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A Phase II Study of Doxorubicin/Paclitaxel Plus G-CSF for Metastatic Breast Cancer

A Phase II Study of Doxorubicin/Paclitaxel Plus G-CSF for Metastatic Breast Cancer

ABSTRACT: This phase II trial was conducted to evaluate the percentage of objective responses and the toxicity profile of combination doxorubicin (Adriamycin) and paclitaxel (Taxol) with granulocyte colony-stimulating factor as first-line therapy for patients with metastatic breast cancer (MBC) not previously exposed to anthracycline-containing regimens. Patients with measurable, visceral-dominant MBC and a performance status of 0 to 2 were included in the study. Doxorubicin 60 mg/m² was administered as a short intravenous infusion, followed by paclitaxel 250 mg/m² as a 3-hour intravenous infusion on day 1. Granulocyte colony-stimulating factor 5 µg/kg/d was given prophylactically as a subcutaneous injection from day 2 until granulocyte recovery to 1,500/mm³ or more. Treatment was repeated every 21 days for a maximum of six courses. Dose reductions (to doxorubicin 50 mg/m² and paclitaxel 175 mg/m²) and/or treatment delay were applied in case of severe toxicity. All 25 women who entered were evaluable for response and toxicity. The main grade 3/4 toxicities observed were leukopenia, thrombocytopenia, and mucositis. Alopecia occurred in all patients. No clinically relevant cardiovascular toxicity was observed. Severe myelosuppression and/or mucositis necessitated dose reductions at courses 2 or 3 in all but one patient. The complete response rate was 28%, and the partial response rate was 52% for an overall objective response rate of 80%. Median progression-free survival for complete responders was 11 months (range, 3 to 24 months), while the progression-free survival was 7+ months (range 2 to 14+ months) for partial responders and 5 months (range, 3 to 9 months) for nonresponders. This combination produces a high objective response rate in women with MBC, but dose reductions were necessary in almost all cases. Toxicity was manageable after dose reduction, allowing patients to be re-treated for two to six courses without life-threatening toxicity or toxic deaths. Unfortunately, the duration of response was limited even among complete responders. Further trials of this combination in patients with MBC should explore improvements in this study regimen. [ONCOLOGY11(Suppl):24-29 1997]


Metastatic breast cancer remains incurable with currently available
therapeutic strategies.[1] Doxorubicin (Adriamycin), a DNA intercalator
that inhibits topoisomerase II,[2] is considered one of the most active
drugs for single-agent treatment of this disease, producing objective responses
in about 30% to 40% of patients.[3] Combination regimens including doxorubicin
may induce
objective responses in 40% to 70% of patients with metastatic breast cancer,
although the percentage of complete remissions is only about 5% to 15%,
and metastatic breast cancer relapses in virtually all cases within a median
follow-up time of 6 to 24 months.[4]

Paclitaxel (Taxol), a novel tubulin-interacting agent that promotes
the formation and stabilization of microtubules, has been shown to produce
objective tumor responses in about 20% to 60% of patients with metastatic
breast cancer.[5] Notably, a response rate of about 20% to 30% has been
observed in heavily pretreated patients.[6] This level of objective response
compares favorably with that observed with most cytotoxic agents previously
tested in phase II trials against this disease.[1,4]

The combination of doxorubicin and paclitaxel exhibits at least partial
synergism against human breast cancer cell lines in vitro.[7] That observation,
added to the comparable levels of antitumor effects of the two agents in
patients with metastatic breast cancer, and the fact that the agents act
through separate and distinct intracellular mechanisms, prompted the design
of a study to evaluate the combined effect of doxorubicin/paclitaxel in
women with metastatic breast cancer.


Over the last few years, various investigators have studied the single-agent
activity of paclitaxel at different doses and infusion times.[8] In a pilot
evaluation conducted at our institution, we administered paclitaxel 250
mg/m², given as a 3-hour intravenous (IV) infusion every 3 weeks,
to a group of 20 heavily pretreated patients with visceral metastatic breast
cancer that had progressed after therapy with a doxorubicin-containing
regimen. An objective response rate of 16% was observed and short-lasting
reversible neutropenia was the main dose-limiting toxicity encountered.
Considering the tolerability of the study regimen in this group of patients,
we decided to evaluate the merits of bolus doxorubicin combined with a
3-hour IV infusion of paclitaxel as first-line therapy in patients with
metastatic breast cancer.[9] Granulocyte colony-stimulating factor (G-CSF)
was added to prevent life-threatening neutropenia, and only women with
visceral-dominant disease were included.


This open-label, nonrandomized phase II study was conducted by the South-American
Office for Anticancer Drug Development in Porto Alegre, Brazil. The trial
was conducted according to guidelines of the local ethics committee and
good clinical research practice. The study was designed to accrue 25 consecutive
and evaluable patients from different institutions. The trial was divided
into two stages to allow its early discontinuation in the event of severe
life-threatening toxicity or lack of efficacy; at least three objective
responses among the first 10 patients were required to continue the study.[10]

Patient Selection

Patients with histologically proven metastatic breast cancer, a life
expectancy of at least 3 months, and a World Health Organization performance
status of 0 to 2 were eligible for study entry. Prior adjuvant chemotherapy
(excluding anthracyclines) and/or hormonal therapy were allowed, but no
cytotoxic therapy for the management of advanced disease was permitted.
Radiotherapy for locoregional management of disease and/or palliation of
bone metastases was allowed, as long as patients who had received radiotherapy
had completed treatment at least 3 weeks prior to study entry and all acute
toxic effects of therapy had resolved.

Study subjects had bidimensionally measurable lesions in areas that
had not been irradiated previously. Only patients with predominantly visceral
disease were included in the trial. Patients who had only skin, soft tissue,
or lymph node (including supraclavicular) involvement were not eligible
for the study; patients with brain metastases also were excluded.

Additional eligibility requirements included adequate bone marrow (white
blood cell count 3,500/mm³or greater, absolute granulocyte count 2,000/mm³or
greater, and a platelet count 100,000/mm³or greater). Patients also
were required to have adequate hepatic (serum bilirubin level 1.5 mg/dLor
greater) and kidney (serum creatinine level 2.0 mg/dL or greater) function.
Patients with active infections or severe concurrent medical conditions
were excluded.

Pretreatment and Follow-Up Evaluation

All patients gave a complete history and underwent physical examination,
complete blood cell count, biochemistry analysis (including renal and liver
tests, and serum electrolytes), urinalysis, chest x-ray, and an electrocardiogram.
During drug treatment, patients were re-examined and laboratory tests were
repeated on a weekly basis. Tumor measurements were taken and toxicity
assessed before each course of therapy. Additional imaging studies, such
as computed tomography scan or magnetic resonance imaging were repeated
every two courses to evaluate marker lesions. Whenever possible, the left
ventricular ejection fraction was measured by ultrasound or radioisotopic
techniques at baseline and after every two treatment courses.

Treatment Plan

Doxorubicin was supplied by Pharmacia Laboratories, Rio de Janeiro,
Brazil; paclitaxel was provided by Bristol-Myers Squibb Laboratories, São
Paulo, Brazil; and G-CSF was supplied by Roche Laboratories, São
Paulo, Brazil. Doxorubicin 60 mg/m² was administered by IV bolus on
day 1, followed immediately by paclitaxel 250 mg/m², administered
as a 3-hour IV infusion. Premedication to avoid allergic reactions to paclitaxel
consisted of dexamethasone 20 mg IV, ranitidine 50 mg IV or cimetidine
200 mg IV, and diphenhydramine 100 mg IV or promethazine 50 mg intramuscularly,
30 minutes prior to paclitaxel administration. As part of the antiemetic
regimen, dexamethasone was repeated at 10 mg IV after 4 and 8 hours, and
then daily at 4 mg orally every 8 hours for an additional 3 days. Cimetidine
200 mg IV was given after 8 hours on day 1 and maintained for 3 days at
300 mg orally every 8 hours to prevent gastrointestinal complications of
dexamethasone. Diphenhydramine 100 mg IV was repeated once after 8 hours
on day 1.

Prophylactic G-CSF 5 µg/kg was administered daily as a subcutaneous
injection, starting on day 2 and continuing until the granulocyte count
reached 1,500/mm³. Treatment was repeated every 3 weeks for a maximum
of six cycles, after which patient management was decided by the individual's
physician. In the case of a granulocyte count lower than 1,500/mm³
and/or a platelet count less than 100,000/mm³ on day 21, treatment
was postponed for 1 week. If counts had returned at least to lower normal
limits by day 28, treatment was repeated at the same dose level. If recovery
was documented only after a 2-week delay (ie, by day 35), or if the patient
developed severe mucositis and/or neutropenic fever necessitating antibiotics
and hospitalization, treatment was repeated at a reduced dose, arbitrarily
set at doxorubicin 50 mg/m² and paclitaxel 175 mg/m². The paclitaxel
dose was based on preliminary information obtained from other concomitant
trials.[5,6,14] Given that complete information on the safety of this dose
level was not yet completed during the treatment period for the current
study, G-CSF was also maintained according to the study protocol. Patients
whose treatment was interrupted for more than 2 weeks were not re-treated
in the protocol but were managed on the basis of clinical judgment.

Response and Toxicity Evaluation

Identification of objective response was based on the response definitions
established by the World Health Organization. Progression-free survival
was calculated as the time from first documentation of objective response
(complete [CR] or partial [PR]) to first documentation of disease progression.
Toxicity evaluation was based on the National Cancer Institute Common Toxicity


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