Future perspectives of docetaxel (Taxotere) in front-line therapy

The recognition that early breast cancer is a systemic disease has led to the development of multimodal treatments incorporating adjuvant hormonal and chemotherapies. Adjuvant strategies have improved the outcome of treatment for early breast cancer, but 50% of women still relapse and develop overt metastatic disease, which is largely incurable. In the search for more effective chemotherapies, the taxoid, docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France), has demonstrated high single-agent activity against metastatic breast cancer, including visceral metastases, and is now in phase III trials of combination adjuvant and front-line therapies. When cytotoxic drugs are used in combination, it is important to consider the dose-response relationships and the toxicity profiles of the agents involved. It often is necessary to reduce the doses of drugs given in combination to avoid excessive toxicity; this may result in the administration of suboptimal doses. Early clinical studies have shown that therapeutic doses of docetaxel (60 to 100 mg/m2) can be used in combinations with doxorubicin, 5-fluorouracil, cyclophosphamide, ifosfamide, vinorelbine, and cisplatin. The most frequent adverse effect of docetaxel is neutropenia (91% of patients), but other effects, such as neurosensory changes and fluid retention, also must be taken into consideration when planning combination therapies. It may be possible to ameliorate some toxicities by preventive measures. Fluid retention, which generally occurs at cumulative doses greater than 500 mg/m2, has been shown to be reduced in severity and delayed in onset by prophylactic corticosteroid treatment from the day before each docetaxel administration for 3 to 5 days. Neutropenia may be reduced by treatment with granulocyte colony-stimulating factor, and neurotoxicity may be reduced by protectants such as amifostine. These strategies are under investigation. The high single-agent activity of docetaxel makes it an excellent candidate for treatments such as induction regimens before high-dose chemotherapy and adjuvant therapies. Short-term treatment regimens such as these should also avoid the cumulative toxicities of docetaxel. It is important that new drugs, such as docetaxel, which have shown promising activity against metastatic disease and could have a significant impact on the natural history of early breast cancer, are investigated as front-line treatments.