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Biweekly Gemcitabine, Doxorubicin, and Paclitaxel as First-Line Treatment in Metastatic Breast Cancer

Biweekly Gemcitabine, Doxorubicin, and Paclitaxel as First-Line Treatment in Metastatic Breast Cancer

ABSTRACT: In a single-center, open, phase II trial, we assessed the toxicity and activity of a triple combination therapy—doxorubicin at 30 mg/m2 (day 1), paclitaxel (Taxol) at 135 mg/m2 (day 2), and gemcitabine (Gemzar) at 2,500 mg/m2 (day 2 after paclitaxel)—administered biweekly in a 28-day cycle for six cycles. This was given as first-line treatment in 41 patients with metastatic breast cancer. Granulocyte colony-stimulating factor was used in 27 patients to permit maintenance of dose density. Hematologic toxicity was moderate. Nonhematologic adverse events were generally mild. The objective response rate was 82.9% (34/41) with 18 patients (43.9%) achieving complete response and 16 (38%) achieving partial response; progressive disease was observed in 4 patients (9.8%). Responses were observed at all metastatic sites, including complete responses in lung, liver, bone, and soft tissue. Median duration of response was 14.1 months and median time to progression was 13.9 months. Median survival was 26.2 months. The biweekly combination of gemcitabine, doxorubicin, and paclitaxel is safe and highly active as first-line treatment in metastatic breast cancer. [ONCOLOGY 15(Suppl 3):44-47, 2001]

Introduction

The combination of paclitaxel (Taxol) and doxorubicin is one of the more
active combinations in metastatic breast cancer.[1,2] Gemcitabine (Gemzar), too,
exhibits activity in a range of solid tumors, including breast carcinoma.[3-7]
The use of gemcitabine in combination with paclitaxel and doxorubicin is
attractive because gemcitabine has a favorable toxicity profile and is at least
partially non-cross resistant with the other agents. Early phase studies have
shown activity of the paclitaxel/gemcitabine combination in a biweekly schedule
in a variety of solid tumors[8] and as first-line treatment of metastatic breast
cancer,[9] and high response rates with the gemcitabine/ doxorubicin combination
in advanced breast cancer.[10]

A phase II study of the triple combination given every other week as
first-line treatment in metastatic breast cancer was performed. The doxorubicin
dose used in this trial was identified in a phase I study[11] of the triple
combination evaluating escalating doxorubicin doses in combination with fixed
doses of gemcitabine and paclitaxel derived from our prior experience with
biweekly gemcitabine/paclitaxel as second-line treatment in metastatic breast
cancer.[12]

Patients and Methods

Eligible patients were age 18 or older with histologically confirmed
metastatic breast cancer not suitable for curative surgery or radiotherapy,
bi-dimensionally measurable lesions, and an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 to 2. Patients also had to have a granulocyte count ³
1.5 ´ 109/L, a platelet count =
100 ´ 109/L, and adequate hepatic
and renal function. Hormonal therapy and radiotherapy were permitted as part of
adjuvant treatment; anthracyclines could have been received as part of previous
adjuvant treatment only if cumulative doses did not exceed 360 mg/m2
for epirubicin (Ellence) or 200 mg/m2 for
doxorubicin. Patients who received adjuvant anthracycline treatment were not to
receive doxorubicin in the last treatment cycle in the current study, to ensure
that a maximum doxorubicin dose of 480 mg/m2 was
not exceeded.

Dosing

Study treatment consisted of doxorubicin at 30 mg/m2
via bolus intravenous (IV) infusion on day 1, paclitaxel at 135 mg/m2
via 3-hour IV infusion on day 2, and gemcitabine at 2,500 mg/m2
via 30- to 60-minute IV infusion following paclitaxel administration on
day 2. Treatment was repeated every 2 weeks in 28-day cycles for a maximum of
six cycles.

Treatment was delayed for grade 3 or 4 hematologic toxicity until recovery of
granulocyte count to > 1.5 ´ 109/L and
platelet count to > 75 ´ 109/L.
Granulocyte colony-stimulating factor (G-CSF [Neupogen]) could be administered
to permit scheduled chemotherapy doses if the absolute neutrophil count was <
1.5 ´ 109/L on the day prior to the next
scheduled dose. The paclitaxel dose was reduced in the case of grade 3
neurotoxicity and discontinued in the case of grade 4 neurotoxicity.

Cardiac toxicity is a serious potential complication of combined doxorubicin
and paclitaxel; all patients underwent electrocardiography, chest x-ray, and
measurement of left ventricular ejection fraction at baseline after the sixth
chemotherapy cycle, and at 6-month intervals thereafter.

Patient Response

Patient responses were categorized as follows:

Complete response: if all measurable lesions were resolved.

Partial response: if there was a reduction of > 50% in lesion size
with no development of new lesions.

Progressive disease: if lesions increased by > 25% in size or new
lesions developed.

Stable disease: in the absence of any of the three categories above.

For patients with complete or partial response, duration of response was
determined as the duration from the start of treatment until disease
progression. Time to progression was determined as the duration from the start
of treatment until disease progression. Median values were calculated using the
Kaplan-Meier method.

Results

Each of the 41 patients enrolled were analyzed for toxicity and response on
an intent-to-treat basis. Patients had a mean age of 55 years (range: 33 to 68
years). ECOG performance status was 0 in 26 patients and 1 in 15. Patients with
metastatic disease included 20 (48.8%) with one metastatic site, 13 (31.7%) with
two sites, and 8 (19.5%) with three. Metastatic sites included lung in 19
patients (46.3%), bone in 19 (46.3%), soft tissue/skin in 18 (43.9%), and liver
in 11 (26.8%). The majority had received adjuvant radiotherapy or hormonal
therapy.

In total, 28 patients had received adjuvant chemotherapy, consisting of
epirubicin (17) and cyclophosphamide (Cytoxan, Neosar)/methotrexate/fluorouracil
(11). The median cumulative study dose of doxorubicin in patients who had
previously received epirubicin was 420 mg/m2, with a range of 300 to
500 mg/m2.

Toxicity

A total of 216 chemotherapy cycles were administered, with a median of six
per patient. Toxicities are shown in Table 1. Neutropenia was the most common
adverse effect, with grade 3 or 4 neutropenia occurring in 18 patients (43.9%)
and in 9.7% of chemotherapy courses; 1 patient had an episode of febrile
neutropenia. Neutropenia was of short duration in all cases.

G-CSF treatment was administered on days 5 to 10 in 27 patients (65.8%).
Grade 3 and 4 thrombocytopenia occurred in two patients (4.8%, 0.9% of cycles)
and one patient (2.4%, 0.5% of cycles), respectively. Grade 3 anemia occurred in
five patients (12.2%, 3.4% of cycles). In total, 10 units of packed red blood
cells were transfused and one patient required platelet transfusion.

Nonhematologic toxicities were generally mild, with no grade 4 toxicities
observed. Nausea/vomiting was the most common nonhematologic toxicity, with
grade 3 toxicity occurring in 14.6% of patients. Of 37 patients with at least
two measurements of left ventricular ejection fraction, three (8.1%) exhibited
decreased ejection fractions, including two who had received adjuvant epirubicin
treatment. None of these patients developed heart failure, and ejection
fractions returned to normal in two of the patients during follow-up.

In total, 21.3% of chemotherapy cycles (n = 46) were delayed, primarily due
to neutropenia. Median delivered dose intensities of the study drugs were
doxorubicin 13.8 mg/m2/wk, paclitaxel 60.3 mg/m2/wk, and
gemcitabine 1,100 mg/m2/wk. Dose reductions were required in two
patients due to mucositis and in one due to grade 3 neurotoxicity.

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