Introduction
Metastatic breast cancer remains incurable with currently available therapeutic strategies.[1] Doxorubicin(Drug information on 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(Drug information on 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.
STUDY RATIONALE
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.
PATIENTS AND METHODS
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(Drug information on dexamethasone) 20 mg IV, ranitidine 50 mg IV or cimetidine(Drug information on cimetidine) 200 mg IV, and diphenhydramine(Drug information on diphenhydramine) 100 mg IV or promethazine(Drug information on 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 Criteria.
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