Combination chemotherapy with Taxol (paclitaxel) in metastatic breast cancer

In three phase I trials reported in the United States, the combination of paclitaxel and doxorubicin has been evaluated in previously untreated patients with metastic breast cancer. At M.D. Anderson Cancer Center, escalating doses of paclitaxel followed by a fixed dose of doxorubicin led to one complete remission (CR) and seven partial remissions (PRs) in 10 patients. Dose-limiting toxic effects were stomatitis and neutropenic fever. The maximum tolerated dose (MTD) was paclitaxel 125 mg/m2 and doxorubicin 48 mg/m2-lower than the starting dose. The reverse sequence (doxorubicin followed by paclitaxel) also was investigated to evaluate the possibility of schedule-dependent toxicity. The MTD of this reverse sequence was doxorubicin 60 mg/m2 and paclitaxel 150 mg/m2, with neutropenic fever as the dose-limiting toxicity. In a study by the National Cancer Institute (NCI), paclitaxel and doxorubicin were given simultaneously over 72 hours and doses of each were escalated resulting in two separate MTDs: paclitaxel/doxorubicin 160/75 and 180/60 mg/m2. Objective responses were 6% CR and 56% PR, and gastrointestinal disturbances were dose-limiting. Schedule-dependence also was addressed in a study at Indiana University, where the drug sequence was alternated for comparison both between and across patients. Preliminary results showed an increase in mucositis when paclitaxel was given before doxorubicin. It is concluded that this is an active combination and that schedule-dependent mucositis can be avoided if doxorubicin is given first. Myelosuppression is dose-limiting, even with granulocyte colony-stimulating factor, and thrombocytopenia occurs with multiple courses.