Weekly paclitaxel with and without concurrent radiation therapy: toxicity, pharmacokinetics, and response

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown in vitro and clinical activity against non-small cell lung cancer and astrocytic brain tumors, tumors traditionally thought of as relatively resistant to chemotherapy and radiotherapy. Because of its ability to block dividing cells in the G2/M portion of the cell cycle (the most radiosensitive phase of the cell cycle), paclitaxel is also a potentially potent radiosensitizer. To exploit these and other properties of paclitaxel, we explored a weekly, outpatient administration schedule, with and without concurrent radiation therapy, in patients with non-small cell lung cancer and astrocytic brain tumors. Our experience has shown that weekly outpatient administration is feasible, that remarkably high dose intensities can be achieved with acceptable toxicity, and that the specific dose-limiting toxicity appears to depend on administration schedule, type of concurrent radiotherapy, and certain patient characteristics. Preliminary response data are very encouraging. At the same time, pharmacokinetic studies have suggested possible reasons for our ability to use such exorbitant dose intensities safely, and also have shown that sustained plasma paclitaxel levels above the putative radiosensitizing threshold can be achieved continuously during a 6-week course of radiotherapy. Specific results, dosing recommendations, and plans for future studies are discussed.