One-Hour Paclitaxel via Weekly Infusion: Dose-Density With Enhanced Therapeutic Index

ABSTRACT: A preliminary report of a phase II trial of paclitaxel (Taxol) administered in a dose-dense manner as first- and second-line therapy for metastatic breast cancer is presented. Patients who had received one or two prior chemotherapy regimens for metastatic disease or in the adjuvant setting were eligible. Prior treatment with an anthracycline was permitted, but patients who had previously received taxanes were excluded. Initial dose was paclitaxel 100 mg/m² infused over 1 hour weekly until disease progression or intolerable toxicity. To date, significant activity and a highly favorable toxicity profile have been observed with 1-hour paclitaxel £ 100 mg/m². Less myelosuppression occurred than would have been expected with a standard regimen (paclitaxel 175 mg/m² given over 3 hours q3wks). Neurotoxicity became dose limiting at paclitaxel > 100 mg/m²/wk. The apparent safety and high therapeutic index of paclitaxel administered in a dose-dense fashion increases therapeutic options for patients with breast cancer, and further studies are warranted.[ONCOLOGY 12(Suppl 1):19-22, 1998]

Inasmuch as the 1980s was the decade of platinum compounds, because of their significant therapeutic impact on the treatment of various solid tumors, the 1990s is clearly the decade of the taxanes. This designation is perhaps most valid in the context of systemic therapy for breast cancer. The efficacy and tolerability of paclitaxel (Taxol) has been established through numerous phase II and III clinical trials that mostly evaluated doses ranging from 135 mg/m² to 250 mg/m² and infusion durations of 3, 24, or 96 hours. No less than five large randomized trials will be completed by 1998 evaluating optimal dose and scheduling of paclitaxel as single-agent therapy for metastatic breast cancer (Table 1).

Much preclinical data demonstrate the schedule-dependent cytotoxicity of paclitaxel against various carcinoma cell lines (where longer is “better”)[1,2], and prolonged 96-hour infusions of paclitaxel can overcome resistance that has emerged after exposure to shorter 3-hour infusions.[3,4] Nevertheless, the infusional approach can be cumbersome in the clinic. To the extent that the efficacy linked to infusion duration relates to capturing a higher proportion of cells in the G²/M phase of the cell cycle, more frequent, shorter infusions should hypothetically accomplish the same. Motivated by the cytokinetic considerations of dose-dense therapy,[5] the demonstrated feasibility of 1-hour infusions[6,7] and the considerations of convenience of drug administration, we performed a phase II trial and pharmacologic investigation of weekly 1-hour paclitaxel infusion as first- and second-line chemotherapy for metastatic breast cancer.

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