prophylactic oral
anticoagulation. Low-dose warfarin should therefore be considered in all
studies using estramustine at daily doses of 600 mg or higher.
In hormone-resistant prostate cancer, combinations of taxanes
and estramustine offer clinically significant activity in a disease that was,
until recently, effectively untreatable. These combinations are now being
compared in front-line phase III studies (eg, SWOG 9916) against the combination
of mitoxantrone (Novantrone) and prednisone.
Estramustine with vinorelbine has also been tested in patients
with hormone-resistant prostate cancer, again with promising results. The
activity of estramustine with single-agent antitubulins thus provides a strong
rationale for the development of triplets comprising a taxane, vinorelbine, and
estramustine. A phase I study of paclitaxel, vinorelbine, and estramustine,
which is being conducted at New York University Medical Center, will soon be
completed. A report on the study is to be made at the American Society of
Clinical Oncology (ASCO) meeting in May 2001 (Sewak et al). A phase II study
will follow in hormone-refractory prostate cancer.
In metastatic breast cancer, combinations of estramustine and
taxanes have moderate activity in taxane-pretreated populations, but the
toxicity profile of the combination currently limits its development in this
disease, which has a far broader range of therapeutic options available.
Finally, although initially developed for use in
hormone-responsive tumors, estramustine, as a modulator should theoretically be
effective in any tumor with sensitivity to antitubulins. Thus
estramustine/antitubulin combinations may have a role in tumors originating in
sites other than the prostate and breast, including lung, head and neck, ovary,
endometrium, and bladder.
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