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

ABSTRACT: This phase II trial was conducted toevaluate the percentage of objective responses and the toxicity profileof combination doxorubicin (Adriamycin) and paclitaxel (Taxol) with granulocytecolony-stimulating factor as first-line therapy for patients with metastaticbreast cancer (MBC) not previously exposed to anthracycline-containingregimens. Patients with measurable, visceral-dominant MBC and a performancestatus of 0 to 2 were included in the study. Doxorubicin 60 mg/m²was administered as a short intravenous infusion, followed by paclitaxel250 mg/m² as a 3-hour intravenous infusion on day 1. Granulocyte colony-stimulatingfactor 5 µg/kg/d was given prophylactically as a subcutaneous injectionfrom day 2 until granulocyte recovery to 1,500/mm³ or more. Treatmentwas repeated every 21 days for a maximum of six courses. Dose reductions(to doxorubicin 50 mg/m² and paclitaxel 175 mg/m²) and/or treatmentdelay 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 relevantcardiovascular toxicity was observed. Severe myelosuppression and/or mucositisnecessitated dose reductions at courses 2 or 3 in all but one patient.The complete response rate was 28%, and the partial response ratewas 52% for an overall objective response rate of 80%. Median progression-freesurvival 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 withMBC, but dose reductions were necessary in almost all cases. Toxicity wasmanageable after dose reduction, allowing patients to be re-treated fortwo to six courses without life-threatening toxicity or toxic deaths. Unfortunately,the duration of response was limited even among complete responders. Furthertrials of this combination in patients with MBC should explore improvementsin this study regimen. [ONCOLOGY11(Suppl):24-29 1997]

Introduction

Metastatic breast cancer remains incurable with currently availabletherapeutic strategies.[1] Doxorubicin (Adriamycin), a DNA intercalatorthat inhibits topoisomerase II,[2] is considered one of the most activedrugs for single-agent treatment of this disease, producing objective responsesin about 30% to 40% of patients.[3] Combination regimens including doxorubicinmay 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 medianfollow-up time of 6 to 24 months.[4]

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

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

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