Paclitaxel-Based Combination Chemotherapy for Breast Cancer
Paclitaxel-Based Combination Chemotherapy for Breast Cancer
The initial clinical trials with single-agent paclitaxel (Taxol) demonstrated
the marked antitumor efficacy of this agent in ovarian and breast cancer.[1,2]
Subsequent clinical trials expanded the experience with this agent and
showed that paclitaxel retained substantial antitumor efficacy in previously
treated patients and that paclitaxel was active against metastatic breast
cancer at a variety of doses and schedules of administration.[3-8] Comparative
clinical trials to determine the optimal dose and schedule of administration
of this agent are completing accrual. Paclitaxel has been extensively evaluated
in combination with other cytotoxic agents with demonstrated activity against
metastatic breast cancer (Table 1).
Soon after the first report of its antitumor activity, the evaluation
of paclitaxel-based combinations started. Since doxorubicin, until the
appearance of the taxanes, was considered the most active antitumor agent
for metastatic breast cancer, the anthracycline/taxane combination was
a logical first step. The University of Texas M. D. Anderson Cancer Center
and the Medicine Branch of the National Cancer Institute (USA) initiated
paclitaxel/doxorubicin combination phase I trials simultaneously.[9-13]
Both groups used the longer durations of infusion of paclitaxel, since
that was the schedule of administration used for single-agent trials. In
addition, to limit cardiac and other nonhematologic toxicity related to
anthracyclines, infusion schedules of administration were used for this
agent, too (Table 2).
Dose-limiting toxicities of these phase I trials included severe mucositis,
diarrhea, tiflitis, and neutropenic fevers. Reversing the sequence of administration
of doxorubicin and paclitaxel in the M. D. Anderson Cancer Center clinical
trials allowed dose escalation by two or three levels, but eventually,
the same dose-limiting toxicity was reached. These initial paclitaxel/doxorubicin
combinations were clearly effective, with overall response rates ranging
from 62% to 80% and with 95% confidence intervals ranging from 38% to 98%.
Furthermore, it is noteworthy that no clinically relevant cardiac toxicity
was observed; specifically, no instances of congestive heart failure were
As the first reports of these combination trials appeared, other investigators
designed new combinations with the same two agents or with other cytotoxic
drugs. Shortening the duration of administration of doxorubicin permitted
the administration of higher doses, yet a schedule-dependent interaction
was noted and confirmed by pharmacokinetic studies.[14-16] Investigators
at the Istituto Nazionale Tumori in Milan, Italy, developed a combination
based on bolus administration of doxorubicin and a 3-hour administration
When the two drugs were given in this schedule of administration, there
was no apparent schedule-dependent interaction of clinical relevance, although
these authors also confirmed the previously described pharmacokinetic variations
related to the sequence of administration. The doses administered could
be increased to 60 mg/m² and 200 mg/m² for doxorubicin and paclitaxel,
respectively, and the antitumor activity increased markedly, with an overall
response rate exceeding 90%, and complete remission rate now greater than
40% (Table 3).
Observers of this trial were concerned by the appearance of congestive
heart failure in 20% of patients and a greater than 15% decrease in left-ventricular
ejection fraction in as many as 75% of patients. In fact, in 22% of patients
who did not develop clinical heart failure, ejection fraction dropped below
50%. A second study that used the same doses and schedule of administration
as the Milan group confirmed these results, both in terms of antitumor
activity and cardiac toxicity. Subsequent experience from the Milan
group, limiting the total cumulative doxorubicin dose to 360 mg/m²
(six cycles), demonstrated the safety of this regimen, with no episodes
of heart failure in nearly 40 patients. [L. Gianni, personal communication,
Currently, several confirmatory trials are ongoing. These trials employ
the same schedule of administration of paclitaxel and anthracycline (in
some studies, epirubicin was substituted for doxorubicin), and although
substantial antitumor activity has been reported, these studies are not
mature enough to fully assess the results in terms of antitumor activity
and toxicity. A randomized phase II study is being conducted at The University
of Texas M. D. Anderson Cancer Center, in which doxorubicin (60 mg/m²)
is administered as an intravenous bolus followed immediately by paclitaxel
(200 mg/m²), either by 1- or 3-hour administration. The study's major
focus is close cardiac monitoring to identify whether this combination
can be administered safely, to determine the regimen's degree of cardiac
toxicity, and to see if the associated cardiac toxicity is the result of
synergistic effects of these drugs. Elements of the study include clinical
evaluation, noninvasive cardiac functional tests, and endomyocardial biopsies.
Cisplatin (Platinol) is reported to have marked antitumor activity in
previously untreated metastatic breast cancer. In addition, cisplatin
is less myelosuppressive than many other useful agents against metastatic
breast cancer and is considered a good candidate for combination with paclitaxel.
One group developed a regimen in which cisplatin was given at 60 mg/m²
with the appropriate premedication and hydration, while paclitaxel was
administered at 90 mg/m² as a 3-hour infusion. The combination
was repeated at 14-day intervals.
In an exploratory study that included mostly patients who had previously
received an anthracycline, there was an overall response rate of 85%, including
an 11% complete response rate (Table 4).
Tolerance was acceptable. There were no episodes of grade 4 nonhematologic
toxicity, although grade 2 to 3 fatigue, peripheral neuropathy, and nausea
were reported. Myelosuppression and neutropenic fevers were also seen.
Wasserheit et al used higher dosages of both cisplatin and paclitaxel
at 3-week intervals. The activity of this regimen was less impressive
than that reported by Gelmon and collaborators, and the toxicity was considerably
higher. Other investigators have also reported successful combinations
of cisplatin and paclitaxel. The optimal dose and schedule of administration
for this combination remain to be established.
Because the mechanisms of action of alkylating agents and taxanes are
different, as are many of the side effects and mechanisms of resistance,
and because cyclophosphamide (Cytoxan, Neosar) is an integral part of most
commonly used combination regimens for breast cancer, this was another
logical combination to explore. Some of these combinations used standard
doses of cyclophosphamide, while others increased the dose of the alkylating
agent to two- to sixfold the standard dose[22-25] (Table
5). Because myelosuppression is an overlapping toxicity of the two
agents, hematopoietic growth factors were used in all these trials.
Tolcher et al reported the results of his dose-escalation study, which
demonstrated a 62% overall response rate in 56 patients treated with 160
mg/m² of paclitaxel infused over 72 hours and 3,300 mg/m² of
cyclophosphamide. Although the combination is clearly active, myelosuppression
is quite considerable, and the need for the systematic addition of granulocyte
colony-stimulating factor (G-CSF [Neupogen]) makes this combination less
attractive than other paclitaxel-based regimens.
Paclitaxel has also been combined with vinorelbine (Navelbine). This
new nor-vinblastine analog is substantially active in metastatic breast
cancer, and it is very well tolerated when administered weekly as a single
agent. Vinorelbine is a tubulin-active agent, and it was anticipated
on the basis of preclinical experiments that the sequence of administration
with a taxane would be an important consideration.
Several phase I or exploratory trials of the vinorelbine/paclitaxel
combination are in progress. The University of Texas M. D. Anderson Cancer
Center group used a simultaneous schedule of administration for vinorelbine
and paclitaxel: both were given as a 3-hour IV infusion every 3 weeks.
Dose-limiting toxicities were neutropenic fever and cumulative neuropathy.
With hematopoietic growth factor (G-CSF) support, additional dose escalation
was possible, and neuropathy became the dose-limiting event. This combination
was also active, with objective response rates in the 50% to 65% range.
In other centers, paclitaxel and vinorelbine are being evaluated in
sequential schedules of administration.[30-32] Although no definitive results
have been reported, peripheral neuropathy appears to be a less prominent
problem in these trials.