Paclitaxel in Breast Cancer
EDITH A. PEREZ
Mayo Foundation and Mayo Clinic Jacksonville, Jacksonville, Florida, USA
Key Words. Paclitaxel · Antineoplastic agents · Breast neoplasms · Clinical trials
A BSTRACT
Paclitaxel has emerged as an important agent in the
treatment of breast cancer. The efficacy and tolerability of
this agent, as well as its lack of cross-resistance with
anthracyclines, have spurred intensive clinical investiga-
tion worldwide. Optimization of paclitaxel dose and sched-
uling and evaluation of the drug in combination regimens
are a central focus of investigations. Recent clinical evi-
dence suggests that optimal dose of single-agent paclitaxel
by 3-h infusion is 175 mg/m2. Trials evaluating adminis-
tration schedule have not found either a 24-h or 96-h
infusion to be superior to a 3-h infusion. Weekly moderate-
dose paclitaxel administration is also generating much
interest, given the high relative dose intensity and dose
density delivered, yet very modest myelosuppression and
manageable neurotoxicity observed.
As first-line therapy in metastatic disease, multiple
studies have documented overall response rates in the
range of 30%-60%. As second-line or salvage single-
agent therapy in metastatic patients, paclitaxel generally
affords an overall response rate of 20%-40%, even in
anthracycline-resistant patients.
The novel mechanism of action and manageable tox-
icity of paclitaxel has led to successful incorporation into
combination chemotherapy regimens. The combination
INTRODUCTION
The role of paclitaxel is being investigated in settings
ranging from first-line, second-line, and salvage therapy for
metastatic disease, as well as adjuvant and neoadjuvant
treatment. Paclitaxel’s place in combination chemotherapy,
as well as optimal dosing and scheduling, are among the
critical issues being addressed in clinical trials worldwide.
A number of large-scale, randomized phase III clinical trials
have been initiated, and recently several have had preliminary
results reported.
Paclitaxel is classified as a taxane, an antimicrotubulin
agent with a unique mechanism of action and potent activity
Correspondence: Edith A. Perez, M.D., Division of Hematology/Oncology, Mayo Clinic Jacksonville, 4500 San Pablo Road,
Jacksonville, Florida 32224, USA. Telephone: 904-953-2000; Fax: 904-953-2315; e-mail: perez.edith@mayo.edu Accepted
for publication September 2, 1998. ©AlphaMed Press 1083-7159/98/$5.00/0
The Oncologist 1998;3:373-389
of paclitaxel and doxorubicin has been the most exten-
sively studied, with the role of this regimen continuing to
evolve. Other combination regimens that appear to hold
substantial promise as first-line metastatic treatment
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are paclitaxel with carboplatin and paclitaxel with
trastuzumab (anti-HER2 antibody). The favorable
results obtained in the metastatic setting have prompted
phase II and phase III investigations of paclitaxel in the
adjuvant and neoadjuvant settings. In the adjuvant set-
ting, a recent phase III study has indicated that the addi-
tion of sequential paclitaxel to standard therapy affords
both disease-free and overall survival benefits.
Current investigations with paclitaxel will con-
tinue to optimize the role of this agent in the treatment
of early- and advanced-stage breast cancer, address-
ing not only response rates but also survival and qual-
ity-of-life issues. The use of paclitaxel on a weekly
schedule or with new therapeutic modalities, such as
monoclonal antibodies, is also receiving much atten-
tion. While it is clear that paclitaxel is a very active
agent in the treatment of breast cancer, it is hoped
that these innovative trials will further maximize the
potential of this agent in patients with breast cancer.
The Oncologist 1998;3:373-389
against several tumor types, including breast cancer. Unlike
other antimicrotubulin agents, paclitaxel achieves its antitu-
mor effect by promoting tubulin dimerization and inhibiting
depolymerization of the microtubules [1].
Paclitaxel is active in the treatment of metastatic breast
cancer as first-line therapy [2-4], as well as in heavily pre-
treated patients [3, 5-7]. Especially encouraging is its activ-
ity in anthracycline-resistant disease [7, 8]. Recognition of
the activity of this agent in advanced breast cancer has led
to its study in earlier stages of the disease. Several phase III
randomized trials are evaluating the efficacy of paclitaxel in
the adjuvant and neoadjuvant settings.
374 Paclitaxel in Breast Cancer

Paclitaxel use is generally associated with manageable
toxicity. Neutropenia and peripheral neuropathy are common
clinical side effects of paclitaxel [1]. The most common dose-
limiting toxicity of paclitaxel, neutropenia, is both dose- and
schedule-dependent. Severe neutropenia is typically of short
duration and rarely associated with other hematologic toxici-
ties. Cumulative peripheral neurotoxicity is typically mild and
often reversible. Hypersensitivity reactions are almost com-
pletely prevented by the use of a premedication regimen
consisting of corticosteroids, cimetidine or ranitidine, and
diphenhydramine.
Paclitaxel infusion schedules of 1 h, 3 h, 24 h, and 96 h
have been studied in the treatment of breast cancer patients.
Because of its convenience in the outpatient setting, a 3-h
The single-agent activity of paclitaxel in metastatic breast
cancer was established in seminal phase II studies. As first- or
second-line treatment, a 24-h infusion of 250 mg/m2 paclitaxel
every 21 days displayed high levels of antitumor activity, with
overall response rates of 56% and 62%, as reported by inves-
tigators at the MD Anderson Cancer Center (MDACC) and the
Memorial Sloan-Kettering Cancer Center (MSKCC), respec-
tively [13, 14]. These studies provided the first evidence that
paclitaxel was very active as single-agent therapy for metasta-
tic breast cancer. Phase I studies have indicated that the maxi-
mum tolerated dose of paclitaxel given by 24-h infusion every
three weeks is 175-200 mg/m2 without G-CSF support and
200-250 mg/m2 with G-CSF support [15, 16].

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infusion is currently the most widely used. Today, clinical
studies are typically employing a 3-h infusion at a dose
range of 135-250 mg/m2 every three weeks. Dosing and
scheduling issues have been investigated in a number of
clinical trials, summarized in Table 1. The results of several
recently reported trials have provided much insight into
optimal dosing and scheduling [9-12]. This review will
describe completed and ongoing clinical trials of paclitaxel
in breast cancer. Promising avenues of further investigation
will also be highlighted.
METASTATIC BREAST CANCER
Single-Agent Therapy
Since chemotherapy in metastatic breast cancer patients
remains palliative, both response and tolerability are important
considerations in evaluating new agents. Paclitaxel has been
shown to achieve comparatively high response rates with an
acceptable toxicity profile.
Phase II Trials of Short Infusion Schedules
Following these early studies, the use of shorter infusion
schedules of paclitaxel was investigated. Studies in ovarian
cancer patients indicated that a 3-h infusion of paclitaxel every
three weeks was safe and was associated with significantly less
myelosuppression than a 24 h-infusion [17]. The shorter
infusion schedule also allowed for outpatient administration.
Phase II studies with single-agent paclitaxel produced
overall response rates of 21%-60% at doses of 135 mg/m2 to
225 mg/m2 administered by 3-h infusion [3, 4, 8, 18, 19].
Treatment was generally well tolerated, and prophylactic use
of hematopoietic growth factors was not required.
As first-line therapy for metastatic disease, overall response
rates of 43% and 32% have been reported in two studies admin-
istering paclitaxel 250 mg/m2 every three weeks [2, 3], and a
third study administering 225 mg/m2 on the same schedule
reported an overall response rate of 60% [4]. Neutropenia was
the most common toxicity encountered in these studies. These
response rates are comparable to the 29%-43% rates obtained
with doxorubicin in first-line regimens [20].

Table 1. Paclitaxel doses and schedules in selected randomized clinical trials

Study Paclitaxel dose Evaluable patients Overall Comments
(mg/m2)/schedule response (%)
Nabholtz [9] 135/3 h 227* 22 No difference in overall response; median time to
175/3 h 223* 29 progression favored higher dose.
Peretz [33] 175 to MTD/3 h 29 No difference in overall response, survival, or time
521*
175 to MTD/24 h 32 to progression when adjusted for prognostic factors.
CALGB 9342 [10] 175/3 h 21 No difference in overall response or overall survival.
210/3 h 325* 28 Improved time to treatment failure with highest dose.
250/3 h 22 Toxicity profile favored lower dose.
NSABP B-26 [11] 250/3 h 40 Significant difference in overall response, but no difference
516* } p = 0.02
250/24 h 50 in overall survival. Toxicity profile favored shorter infusion.
MDACC [12] 250/3 h 88* 23 No difference in response or survival. Toxicity profile
140/96 h 91* 30 and feasibility favored shorter schedule.

*All arms combined. CALGB = Cancer and Leukemia Group B; NSABP = National Surgical Adjuvant Breast and Bowel Program;
MDACC = MD Anderson Cancer Center.
Perez 375

Response in Anthracycline-Resistant Patients
Heavily pretreated breast cancer patients usually have a
very poor prognosis, and few treatment options are available.
Most will have failed anthracycline therapy, and anthracy-
cline resistance is an indicator of very poor prognosis. In the
pre-taxane era, patients with anthracycline-resistant metasta-
tic breast cancer faced a median survival of about four
months. Responses to all other treatment regimens, whether
single-agent or combination, were less than 15% [21].
In the phase II setting, response rates of approximately
20%-40% were obtained with single-agent paclitaxel in
patients who failed prior anthracycline therapy (Table 2) [3, 7,
8, 18, 19]. In heavily pretreated patients, response rates of
up to 22% were achieved [19]; however, in patients who
reported a 22% overall response rate to paclitaxel following
anthracycline failure [23, 24].
Weekly Paclitaxel
Another area of considerable interest is the administra-
tion of weekly cycles of paclitaxel. With weekly adminis-
tration of moderate doses of paclitaxel, higher cumulative
doses can be achieved than with an every-three-weeks
schedule, yet myelosuppression is generally modest [25-29].
Seidman et al. administered paclitaxel 100 mg/m2 weekly
via 1-h infusion to patients with previously treated metastatic
breast cancer and observed a 53% overall response rate, with
10% complete responses [25]. In the subgroup with anthracy-
cline-resistant disease, the response rate was 50%. Therapy

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had received ≥2 prior chemotherapy regimens containing
doxorubicin or epirubicin, response rates were lower, at
6% [22]. Phase III studies have confirmed the activity of
paclitaxel in anthracycline-resistant patients. An overall
response rate of 25% was observed in anthracycline-pre-
treated patients who received paclitaxel 135 or 175 mg/m2
over 3 h [9]. In addition, the intergroup trial E-1193, a
phase III study in which patients randomized to received
single-agent doxorubicin could be crossed over to receive
paclitaxel (24-h infusion) upon disease progression,
was well tolerated, with a lack of cumulative neutropenia and
manageable neurotoxicity.
Neurotoxicity, which can be cumulative with paclitaxel
treatment, is generally not a problem with weekly paclitaxel
doses up to 80 mg/m2 [26]. Perez et al. at the Mayo Clinic
Jacksonville are currently conducting a multicenter phase
II trial of continuous, weekly paclitaxel 80 mg/m 2 in
patients with metastatic breast cancer and to date have
not encountered difficulty with cumulative neurotoxicity
or myelosuppression.

Table 2. Single-agent paclitaxel therapy in anthracycline-treated or anthracycline-resistant breast cancer

Study Trial Dose/schedule Evaluable Overall Comments
design patients response (%)
Phase II Trials
Seidman [3] Phase II 125 mg/m2 i.v., 3-h infusion 24 21 Two or more prior regimens for
Cycles repeated q 3 wk metastatic disease.
Seidman [7] Phase II 200-250 mg/m2 i.v., 24-h infusion 76 33 At least one prior therapy for
Cycles repeated q 3 wk metastatic disease.
Abrams [6] NCI treatment 135 or 175 mg/m2 i.v., 24-h infusion 153 24 Patients had progressed either while
referral Cycles repeated q 3 wk on doxorubicin or within 6 months
after doxorubicin.
Fountzilas [8] Phase II 175 mg/m2 i.v., 3-h infusion 33 42 Anthracycline resistant.
Cycles repeated q 3 wk
Gianni [18] Phase II 175 or 225 mg/m2 i.v., 3-h infusion 50 38 Up to two prior regimens, one
Cycles repeated q 3 wk adjuvant and one metastatic.
Vici [19] Phase II 135 or 175 mg/m2 i.v., 3-h infusion 41 22 Two to five prior therapies for
Cycles repeated q 3 wk advanced disease.
Vermorken [22] European 250-300 mg/m2 i.v., 3-h infusion 33 6 Two or more prior anthracycline-
Cancer Center Cycles repeated q 3 wk containing regimens.
Trial
Phase III Trials
Nabholtz [9] Multicenter 135 or 175 mg/m2 i.v., 3 h infusion 303 25 One prior regimen, adjuvant or
Cycles repeated q 3 wk metastatic, or one each adjuvant
and metastatic.
376
A higher-dose weekly paclitaxel regimen, 175 mg/m2 by
3-h infusion for six weeks of an eight-week cycle, is under
investigation by the Brown University Oncology Group
as first-line treatment for locally advanced or metastatic
breast cancer. The overall response rate was 78%, with 16%
complete responses; however, most patients required dose
modification secondary to cumulative toxicities [30, 31].
Phase III Trials: Dose Response
Phase III trials have confirmed the high, single-agent
activity of paclitaxel in advanced breast cancer. Issues of
paclitaxel dose have recently been studied by Nabholtz et
al. [9] and CALGB trial 9342 [10]. The trial reported by
Nabholtz et al., which compared doses of paclitaxel 135
and 175 mg/m2 deliv-
ered by 3-h infusion
every three weeks,
It appears that a dose and
reported overall
response rates of 22%
schedule of 175 mg/m by 3-h
and 29%, respectively, infusion every 21 days is both
and complete response
rates of 5% and 2%, for effective and well tolerated,
each of the doses,
respectively [9]. These and a reasonable therapeutic
differences were not sta-
tistically significant; choice.
however, there was a
significant difference in time to progression, with the
higher dose producing a median time to disease progres-
sion of 4.2 months, compared with 3.0 months for the
lower dose.
Preliminary results of CALGB 9342 have recently been
reported [10, 32]. In this phase III trial, single-agent paclitaxel
doses of 175, 210, and 250 mg/m2 were administered as a 3-
h infusion every three weeks to patients who had received up
to one prior therapy for metastatic disease. In updated results
presented at the 1998 American Society of Clinical Oncology
(ASCO) annual meeting in Los Angeles, response rates and
overall survival were not statistically different among the
three arms; however, time to treatment failure was statisti-
cally longer for patients receiving the highest dose.
Although all dose levels were well tolerated and overall
quality of life was not different among the three arms of the
trial, grade III neurosensory toxicity and grade IV hemato-
logic toxicity were more frequent with the 250 mg/m2 dose
than with either 175 or 210 mg/m2.
These studies have not shown a clear-cut dose-response
relationship for paclitaxel in the treatment of metastatic breast
cancer. Although time to treatment failure may favor higher
doses, there have been no differences in overall response or
survival between arms of the studies. Given this information,
Paclitaxel in Breast Cancer
it appears that a dose and schedule of 175 mg/m2 by 3-h infu-
sion every 21 days is both effective and well tolerated, and a
reasonable therapeutic choice.
Phase III Trials: Infusion Schedule
Two phase III trials have addressed the issue of com-
parative efficacy and safety of 3-h versus 24-h paclitaxel
infusions in patients with advanced breast cancer. A pre-
liminary report by Peretz et al. of the results of a
European phase III trial evaluating 3-h versus 24-h pacli-
taxel infusion, each at 175 mg/m 2, did not show either
schedule superior [33]. Patients were stratified according
to no prior chemotherapy, adjuvant chemotherapy, or
chemotherapy for advanced disease. Overall, there were
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no differences in cumu-
lative response rates,
median progression-free
2
survival, or overall sur-
vival between the two
groups when adjusted
for prognostic factors. In
the salvage setting, the
24-h infusion had some
efficacy advantage, but
did not confer a signifi-
cantly greater patient
benefit when compared
with 3-h infusion. More grade 3 and 4 neutropenia was
reported in patients receiving the 24-h infusion, while
peripheral neuropathy was more common in the 3-h
schedule.
Preliminary results of NSABP B-26, which compared a
3-h versus 24-h infusion of paclitaxel 250 mg/m2 have
recently been reported [11], with updated data presented at
the 1998 ASCO meeting [34]. Patients enrolled had stage
IIIB or IV breast cancer, and only prior adjuvant
chemotherapy was allowed. The overall response rate for all
patients was significantly higher in the 24-h infusion group
(50%) than in the 3-h group (40%) [11]. For the subset of
patients with stage IV disease, the overall response rates
were 48% and 36% for the 24-h and 3-h infusions, respec-
tively. The median time to progression was 7.1 months for
the 24-h arm, and 6.4 months for the 3-h arm [34]. Despite
the difference in response, there was no difference in overall
survival between the 24-h infusion (21 months) and the 3-h
infusion (20.7 months). Although the median overall survival
for the subset of patients with stage IIIB disease had not been
reached at the time of presentation in May 1998, the median
overall survival for stage IV patients was 18.2 months for the
24-h infusion and 20.3 months for the 3-h infusion arm. As
with the European phase III trial, the 24-h schedule was
Perez
associated with more severe hematologic toxicity, and severe
neurotoxicity was more common with 3-h infusions. The
authors concluded that although the 24-h schedule offered a
higher overall response rate, this did not translate to an
increase in event-free or overall survival as compared with
the 3-h arm. Because of the increased toxicity and costs asso-
ciated with the 24-h infusion, the authors concluded that the
3-h infusion was generally preferable.
A third phase III multicenter trial, coordinated by
MDACC, evaluated 3-h versus 96-h infusions of paclitaxel in
metastatic breast cancer [12]. Doses of 250 mg/m2 by 3-h
infusion and 140 mg/m2 for the 96-h infusion were adminis-
tered every three weeks. There were no differences in overall
response, response duration, or overall survival between study
arms. The investigators concluded that the extra logistical
support required for 96-h
infusion was not justified. Paclitaxel has demonstrated
Phase III Trials: significant activity in patients with
Comparison Studies
anthracycline-resistant breast cancer.
Paclitaxel versus CMFP
Preliminary results of a phase III study from New
Zealand and Australia reported by Bishop et al. indicate
that single-agent paclitaxel yields response rates equivalent
to standard combination cyclophosphamide/methotrex-
ate/5-fluorouracil (5-FU)/prednisolone (CMFP) at equi-
toxic doses in patients with previously untreated metastatic
breast cancer [35-37]. In their preliminary report, the over-
all response rate was 30% with paclitaxel and 36% with
CMFP [35]. Median time to progression was 5.3 months for
paclitaxel and 6.5 months for CMFP. Paclitaxel was associ-
ated with significantly less severe leukopenia, thrombocy-
topenia, mucositis, infections, and nausea/vomiting.
Alopecia, peripheral neuropathy, and myalgia/arthralgia
were more frequent with paclitaxel. Patient assessment of
quality of life appeared to improve with paclitaxel, but
deteriorate with CMFP. The investigators concluded that
single-agent paclitaxel is well tolerated, has efficacy com-
parable to CMFP, and may have additional benefits with
respect to quality of life.
Paclitaxel versus Doxorubicin
Results were recently reported from another multi-
institutional phase III trial comparing paclitaxel with dox-
orubicin, each as single agents, as first-line treatment of
metastatic breast cancer [38]. In this European Organiza-
tion for Research and Treatment of Cancer (EORTC) trial
of 331 anthracycline-naive patients, doxorubicin 75 mg/m 2
produced a higher response rate, 41%, and longer progres-
sion-free survival, 7.3 months, as compared with paclitaxel
377
200 mg/m2 by 3-h infusion, which demonstrated a 25% over-
all response rate and 4.0 months progression-free survival.
However, the doxorubicin arm was associated with greater
hematologic, gastrointestinal, and cardiac toxicities, sug-
gesting that the drugs were not compared in equitoxic doses.
In contrast to the EORTC study, U.S. Intergroup Study E-
1193, a randomized Phase III trial, failed to reveal any differ-
ence between doxorubicin and paclitaxel as single agents in
overall response rate, time to disease progression, or overall
survival [23, 24]. This three-arm study compared doxorubicin
60 mg/m2 with paclitaxel 175 mg/m2 by 24-h infusion versus
a combination of doxorubicin 50 mg/m2 and paclitaxel 150
mg/m2 by 24-h infusion. In the preliminary report, overall
response rates prior to any crossover therapy were 36% for
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single-agent doxorubicin, 34% for single-agent paclitaxel,
and 47% for the combina-
tion. The combination had
a statistically superior
response; however, there
was no statistical differ-
ence in response between
the two single-agent arms.
Paclitaxel versus Docetaxel
An ongoing U.S. multicenter trial is comparing pacli-
taxel 175 mg/m2 by 3-h infusion with docetaxel 100 mg/m2
by 1-h infusion as first- or second-line therapy of advanced
breast cancer [39]. The question of an equitoxic dose com-
parison arises, as the maximum tolerated dose for docetaxel
is 100 mg/m2, while paclitaxel has been shown to be well
tolerated up to 250 mg/m2. While the paclitaxel dose
appears reasonable based on current information, the opti-
mal dose of docetaxel, in terms of efficacy and toxicity, is
not yet defined and awaits the results of a separate trial
evaluating docetaxel 60 mg/m2 versus 75 mg/m2
versus 100 mg/m2.
In summary, paclitaxel has substantial activity as a sin-
gle agent in the treatment of metastatic breast cancer. While
response rates are highest in the first-line setting, single-
agent paclitaxel maintains very good activity as second-line
and salvage therapy. The response rate to single-agent pacli-
taxel is reasonably comparable to that of single-agent dox-
orubicin. Of importance, paclitaxel has demonstrated
significant activity in patients with anthracycline-resistant
breast cancer. Although a well-defined dose-response rela-
tionship has not been established for 3-h infusions of pacli-
taxel on an every-three-weeks schedule, a dose of 175 mg/m2
appears to offer the best balance of efficacy and tolerability.
With regard to infusion schedule, when overall survival is
considered, neither 24-h nor 96-h schedules appear to offer
survival benefits over a 3-h schedule. Although the 24-h
378
schedule has been associated with a higher overall response
rate, this did not translate into a survival difference. Overall,
a 3-h schedule of paclitaxel 175 mg/m2 every three weeks
appears to be a reasonable option for the treatment of breast
cancer. Weekly studies with moderate-dose, single-agent
paclitaxel appear very promising in terms of both efficacy
and tolerability. A relatively high rate of dose delivery com-
bined with a remarkably tolerable toxicity profile has been
observed, encouraging continued investigation.
Combination Chemotherapy
Combination chemotherapy is the standard approach to
the treatment of breast cancer. Multidrug regimens have gen-
erally resulted in higher complete and overall response rates,
with improvements in response durations. The novel mecha-
nism of action of paclitaxel, its demonstrated single-agent
activity, and its manageable toxicity profile make it an attrac-
tive candidate for inclusion in combination chemotherapy
regimens.
Paclitaxel has been studied in combination with a number
of other agents effective in breast cancer. The largest number
of studies have been conducted with the paclitaxel/doxoru-
bicin combination as first-line therapy in advanced breast can-
cer [24, 40-48]. Other combinations for both first-line and
salvage therapy have included paclitaxel and 5-fluorouracil
(5-FU) [49, 50], paclitaxel and cyclophosphamide [51-55],
and paclitaxel with a platinum compound [56-65].
New insights in molecular biology have led to combination
chemotherapy and antibody studies. With respect to breast
cancer in particular, the investigation of combination pacli-
taxel or anthracycline/cyclophosphamide with anti-HER2 anti-
body has generated much interest.
Paclitaxel/Anthracycline or Anthracenedione Combinations
Paclitaxel and Doxorubicin
The high individual activity of doxorubicin and paclitaxel
in breast cancer and their incomplete clinical cross-resistance
make combination therapy with these two agents an attractive
option for first-line treatment of metastatic breast cancer. This
combination has been extensively evaluated in phase II trials
of breast cancer patients worldwide. Response rates—among
the highest reported for first-line metastatic treatment—have
been encouraging (Table 3).
The first two trials of combination doxorubicin and pacli-
taxel involved administration of both drugs as prolonged
infusions. In a National Cancer Institute study, paclitaxel and
doxorubicin were administered concurrently as a 72-h infu-
sion. The overall response rate was 72% [66]. An MDACC
trial of paclitaxel by 24-h infusion and doxorubicin by 48-h
infusion also investigated the effect of drug sequencing. As
Paclitaxel in Breast Cancer
reported by Holmes et al., the overall response rate was
higher (80%) when paclitaxel preceded doxorubicin versus
57% when the order was reversed, but tolerability was clearly
lower [67]. Mucositis, fever, neutropenia, and diarrhea were
dose-limiting in the above trials. A pharmacokinetic study
revealed that when paclitaxel administration preceded that of
doxorubicin, the clearance of doxorubicin was decreased by
32% [68]. An Eastern Cooperative Oncology Group (ECOG)
study also observed substantially more mucositis when pacli-
taxel by 24-h infusion preceded a doxorubicin bolus than
when the drugs were administered in the reverse order [69].
Moreover, preclinical studies had shown that doxorubicin
followed by paclitaxel has a synergistic or additive effect in
primary breast cancer cell cultures or breast cancer cell
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lines [70]. Consequently, the sequence of doxorubicin fol-
lowed by paclitaxel has been preferred in subsequent trials.
The desire to deliver paclitaxel and doxorubicin in
combination on an outpatient basis led to studies of shorter
administration times [40-44, 48]. These short-infusion stud-
ies provided evidence of high overall and complete response
rates (Table 3).
In all trials conducted to date, the paclitaxel/doxorubicin
combination has resulted in high rates of response. However,
in trials reported by Gianni et al. [40] and Gehl et al. [41], high
response rates were accompanied by an increased incidence of
congestive heart failure (CHF), an incidence much higher than
expected in light of the cumulative doses of doxorubicin
administered. A pharmacokinetic analysis revealed apparent
interference by paclitaxel in the elimination of doxorubicin,
resulting in increased concentrations of both doxorubicin and
its major metabolite, doxorubicinol [71]. Other investigations
have also documented a pharmacokinetic interaction between
paclitaxel and doxorubicin [68, 72].
Recently, the international experience with combination
paclitaxel and doxorubicin therapy in patients with advanced
breast cancer has been analyzed with respect to cardiac tox-
icity [73]. Of the total of 656 patients treated on a combi-
nation of 10 different trials, 31 patients (5%) developed
CHF. In patients receiving a cumulative doxorubicin dose
of up to 380 mg/m2, the incidence of CHF was less than 5%,
similar to that expected with doxorubicin alone. Above this
dose, an increase in CHF was apparent. Therefore, the cur-
rent recommendation for combination doxorubicin/pacli-
taxel therapy is to limit the maximum cumulative doses of
doxorubicin to 380 mg/m2, with a maximum single dose of
50-60 mg/m2.
Data from the only phase III trial of combination pacli-
taxel and doxorubicin, the Intergroup study E-1193, were
included in the above analysis [23, 24]. As has been noted,
this trial allowed for comparison of efficacy and toxicity of
paclitaxel and doxorubicin, each as single agents, to the
Perez 379

Table 3. Doxorubicin/paclitaxel as first-line therapy in metastatic breast cancer

Study Dose/schedule Evaluable Response Comments
patients (%)
Phase I/II or II trials CR PR OR

Gianni [40] T 200 mg/m2 i.v., 3-h infusion 32 41 53 94 No prior chemotherapy.

A 60 mg/m2 i.v. bolus
Cycles repeated q 3 wk, maximum
8 cycles

Gehl [41] T 155-200 mg/m2 i.v., 2-3-h infusion 29 24 59 83 ≤1 prior adjuvant regimen;
A 30 mg/m2 i.v. bolus, d 1 and 8 no prior anthracycline.

Amadori [42] A 50 mg/m2 i.v. bolus 16 h before T 32 31 47 78 No prior chemotherapy for

T 130-250 mg/m2 i.v. 3-h infusion metastatic disease; adjuvant
Cycles repeated q 3 wk chemotherapy allowed.

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Schwartsmann [43] T 250 mg/m2 i.v., 2-3-h infusion 25 28 52 80 No prior chemotherapy for
A 60 mg/m2 i.v. bolus metastatic disease; adjuvant
Cycles repeated q 3 wk, maximum chemotherapy allowed.
6 cycles

Sparano [48] A 60 mg/m2 i.v. bolus 47 6 47 53 No prior chemotherapy for

T 200 mg/m2 i.v., 3-h infusion 15 min metastatic disease; adjuvant
after A chemotherapy allowed other
Cycles repeated q 3 wk, maximum than A or T.
6 cycles

Jovtis [44] A 50 mg/m2 i.v. short infusion 50 NR NR 72 No prior chemotherapy for

T 200 mg/m2 i.v., 1-h infusion after A metastatic disease; adjuvant
Cycles repeated q 3 wk, maximum chemotherapy (without
10 cycles anthracyclines) allowed.

Latorre [45] A 50 mg/m2 i.v. bolus 1 d before T 30 23 47 70 No prior chemotherapy for

T 130-250 mg/m2 i.v., 3-h infusion metastatic disease; adjuvant
Cycles repeated q 3 wk chemotherapy allowed.

Phase III trials CR PR OR

Sledge [24] A 60 mg/m2 or 230 NR NR 47 First-line therapy; adjuvant

T 175 mg/m2/24 h or chemotherapy allowed other
A+T, 50 mg/m2 and 150 mg/m2/24 h than A or T.

Abbreviations: T = paclitaxel; A = doxorubicin; NR = not reported; CR = complete response; PR = partial response; OR = overall response.

combination of the two. For patients enrolled on either sin-
gle-agent arm, crossover to the other agent was allowed at
disease progression. In this trial, the concurrent administra-
tion of paclitaxel and doxorubicin was not associated with
any greater cardiac toxicity than that observed with single-
agent doxorubicin. With respect to response, the combina-
tion had an overall response rate of 47%, statistically higher
than either paclitaxel (34%) or doxorubicin (36%) as single
agents. The crossover design resulted in a similar survival
rate in the three study arms, independent of randomization
assignment [24]. Also, analysis of the crossover responses
revealed that 22% of patients responded to paclitaxel fol-
lowing progression on doxorubicin, and that 20% of
patients responded to doxorubicin after progression on
paclitaxel.
In addition to limiting the cumulative dose of doxorubicin,
several other avenues aimed at reducing the risk of cardiac tox-
icity are under investigation [74]. These include adjusting the
timeframe between doxorubicin and paclitaxel administration,
[42, 75], and evaluation of the use of cardioprotective agents
[76]. Studies are also evaluating the combination of paclitaxel
with epirubicin, a reputedly less cardiotoxic anthracycline [77].
The combination of paclitaxel and doxorubicin is highly
active in the treatment of advanced and metastatic breast can-
cer. Due to cardiac toxicity considerations, it is recom-
mended that the cumulative dose of doxorubicin not exceed
380
380 mg/m2. Therefore, a regimen of paclitaxel 175 mg/m2 by
3-h infusion with doxorubicin 50 to 60 mg/m2 every three
weeks for four to six cycles is a reasonable option. Ongoing
clinical trials will further define the role of combination
paclitaxel and doxorubicin in advanced breast cancer.
Two European phase III trials are comparing pacli-
taxel/anthracycline combinations with cyclophosphamide/
anthracycline combinations. EORTC 10961 is evaluating
a paclitaxel/doxorubicin combination in comparison with
a cyclophosphamide/doxorubicin combination as first-line
metastatic therapy. An MRC-UK Coordinating
Committee on Cancer Research trial (AB01) is conducting
a similar comparison using epirubicin as the anthracycline
agent.
Paclitaxel and Epirubicin
Epirubicin, a stereo-
Overall, while the combination of
isomer of doxorubicin, paclitaxel and cisplatin is
is associated with a
comparatively lower active in patients with advanced
rate of cardiotoxicity.
Although this agent is breast cancer, serious toxicity
not currently available
in the United States, it concerns, particularly neurotoxicity,
had been studied in
combination with pacli- preclude its general use.
taxel in Europe and
South America [77-84]. As first-line therapy for
metastatic disease, overall response rates of 43%-85%,
with complete responses of 0%-29%, have been
reported [77-84]. In two of the studies, cardiotoxicity
was encountered, but, in general, clinical cardiotoxicity
has been low.
Paclitaxel and Mitoxantrone
Paclitaxel has also been studied in combination with the
anthracenedione mitoxantrone [85-87]. Overall response
rates of 56%-69% were observed in patients with advanced
disease. As first-line therapy, the combination resulted in a
69% overall response rate, with a 25% complete response
rate [87]. Therapy was generally well tolerated.
Paclitaxel/Platinum Compound Combinations
Paclitaxel has been investigated with both cisplatin and
carboplatin as first-line therapy and salvage therapy in
patients with metastatic breast cancer. The combination of
paclitaxel with a platinum agent is familiar in the setting of
lung cancer and ovarian cancer. Unlike cisplatin, carbo-
platin does not share the potential for overlapping neuro-
toxicity with paclitaxel [88], and may be the preferred
platinum for combination studies.
Paclitaxel in Breast Cancer
Paclitaxel and Cisplatin
First-line therapy with paclitaxel and cisplatin therapy
has had variable results. Gelmon et al. reported a response
rate of 85% with a novel paclitaxel/cisplatin combination in
which both agents were administered biweekly at modestly
reduced doses (90 mg/m2 and 60 mg/m2, respectively) [56].
However, two confirmatory trials by the ECOG and
Hoosier Oncology Group using the same doses and sched-
ule as first-line therapy for metastatic cancer failed to
achieve comparable response rates, and severe and life-
threatening toxicity occurred in 38% and 50% of the patients,
respectively [57, 65]. In the ECOG study, the overall
response rate was only 21% [65]. In another phase II study,
significant dose-limiting neurotoxicity was an issue [59].
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In patients previously
treated with anthracy-
clines, the combination of
paclitaxel and cisplatin
has been shown to be
active, but not without
toxicity. In one study of
17 patients, a relatively
low dose of paclitaxel,
135 mg/m2, was adminis-
tered with cisplatin, and
although an 89% overall
response rate was
attained, three patients had to be withdrawn from the study
due to toxicity [89]. In a more recent study using the same
dosages of the paclitaxel/cisplatin combination in anthra-
cycline-resistant relapsing patients, a response rate of only
35% was observed [64].
Overall, while the combination of paclitaxel and cis-
platin is active in patients with advanced breast cancer,
serious toxicity concerns, particularly neurotoxicity, preclude
its general use.
Paclitaxel and Carboplatin
Carboplatin is a derivative of cisplatin that offers an
improved toxicity profile. The renal, neurologic, ototoxic,
and emetic effects of carboplatin are substantially reduced
compared with those of cisplatin. Carboplatin as a single
agent is active in metastatic breast cancer, with response
rates of 25%-35% in previously treated patients and 37% in
untreated patients [90, 91].
Early results of the combination of paclitaxel/carbo-
platin as first-line metastatic treatment are promising [58,
60, 61]. The combination appears to be tolerable, with less
hematopoietic toxicity than expected based on the expected
toxicities of each agent [92]. In a multi-institutional phase II
trial conducted by the North Central Cancer Treatment Group
Perez
(NCCTG), treatment with paclitaxel (200 mg/m2 over 3 h) fol-
lowed by carboplatin AUC 6 resulted in a 62% overall
response rate; median survival time had not been reached
but was >16 months. Therapy was well tolerated, with a low
incidence of serious leukopenia and neurotoxicity. These
results are similar to those reported by Fountzilas et al., who
administered paclitaxel 175 mg/m2 with carboplatin AUC 6
every three weeks, and reported an overall response rate of
53% [60]. In a separate study, Fountzilas et al. also evaluated
a slightly different schedule, paclitaxel 200 mg/m2 with carbo-
platin AUC 7 every four weeks with G-CSF support, in anthra-
cycline-resistant advanced breast cancer patients [61]. The
overall response rate was 43%, with a median overall survival
of 11.1 months. Again, therapy was well tolerated, with 71%
of cycles delivered on schedule. Clearly, paclitaxel in combi-
nation with carboplatin is an active and well-tolerated regimen
deserving of continued study.
Paclitaxel/Other Agent Combinations
Paclitaxel and 5-FU
The combination of paclitaxel and 5-FU with leucovorin
has been evaluated in several studies and is considered by
many to be an option for patients who have already received
their maximum lifetime anthracycline dose or for whom
anthracycline-based therapy is not desirable. Several phase II
trials have evaluated the paclitaxel/5-FU combination in
previously treated patients (including heavily pretreated
patients and patients with anthracycline exposure or resis-
tance) and have demonstrated overall response rates of
52%-54%, including 50%-55% response rates in patients
previously treated with anthracyclines [49, 50]. Treatment
was well tolerated.
However, the triple combination paclitaxel/5-
FU/mitoxantrone, while producing an overall response rate
of 51% in patients receiving first- or second-line metastatic
therapy, was associated with unexpectedly severe myelo-
suppression, with 76% of cycles resulting in grade 3 or 4
leukopenia. Four treatment deaths were reported [93].
Klassen et al. reported a trial of first-line treatment of
weekly high-dose 5-FU plus leucovorin combined with cis-
platin 50 mg/m2 on days 1 and 22 and paclitaxel 175 mg/m2
on days 0 and 21 of a 50-day cycle [94]. An overall response
rate of 83%, with a complete response rate of 29%, was
observed and although generally tolerable, the regimen was
associated with mild to moderate cumulative neurotoxicity.
A recent phase II trial of weekly paclitaxel 80 mg/m2
with weekly 5-FU/leucovorin reported an overall response
of 47% as first-line therapy for metastatic breast cancer [95].
Toxicity was moderate, with dose reductions necessary by
week 4 in many patients secondary to neutropenia.
381
Other Agents
Other agents with which paclitaxel is being investigated
in metastatic breast cancer include cyclophosphamide,
vinorelbine, and gemcitabine. These studies are still pre-
liminary, and it is not yet clear what role such combinations
will play in therapy.
As with doxorubicin and cisplatin, a sequence-dependent
toxicity has been observed with the paclitaxel/cyclophos-
phamide combination [52]. More severe toxicity was seen in
courses in which paclitaxel was administered first. In a pilot
study of this combination, the overall response rate was 64%,
with 29% complete responses; however, 88% of patients
required hospitalization for neutropenic fever [96]. Another
study revealed more modest antitumor activity, with overall
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response rates of 25% and 50%, respectively, in patients with
and without prior chemotherapy for metastatic disease [97].
The response rate in women with anthracycline-resistant
disease was 8%.
Vinorelbine acts primarily at the level of microtubules
and the mitotic spindle. Its action is distinct from that of pacli-
taxel, and the two agents have been tested as a combination.
Both drugs cause neurotoxicity. In two phase II combination
trials, paclitaxel was administered at the relatively low dose of
135 mg/m2, resulting in 35%-43% overall response rates [98,
99]. In both studies, the complete response rate was 7%.
Although an overall response rate of 53% was seen in anthra-
cycline-resistant patients in one of the studies, life-threatening
dehydration occurred in 3% of patients [99]. In a study of
paclitaxel and vinorelbine as first-line treatment, the response
rate was 76%, with 14% complete remissions [100].
Preliminary results from a phase II trial in which paclitaxel
and gemcitabine, a nucleoside analog, were administered in a
biweekly schedule to anthracycline-resistant patients indicated
a response rate of 41%, with 9% complete responses [101].
One reversible episode of cardiac toxicity was observed.
Combination Chemotherapy/Monoclonal Antibody Therapy
Paclitaxel and Anti-HER2 Antibody
A trial that has recently generated much notice is the com-
bination of the anti-HER2 antibody, trastuzumab
(Herceptin®), with chemotherapy in patients with metastatic
breast cancer overexpressing the HER2 receptor [102]. In this
multinational controlled phase III trial, patients were treated
with either combination doxorubicin 60 mg/m2 or epirubicin
75 mg/m2 with cyclophosphamide 600 mg/m2, or with pacli-
taxel 175 mg/m2 by 3-h infusion if they had already received
adjuvant anthracycline therapy. Patients in each group were
then stratified to receive anti-HER2 antibody therapy in addi-
tion to chemotherapy. A total of 469 patients were enrolled.
The overall response rate to all chemotherapy with anti-HER2
382
antibody was 48%, with a median time to progression of 7.6
months, higher than chemotherapy without the antibody
(overall response 32%, median time to progression 4.6
months, p = 0.001). Specifically for paclitaxel, the overall
response rate with antibody was 42%, with a time to progres-
sion of 6.9 months, statistically greater than paclitaxel alone,
which had an overall response rate of 16% (p = 0.001) and a
three-month median time to progression (p = 0.0001).
Although the overall response rate for paclitaxel alone was
low, it may have been a result of prior selection for anthracy-
cline-pretreated patients along with the impact of tumors that
overexpressed HER2. For the combination of doxorubicin
and cyclophosphamide, the overall response rate was 52%
with anti-HER2 antibody and 43% without (p = 0.0025), with
median time to progression of 8.1 months and 6.1 months (not
statistically different), respectively. Of concern, the incidence
of symptomatic cardiac toxicity (NYHC CHF grade III-IV)
was higher than expected, 16%, in patients who had received
anthracycline and cyclophosphamide with antibody as com-
pared with those who received no antibody, 2%. Cardiac tox-
icity was not increased in the paclitaxel-treated patients, with
0% incidence of symptomatic cardiac toxicity observed in the
paclitaxel-alone arm and a 2% incidence in the patients
receiving paclitaxel with anti-HER2 antibody.
The exact mechanism underlying the increased incidence
of cardiac events in the anthracycline/cyclophosphamide plus
anti-HER2 antibody arm has not been fully elucidated; how-
ever, it does appear that this increased incidence is related to
concurrent administration of the agents. Because of concerns
of cardiac toxicity when the antibody was combined with
anthracycline/cyclophosphamide, it was suggested that future
studies administering concurrent chemoimmunotherapy with
anti-HER2 antibody focus on paclitaxel-based therapy.
Currently, clinical trials of paclitaxel and anti-HER2 anti-
body are being developed for patients with locally advanced
breast cancer, as well as trials of doxorubicin/cyclophos-
phamide with dexrazoxane and anti-HER2 antibody. Along
with these agents, combination antibody therapy with other
drugs, such as carboplatin, may be warranted. It is clear that
evaluation of chemotherapy/antibody trials in breast cancer
will be a priority in the coming years.
PACLITAXEL IN ADJUVANT THERAPY
While the majority of breast cancer patients present with
disease confined to the breast, many subsequently relapse
and eventually succumb to metastatic disease. Accordingly,
a major goal of adjuvant chemotherapy is elimination of
micrometastatic disease likely to be present at the time of ini-
tial diagnosis. The importance of adjuvant treatment for
breast cancer has been widely accepted since the 1970s.
Further evidence supporting this view was a 1992 worldwide
Paclitaxel in Breast Cancer
meta-analysis of 10-year follow-up results from randomized
trials, which revealed significant improvements in disease-
free and overall survival in patients receiving adjuvant
chemotherapy [103].
The activity and tolerability of paclitaxel in metastatic dis-
ease has led to the investigation of this agent in the adjuvant and
neoadjuvant settings. The feasibility of including paclitaxel in
adjuvant regimens for node-positive breast cancer patients was
demonstrated in a pilot trial using a dose-intensified regimen of
doxorubicin/cyclophosphamide with granulocyte colony-
stimulating factor (G-CSF) support followed by paclitaxel
in high-risk patients with multiple positive nodes [104].
Randomized clinical trials incorporating paclitaxel have
been initiated, with one phase III trial recently reporting pre-
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liminary results and a second to complete accrual in the near
future. Trials such as these often require three to four years
to complete accrual.
Adjuvant Clinical Trials
Pilot trials have been completed at MSKCC evaluating
the addition of paclitaxel to sequential regimens of dox-
orubicin and cyclophosphamide in node-positive breast
cancer patients. The initial pilot trial evaluated treatment
with doxorubicin followed by paclitaxel followed by
cyclophosphamide compared with the sequence of doxoru-
bicin followed by cyclophosphamide, as used in a previous
MSKCC trial. Recipients of the paclitaxel-containing reg-
imen achieved a disease-free survival rate of 81% [105].
By comparison, the disease-free survival rate was 58%
among patients in the earlier trial who did not receive
paclitaxel. The toxicity of the paclitaxel-containing regi-
men was significant but manageable, necessitating hospi-
talization in 69% of patients and 17% of total cycles [106].
However, cardiotoxicity was not observed.
A second pilot trial at MSKCC evaluated a regimen of
doxorubicin followed by paclitaxel followed by cyclophos-
phamide, compared with the sequence of doxorubicin fol-
lowed by concurrent paclitaxel/cyclophosphamide [51]. With
a median follow-up time of 10 months, no relapses were
observed. The regimen delivering the three drugs sequentially
was found to be more tolerable than the regimen using
concurrent paclitaxel/cyclophosphamide [51].
As summarized in Table 4, current clinical trials are
focusing on adjuvant therapy using differing sequences of
standard chemotherapeutic agents with and without the
addition of paclitaxel to the regimens. Preliminary results
of CALGB 9344 were recently made available [107]. This
trial investigated the effects of doxorubicin dose intensifi-
cation as well as sequential therapy with paclitaxel in
women with resected, node-positive breast cancer. In the 3
× 2 factorial design, patients were randomized to receive
 Perez 383

Table 4. Adjuvant paclitaxel clinical trials

Trial Design Patients Chemotherapy Criteria Results
Completed trials DFS OS
CALGB 9344 [107] Phase III 3,170** AC Resected, n > 0 86% 95%
versus p = 0.0077 p = 0.039
AC→T 90% 97%
MSKCC [51, 105, 106] Pilot trials 112** A→C versus A→T→C; Resected, n > 0 Addition of paclitaxel resulted in improved
disease-free survival rate.
41** A→T→C versus A→TC Sequential therapy better tolerated than
combination.
Current trials Comments
NSABP-B-28 [108] Phase III 3,050** AC versus AC→T Resected (stage II/IIIA), n > 0 Ongoing
Milan (INT-23/96)* Phase III 900** A→CMF versus AT→CMF Operable (stage II/III), tumor >2 cm Ongoing

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SWOG-S9623 Phase III 1,000** A→T→C versus AC→STAMP I or V Resected (stage II/IIIA), N4-9 Ongoing
CALGB C9741 Phase III 1,584** A→T→C versus AC→T Operable (stage II/IIIA), N1-2 Ongoing

Abbreviations: A = doxorubicin; C = cyclophosphamide; T = paclitaxel; M = methotrexate; F = 5-FU; STAMP I = cyclophosphamide/cisplatin/carmustine;

STAMP V = cyclophosphamide/carboplatin/thiotepa; DFS = disease-free survival; OS = overall survival.
*Neoadjuvant arm of this trial summarized in Table 5; **450 in each arm.

doxorubicin 60, 75, or 90 mg/m2 with cyclophosphamide
600 mg/m2, and then randomized again to receive continued
therapy with paclitaxel 175 mg/m2 by 3-h infusion for four
cycles or no further therapy. The trial enrolled 3,170
patients. The interim analysis reported results at a median
of 18 months’ follow-up, where it was found that the addi-
tion of paclitaxel to doxorubicin/cyclophosphamide
resulted in statistically significant increases in both disease-
free (p = 0.0077) and overall survival (p = 0.039) (Table 4).
The dose level of doxorubicin administered had no impact
on survival. No unexpected toxicities were observed, and
therapy was well tolerated overall. The authors concluded
that the addition of paclitaxel to standard therapy with dox-
orubicin and cyclophosphamide significantly improved sur-
vival outcomes at the time of analysis. Reports of results at
longer follow-up intervals are eagerly awaited to better
define the impact of sequential paclitaxel therapy in these
patients.
NSAPB study B-28 is also evaluating the effect of the
addition of sequential paclitaxel to doxorubicin/cyclophos-
phamide therapy in patients with resected, node-positive
breast cancer. The target accrual for the study, over 3,000
patients, has been met; data analyses are pending [108].
A phase III trial in progress at the Istituto Nazionale
Tumori of Milan is comparing a treatment sequence consist-
ing of doxorubicin/paclitaxel followed by cyclophosphamide/
methotrexate/5-FU (CMF) with an otherwise identical regi-
men omitting paclitaxel. This trial involves previously
untreated stage II/III breast cancer patients with tumors
exceeding 2 cm in maximum diameter.
The Southwest Oncology Group (SWOG) is leading a
randomized multicenter phase III Intergroup trial (S9623)
comparing a regimen of sequential doxorubicin, paclitaxel,
and cyclophosphamide with a regimen of concurrent stan-
dard-dose doxorubicin/cyclophosphamide followed by high-
dose cyclophosphamide/cisplatin/carmustine (STAMP I)
or cyclophosphamide/carboplatin/thiotepa (STAMP V) with
autologous stem cell rescue. Study participants are previously
untreated stage II/IIIA breast cancer patients with involvement
of four to nine axillary lymph nodes.
Accrual commenced in late 1997 for a randomized
Intergroup trial (CALGB C9741) of adjuvant therapy in pre-
viously untreated node-positive, stage II/IIIA breast cancer
patients. The sequence of doxorubicin followed by paclitaxel
followed by cyclophosphamide is being compared with a
regimen of concurrent doxorubicin/cyclophosphamide fol-
lowed by paclitaxel. In addition to comparing two different
sequences of administration of the chemotherapeutic agents,
CALGB C9741 will compare a shorter, more dose-dense
intertreatment interval of 14 d with an interval of 21 d.
Neoadjuvant Clinical Trials
Novel chemotherapeutic strategies that prove successful
in the metastatic and adjuvant settings may potentially also
find application in neoadjuvant treatment. By diminishing
primary tumor size, neoadjuvant therapy may allow a patient
to undergo more conservative surgery or even render an oth-
erwise inoperable patient operable. Also, therapy may impact
local and distant relapse [109]. Neoadjuvant paclitaxel treat-
ment is under study in a number of clinical trials (Table 5).
384
Table 5. Neoadjuvant paclitaxel clinical trials
Trial Design Patients
Phase II
Austrian Multicenter Phase II 33
Brown University Phase II 39
Oncology Group
Mayo/USC Phase II 40
Mayo/USC Phase II 40
Phase III
MDACC Phase III 104
Milan (INT-23/96)* Phase III 450
Abbreviations: F = 5-FU; A = doxorubicin; C = cyclophosphamide; T = paclitaxel; M = methotrexate; RT = radiation therapy.
*Adjuvant arms of this trial summarized in Table 4.
Follow-up is ongoing in a prospective randomized trial
at MDACC, evaluating neoadjuvant paclitaxel versus 5-
FU/doxorubicin/cyclophosphamide (FAC) in patients with
operable breast cancer [110]. Preliminary data suggest that
paclitaxel alone is comparable in antitumor activity to
FAC in the treatment of early breast cancer. The extent of
cytoreduction was similar with the two induction regimens,
both of which were well tolerated. However, paclitaxel
treatment was associated with an increased incidence of
neutropenic fever.
The previously described trial at the Istituto Nazionale
Tumori of Milan includes a neoadjuvant arm. The trial is
investigating neoadjuvant doxorubicin/paclitaxel followed
by CMF in patients with operable stage II/III breast cancer.
An Austrian multicenter, open-label, dose-escalating
phase II trial of neoadjuvant paclitaxel has been completed
[111]. An overall response rate of 61% was observed in
patients treated with paclitaxel 250 mg/m2 for a minimum of
four cycles or best response, followed by surgery. Among the
33 study patients, neoadjuvant paclitaxel allowed modified
radical mastectomy to be performed in 23 and partial resection
in eight. Three of the nine patients originally with T3 disease
were able to be downstaged.
An ongoing phase II trial of neoadjuvant paclitaxel in
patients with locally advanced or metastatic disease is being
carried out by investigators at Brown University [31, 110].
This dose-intense regimen delivers weekly paclitaxel 175
mg/m2 by 3-h infusion for six weeks of an eight-week cycle.
Of 14 evaluable patients with locally advanced disease,
three achieved a complete remission and eight had partial
responses. Hematologic toxicity was manageable. Patients
experiencing neurotoxicity improved with interruption of
paclitaxel therapy, and dose reductions allowed patients to
Paclitaxel in Breast Cancer
Chemotherapy Criteria Status
T Stage T3-4, N0-3, M0 Completed
T Locally advanced or metastatic Ongoing
T Stage T2-3 Ongoing
T (biweekly with RT) Locally advanced Ongoing
FAC versus T Stages T2-3, N0-1, M0 Fully accrued;
in follow-up.
AT→CMF Operable (stage II/III), tumor > 2 cm Ongoing
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continue treatment with stable or improving neurologic
symptoms.
A phase II trial of neoadjuvant weekly paclitaxel during
radiation therapy is being conducted in patients with locally
advanced breast cancer by investigators at the University of
Southern California (USC) and Mayo Clinic Jacksonville.
Patients will receive paclitaxel 30 mg/m2 over 1 h twice
weekly during radiation therapy and prior to surgery. This
approach may gain advantage from the radiosensitizing
activity of paclitaxel. The endpoints of the trial will be
the pathologic assessment of tumor response at mastec-
tomy and evaluation of cellular and molecular correlates
associated with pathologic response. These endpoints
will also be assessed in a pilot trial at USC, New York
University (NYU) and Mayo Clinic Jacksonville of
neoadjuvant paclitaxel therapy in T2 premenopausal
breast cancer patients.
CONCLUSIONS
Paclitaxel is among the most effective agents in the treat-
ment of breast cancer. Both as a single agent and in combina-
tion regimens, paclitaxel is effective as first-line therapy and as
salvage therapy in patients with advanced disease. Paclitaxel
has also demonstrated efficacy in patients who have received
prior anthracycline therapy and those with anthracycline-resis-
tant disease. In the adjuvant setting, data from a randomized
study have supported the sequential use of paclitaxel after ther-
apy with doxorubicin and cyclophosphamide for patients with
node-positive disease.
The unique mechanism of action of paclitaxel and its
relatively well-tolerated toxicity profile have made it a can-
didate for combination therapy with other active agents in
breast cancer. Combination regimens with paclitaxel and
Perez
anthracyclines have demonstrated very good response rates.
With doxorubicin, however, one must be aware of the poten-
tial for undue cardiac effects and limit the cumulative dox-
orubicin dose to 380 mg/m 2 or lower. In Europe,
combination therapy with epirubicin has produced promis-
ing results; these may be of particular interest to clinicians
in the U.S. as epirubicin may soon become available in this
country.
With respect to platinum agents, combination paclitaxel
and carboplatin has produced very high response rates as first-
line therapy in patients with metastatic disease. The combina-
tion is also effective in patients who have failed anthracycline
therapy. Combination therapy with cisplatin, while potentially
active, is associated with an undesirable rate of toxicity.
Combination regimens with other agents, including 5-FU,
vinorelbine, and gemcitabine also appear to be promising.
Recent phase III studies have helped define the opti-
mal dose and schedule of paclitaxel in advanced breast
cancer. CALGB 9342 did not detect a dose-response rela-
tionship in either overall response or overall survival
among doses of 175, 210, or 225 mg/m2 by 3-h infusion.
Given that hematologic and neurologic toxicities
increased with dose, a recommendation for a paclitaxel
dose of 175 mg/m2 was made. NSABP study B-26 and a
trial at MDACC evaluated the effect of schedule on pacli-
taxel efficacy. Although the overall response rate in
NSABP B-26 was higher with the 24-h schedule than with
the 3-h schedule, no survival advantage was observed. In
the MDACC study of 3 h versus 96 h of paclitaxel, no dif-
ference in response or survival was observed. As a result,
the 3-h schedule of paclitaxel was deemed more appropri-
ate, considering the logistics and hematologic toxicities
encountered with the longer schedules. Taken together, a
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385
dose of 175 mg/m2 by 3-h infusion every three weeks
appears to be very reasonable in the treatment of advanced
breast cancer. In combination therapy, this dose is often
easily combined with other agents, producing manageable
toxicity and not usually requiring hematopoietic growth
factor support.
The issue of weekly paclitaxel is particularly intriguing,
as it appears that this schedule allows for a greater dose den-
sity while disassociating from a common toxicity, neutrope-
nia. Trials with moderate-dose weekly paclitaxel (80-100
mg/m2) have observed very good response rates with remark-
ably little toxicity, even in heavily pretreated patients.
Neutropenia is generally mild, and neuropathy, although
more common, is generally less than grade 2. Further investi-
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gation into the role of weekly paclitaxel, both as a single agent
and as part of combination and sequential therapy, is ongoing.
Finally, the addition of paclitaxel to anti-HER2 antibody
therapy has resulted in much interest over the response and tol-
erability of this combination. This trial not only demonstrates
the improved efficacy of combination antibody therapy with
traditional chemotherapy in advanced breast cancer, it her-
alds the arrival of a new and anxiously awaited class of anti-
cancer agents. Much activity in this area is expected in the
coming years.
In summary, paclitaxel is effective in the treatment of
breast cancer on a number of different levels. It has proven
efficacy in the advanced and metastatic settings as well as in
adjuvant treatment. The drug may be used as a single agent, as
sequential therapy, or in combination with other chemotherapy
agents and immunologic agents. Therapy on weekly and
every-three-week schedules has been effective. Ongoing trials
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