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Paclitaxel and Gemcitabine as Salvage Treatment in Metastatic Breast Cancer

Paclitaxel and Gemcitabine as Salvage Treatment in Metastatic Breast Cancer

ABSTRACT: Both paclitaxel and gemcitabine (Gemzar) have shown activity and manageable toxicity when used as single agents in heavily pretreated patients with metastatic breast cancer. This phase II study evaluated their use in combination for metastatic breast cancer patients whose disease recurred or progressed following treatment with anthracyclinecontaining regimens. Twenty-nine patients ranging from 32 to 68 years of age received paclitaxel at 175 mg/m² IV over 3 hours on day 1 and gemcitabine at 1,000 mg/m² IV on days 1, 8, and 15 every 28 days. Because of unacceptable thrombocytopenia in the first five patients, the gemcitabine schedule was changed to days 1 and 8 of a 21-day cycle for the remainder of the study. All 29 patients were evaluable for response and toxicity. Seventeen patients (59%) were considered truly anthracycline- or anthracenedione-refractory. A total of 137 cycles (median: 4 per patient) were administered. The regimen was well tolerated. Grade 3/4 thrombocytopenia was observed in 5 (18.5%) of the first 27 cycles and in 6 (5.4%) of the 110 cycles following dosage reduction (P = .04). Five patients had grade 1 and two patients had grade 3 neuropathy. Eight patients had grade 3 neutropenia, two had grade 4 neutropenia with fever at the higher dosage, and eight had grade 1/2 myalgia and fatigue. Five patients (17%) had a complete response and 11 (38%) a partial response, yielding an objective response rate of 55% (95% confidence interval = 36%–73%). Six patients (20.7%) had stable disease. Median response duration was 8 months (range: 4–26 months), and median overall survival was 12 months (range: 4–48+ months). Survival at 1, 2, 3, and 4 years was 45%, 30%, 20%, and 10%, respectively. The combination of paclitaxel on day 1 with gemcitabine on days 1 and 8 of a 21-day cycle appears to have promising activity in heavily pretreated patients with metastatic breast cancer. Phase III trials comparing this promising doublet to paclitaxel monotherapy and to other chemotherapeutic strategies for advanced breast cancer will clarify the role of this regimen.

Treatment of refractory metastatic
breast cancer remains a
major challenge to the medical
oncologist. Second-line treatment after
failure of initial chemotherapy is
primarily palliative.[1] Although objective
responses can be produced with
various drug combinations in about
20% to 40% of cases, nearly all patients
tend to show rapid tumor progression.[
2,3] Therefore, efforts at improving
the outcome of patients with
this disease are of major interest.

Previous TrialsPaclitaxel as Monotherapy
Paclitaxel, a novel antimicrotubule
agent derived from the bark of the
western yew Taxus brevifolia, is one
of the most active anticancer drugs
introduced into the clinic during recent
years.[4] Unlike other microtubule
poisons in use, such as vincristine
and vinblastine, paclitaxel promotes
the formation of tubulin dimers
and stabilizes microtubules against depolymerization,
resulting in growth
inhibition and loss of cell viability.[5,6]

Early phase II trials of paclitaxel
revealed significant antitumor activity in various types of solid tumors, including
ovarian,[7] non-small-cell
lung,[8] and head and neck[9] carcinomas.
In previously treated metastatic
breast cancer patients, paclitaxel
given at doses ranging from 135 to 250
mg/m2 has produced objective responses
in 30% to 60% of cases.[10]

In a phase II trial performed at
Memorial Sloan-Kettering Cancer
Center, where 250 mg/m2 of paclitaxel
was given as initial therapy for advanced
disease as a continuous IV infusion
every 21 days with hematologic
support (recombinant human granulocyte
colony-stimulating factor), objective
responses were documented in 16
(62%) of 26 evaluable patients, including
three (12%) complete responses.
Although neutropenia was the doselimiting
toxicity, the incidence of
life-threatening infectious complications
in that study was considered

These observations were confirmed
in other phase II trials, where 175 to
250 mg/m2 of the drug was given as a
3-hour IV infusion.[12,13] With the
confirmation of initial reports of the
antitumor activity of single-agent
paclitaxel in metastatic breast cancer
patients who have undergone prior
chemotherapy, interest in this agent
has increased substantially.[9-12]

Nabholtz et al,[14] in a multicenter
randomized trial, compared two different
doses of paclitaxel given as a
3-hour infustion in patients with metastatic
breast cancer who had failed to
respond to previous chemotherapy. A
total of 471 patients were randomized
to receive intravenous paclitaxel at a
dose of 175 or 135 mg/m2 every 3
weeks. Better treatment results were
achieved with high-dose vs low-dose
paclitaxel: overall response rate, 29%
vs 22% (P = .108); complete response
rate, 5% vs 2% (P = .088); median
time to disease progression, 4.2 vs 3.0
months (P = .027); and median survival
time, 11.7 vs 10.5 months (P =
.321). Patients previously exposed or
resistant to anthracyclines were as
likely to respond as those without such
prior exposure.

Treatment was well tolerated, as
documented by the number of administered
treatment courses (median, 6
[range:1-17] vs 5 [range:1-18]), the
low frequency of dose reductions
(14% vs 7%, P = .024), and the small
number of patients (n = 9 [4%] vs n =
5 [2%]) who required treatment discontinuation
for adverse reactions.
The incidence and severity of neutropenia
and peripheral neuropathy were
dose-related. After quality-of-life adjusted
time-to-progression analysis,
the 175 mg/m2 arm retained its advantage
over the 135 mg/m2 arm.

Follow-up studies have not only
confirmed the partial lack of clinical
cross-resistance between paclitaxel
and anthracyclines, but have also revealed
its significant single-agent activity
in nonpretreated patients.[10,11]
Indeed, paclitaxel can be considered
at least as active as doxorubicin when
used as a single agent in phase II trials
that have been conducted in patients
with metastatic breast cancer. For that
reason, it has been progressively incorporated
into experimental combination
regimens for both first-line and salvage
treatment of this disease.[15-19]

Gemcitabine as Monotherapy
Gemcitabine (Gemzar) is a novel
nucleoside analog of deoxycytidine
with a broad range of activity against
various tumors and an especially favorable
toxicity profile, including mild
myelosuppression and minimal
nonhematologic toxicity.[20] Several important phase II studies of singleagent
gemcitabine as first- or secondline
chemotherapy have been conducted
in patients with metastatic
breast cancer.

In a US study,[21] gemcitabine at
1,200 mg/m2, given on days 1, 8, and
15 as first-line palliative therapy,
achieved an overall response rate of
46% (2 complete responses and 10
partial responses among 26 evaluable
patients). The same gemcitabine regimen
administered to patients who received
a prior anthracycline-based
regimen resulted in a remission rate
of 30% (2 complete and 6 partial responses
among 27 evaluable patients).[22]

In a study known as the "European"
study,[23] gemcitabine was given as
first- or second-line therapy at a mean
dose of 725 mg/m2 once weekly for 3
weeks, followed by a rest period of 4
weeks. Although this dose was relatively
low, patients had a remission
rate of 25% (3 complete and 7 partial
responses among 40 evaluable patients).
A study was initiated that used
a similar regimen but a higher
gemcitabine dose (1,000 mg/m2) on
days 1, 8, and 15 of a 4-week
cycle.[24] Of the 40 patients evaluable for response, there were three complete
and seven partial responders, for
an overall response rate of 25%.
Twenty-six of these patients had received
prior chemotherapy (including
seven in the adjuvant setting). All patients
had stage IV disease. Median
survival reported in these two studies
was 11.5 months.

In a recent study that used the same
gemcitabine regimen, no complete responses
were observed, but there were
six partial responses, for an overall
response rate of 14.3% among 42
evaluable patients.[25] Median survival
for all 42 patients was 15.2
months. Patients received up to one
prior chemotherapy regimen in the
adjuvant setting. The majority of patients
(67%) had visceral disease at
study entry.

In these phase II studies, hematologic
and nonhematologic toxicities
with single-agent gemcitabine treatment
were mild, with neutropenia being the
most clinically relevant untoward event.
Treatment delays or withdrawals from
treatment were infrequent.

Considering the single-agent activity
of both paclitaxel and gemcitabine
in metastatic breast cancer patients,
their different mechanisms of action,
and their distinct nonhematologic toxicity
profile, we designed this phase
II trial in which a combination of the
two drugs was evaluated as salvage
therapy in patients failing first- or second-
line chemotherapy regimens.

Patients and MethodsEligibility Criteria
Eligible patients had histologically
confirmed metastatic breast cancer
with bidimensionally measurable disease.
All had already received first- or
second-line therapy with an anthracycline-
containing regimen, but had
no prior exposure to paclitaxel or gemcitabine.
Other eligibility criteria included
an Eastern Cooperative Oncology
Group (ECOG) performance status
of 0 to 2, age > 70 years with an
anticipated life expectancy > 12 weeks,
adequate renal and hepatic function, no
active infection, no central nervous system
involvement or evidence of carcinomatous
meningitis, white blood cell
count ≥ 4 * 109/L, absolute neutrophil
count ≥ 2 * 109/L, hemoglobin level
≥ 10 g/dL, platelet count ≥ 130 * 109/L,
and signed written informed consent.

Exclusion criteria included a history
of prior malignancy other than
nonmelanoma skin cancer or cervical
carcinoma in situ, significant cardiac
disease, and a history of or existing
peripheral neuropathy. Prior radiation
completed at least 4 weeks from the date
of study registration was permitted, as
long as it encompassed less than 30%
of the total marrow-bearing skeleton.
Any hormonal therapy was discontinued
at least 3 weeks before study entry.

Treatment Plan
Twelve hours before administration
of paclitaxel, all patients were given
oral 8 mg of dexamethasone. This dose
was repeated IV 15 minutes before
paclitaxel was started. In addition, dimenhydrinate
at 100 mg IV, ranitidine
at 50 mg IV, and promethazine at
50 mg intramuscularly were given 30
minutes prior to paclitaxel administration.

Treatment on day 1 consisted of
paclitaxel at 175 mg/m2 IV (diluted in
500 mL of 0.9% normal saline and
infused over a period of 3 hours), followed
by gemcitabine at 1,000 mg/m2
IV (diluted in 250 mL of 0.9% normal
saline). On day 8, gemcitabine
alone was given at the same dose
(schedule G-1,8). Cycles were repeated
every 21 days on an outpatient
basis for a maximum of eight cycles.
In the first five patients, gemcitabine
was given at the same dose on days 1,
8, and 15 every 28 days (schedule G-
1,8,15). However, this produced an
unacceptable level of thrombocytopenia,
and the regimen was modified to
G-1,8 every 21 days.

Cycles were repeated if the neutrophil
count exceeded 1 * 109/L and
platelet count exceeded 120 * 109/L.
If either of these hematologic parameters
were not within their respective
range on the scheduled treatment day,
therapy was delayed for a week. If after
a delay of 2 weeks these values
were still not in the appropriate range,
the patient was removed from the
study. The doses of paclitaxel and
gemcitabine were reduced by 50% in
the treatment cycle if febrile neutropenia
occurred or if a neutrophil count
nadir < 0.5 * 109/L or platelet count
nadir < 50 * 109/L was documented.
Patients with progressive disease after
the second cycle and those whose
disease stabilized or progressed after
the fourth cycle of chemotherapy were
also removed from the study.

Pretreatment Evaluation
and Follow-up Studies

Before protocol enrollment, all patients
underwent a complete history
and physical examination. Laboratory
evaluation included a complete blood
count (CBC) with differential and
platelet count, a urinalysis and biochemical
profile, determination of serum
CA 15-3 and lactate dehydrogenase
levels, a baseline electrocardiogram,
assessment of ECOG performance
status, chest x-ray, and ultrasound
examination and computed tomography
of the abdomen and suspicious
areas, including a bone scan. A
CBC was repeated on day 8 and day
15, initially, of each cycle. Physical
findings, ECOG performance status,
CBC with differential and platelets, biochemical
profile, and serum CA 15-3
were reevaluated after each cycle.
Complete tumor measurements were
documented at the end of the second
cycle and again at the end of the study.
Patients responding to therapy had to
repeat the evaluation 4 weeks later
using the same methods for response

Response Criteria
All eligible patients were considered
for response analysis. Lesions
(eg, metastatic pulmonary nodules,
lymph nodes, subcutaneous masses,
and hepatic metastases) had to be measurable
in two dimensions with rulers
or calipers, and their surface area was
determined by multiplying the longest
diameter by the greatest perpendicular
diameter. Bone lesions only
were not considered measurable disease.
For multiple lesions, total tumor
size was defined as the sum of the
products of the largest perpendicular
diameters of each lesion.[26]

The definition of response was
based on World Health Organization
(WHO) recommendations.[27] Complete
response meant the complete disappearance
of all known disease determined
by two observations made no
less than 4 weeks apart, without the
appearance of a new lesion. Partial
response was documented by a decrease
of at least 50% (for bidimensionally
measurable lesions) of the
sum of the products of the two perpendicular
diameters of all measured
lesions and no new lesion or progression
of any lesion, based upon two
observations made no less than 4
weeks apart. No change was considered
a decrease of > 50%, or < 25%
increase in the sum of the products of
the two perpendicular diameters of all
measured lesions and no new lesions.
Progressive disease meant an increase
of at least 25% in the size of at least one
measurable lesion or the appearance of
a new lesion. The occurrence of pleural
effusion or ascites was also considered
progressive disease if documented by
positive cytology. Pathologic fracture
was not automatically considered evidence
of disease progression.

Evaluation of Adverse Events
Any patient who had received at
least one course of paclitaxel/
gemcitabine was evaluable for safety
and toxicity. The type and severity of
these toxicities was determined using
WHO criteria.

Statistical Considerations
The two-stage phase II design described
by Gehan was applied to this
study.[28] The 95% confidence intervals
(CI) for response rates were calculated
using the binomial theorem.
Survival and response duration were
calculated using the Kaplan-Meier
method, using a microcomputer-assisted

ResultsPatient Characteristics
Twenty-nine patients with a median
age of 46 years (range: 32-68 years)
were enrolled. All were considered
eligible for evaluation of response and
toxicity. Patient characteristics are
summarized in Table 1. Previous chemotherapy
included (1) fluorouracil
(5-FU), doxorubicin (Adriamycin),
and cyclophosphamide (Cytoxan,
Neosar), known as FAC (14 cases of
first-line therapy and four cases of second-
line therapy after failure of cyclophosphamide,
methotrexate, and
5-FU [CMF]); (2) 5-FU, epirubicin
(Ellence), and cyclophosphamide, or
FEC (four cases of first-line therapy);
(3) mitoxantrone (Novantrone) plus
CMF (four cases of first-line therapy);
and (4) cisplatin, vinblastine, and mitomycin
(Mutamycin) (three cases of
second-line therapy after failure of
FAC). All but four patients had a tumor
response with prior chemotherapy.
Seventeen (59%) patients
were considered truly anthracyclineor
anthracenedione-refractory (ie, they
had progressed during the use of regimens
containing these agents). The
median follow-up was 22 months.

Safety and Toxicity
A total of 137 cycles (median: 4 per
patient) were administered. Treatment
delays occurred in 13 cycles (9.5%),
and dose reductions were needed in
17 (12.4%) cycles. Cycle delays occurred
in eight cycles (5.8%) due to
thrombocytopenia and in four cycles
(2.9%) due to neutropenia. Dose reductions
due to myelotoxicity occurred
in nine cycles (6.6%). No hypersensitivity
reactions were seen.
The regimen was well tolerated
(Table 2). Nausea/vomiting (grade 1),

The regimen was well tolerated
(Table 2). Nausea/vomiting (grade 1),
alopecia (grades 2/3), and neutropenia
(grade 1) were seen in most patients.
Five patients had grade 1 and
two patients had grade 3 neuropathy.
Grade 3/4 thrombocytopenia was observed
in five (18.5%) of the first 27
cycles (schedule G-1,8,15), although
no bleeding was observed, and in six
(5.4%) of the 110 subsequent cycles
(schedule G-1,8). The difference in
frequency of grade 3/4 neutropenia
between the two dosing schedules was
significant (P = .04, Fisher's exact
test). Eight patients had grade 3 neutropenia
(5 with schedule G-1,8,15).
In addition, grade 4 neutropenia was
associated with fever in two cases and
in four cycles (schedule G-1,8,15).
Three patients received blood transfusions
due to anemia. Grade 1/2 myalgia
and fatigue were also reported in
eight patients. One patient developed
a reversible bradycardia during
paclitaxel infusion. No death due to
toxicity occurred.

Responses and Survival
There were 16 (55%) objective responses
(95% CI = 36%-73%), including
five (17%) complete responses
(95% CI = 3%-30%) and 11 (38%)
partial responses (95% CI = 19%-
56%). Six (20.7%) patients attained
disease stabilization (Table 3). Median
response duration was 8 months
(range: 4-26 months), and median
overall survival was 12 months
(range: 4-48+ months). Survival at 1,
2, 3, and 4 years was 45%, 30%, 20%,
and 10%, respectively. The overall
survival curve is depicted in Figure 1
and the response duration curve in
Figure 2.

Addition of Trastuzumab
Twenty-two patients were tested for
HER2/neu overexpression after tumor
progression. In seven, HER2/neu was
3+ positive by immunohistochemistry
analysis (HercepTest with monoclonal
antibody 4D5). For these patients we
added trastuzumab (Herceptin) at 4
mg/kg IV (loading dose), followed by
2 mg/kg IV weekly until progression
to the same regimen of paclitaxel and
gemcitabine for four additional cycles
(postprotocol therapy, at the discretion
of the treating oncologist). In three patients
(42.9%) we observed a partial response, with a median response duration
of 5 months (range: 3-11+


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