RTOG #89-06: A phase I study to evaluate intraoperative radiation therapy and the hypoxic cell sensitizer etanidazole in locally advanced malignancies

Purpose: To identify the maximum tolerated dose of the oxygen mimetic radiation sensitizer Etanidazole in the setting of surgery and intraoperative radiation therapy. 12 grams/meter² was the maximum chosen target dose based on tolerance from other trials. Methods and Materials: 42 patients were entered in an escalating dose scheme, 5.5, 7.5, 9, 10.5, and 12.0 grams/meter². Etanidazole was given via intravenous infusion over 15 minutes, followed within 20 to 30 minutes by intraoperative radiation therapy. Multiple tissue samples from tumor, tumor bed, and/or normal tissue were obtained with simultaneous plasma samples. Etanidazole concentrations in tissue and serum were determined in 33 of the 42 patients. Results: The median time to maximum serum concentration was 25 minutes. Median time to maximum tissue concentration was 40 minutes. Tissue concentrations began falling approximately one hour after infusion. Acute drug toxicities were minimal. Toxicities reported during follow-up related to surgery and/or radiation, not to drug. The concentration of sensitizer in tumor/tumor bed tissues was ten-fold greater than in previous trials. A sensitizer enhancement ratio for the hypoxic cells of 2 to 2.5 is projected. Conclusion: On the basis of tissue biopsy information, intraoperative radiation therapy will be given 40 minutes after the start of the 15 minute infusion allowing time for maximum intracellular uptake into tumor cells. In view of these findings, a Phase III trial testing etanidazole with intraoperative radiation therapy will be conducted. The tolerable single dose level of 12 grams/meter² has potential with other high-dose radiation settings such as brachy-therapy or stereotactic radiosurgery.