Phase I study of Paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally...

Paclitaxel is active in non-small-cell lung cancer (NSCLC) and is a radiosensitizer with a dose-response relationship that depends more on duration of exposure than peak concentration. A continuous infusion prolongs exposure and may maximize the drug-radiation interaction. The goal of this National Cancer Institute-sponsored phase I study was to determine the feasibility and toxicity of a continuous infusion paclitaxel (24 hours/day, 7 days/week, 7 weeks total) concurrent with standard radiation therapy (RT) for locally advanced NSCLC.

Eligible patients had locally advanced (T4, N1-3, M0 or Tany, N2-3, M0) NSCLC, performance status less than or equal to 2, and adequate hematological, hepatic, renal, and pulmonary function. RT was given to a total dose of 64.8 Gy at 1.8 Gy/day. Paclitaxel was delivered by infusion beginning 48 hours before and then continuously throughout the 7 weeks of RT. The paclitaxel concentration was escalated in sequential dose cohorts ranging from 0.5 to 17 mg/m/d, and each contained at least three patients in a standard phase I design.

Twenty-nine patients were enrolled. Significant grade 3+ toxicity was observed in one patient, who experienced grade 3 pneumonitis at the 6.5-mg/m/day dose level. This cohort was expanded, but none of four additional patients experienced significant toxicity. Three patients completed the 15-mg/m/day dose level without serious or dose-limiting toxicity. The two patients entered at the 17-mg/m/day dose level had grade 4 neutropenia requiring a delay in therapy of more than 1 week. The median survival of all patients was 12 months; however, 4 of 27 patients (15%) survived longer than 60 months (mean 63.4 months).

The maximally tolerated and recommended phase II paclitaxel dose delivered by protracted continuous infusion is 15 mg/m/day when combined with thoracic RT. This schedule allows for the delivery of more total paclitaxel than other published regimens and may have less esophagitis than weekly paclitaxel regimens. This regimen has the potential to achieve a radiosensitizing serum concentration of paclitaxel continuously for 7 weeks without exceeding levels associated with neutropenia or neurotoxicity. There were four long-term survivors in this phase I study. These data suggest that continuous paclitaxel infusion with concurrent RT is safe and should be of interest to explore in combination with other cytotoxic or targeted therapies.