Docetaxel and hyperthermia: factors that modify thermal enhancement

Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents and recent studies suggest that docetaxel may show improved response at elevated temperatures. Factors that may modify the thermal enhancement of docetaxel were studied to optimize its clinical use with hyperthermia.

The tumor studied was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, Fsa-II. All studies were approved by the Animal Care and Use Committee. Docetaxel was given as a single intraperitoneal injection. Hyperthermia was achieved by immersing the tumor-bearing foot into a constant temperature water bath. Four factors were studied: duration of hyperthermia, sequencing of hyperthermia with docetaxel, intensity of hyperthermia, and tumor size. To study duration of hyperthermia tumors were treated at 41.5 degrees C for 30 or 90 min immediately after intraperitoneal administration of docetaxel. For sequencing of hyperthermia and docetaxel, animals received hyperthermia treatment of tumors for 30 min at 41.5 degrees C immediately after drug administration, hyperthermia both immediately and 3 hr after docetaxel administration and hyperthermia given only at 3 hr after administration of docetaxel. Intensity of hyperthermia was studied using heat treatment of tumors for 30 min at 41.5 or 43.5 degrees C immediately following docetaxel administration. Effect of tumor size was studied by delaying experiments until three times the tumor volume (113 mm(3)) was observed. Treatment of tumors lasted for 30 min at 41.5 degrees C immediately following drug administration. Tumor response was studied using the mean tumor growth time.

Hyperthermia in the absence of docetaxel had a small but significant effect on tumor growth time at 43.5 degrees C but not at 41.5 degrees C. Hyperthermia at 41.5 degrees C for 90 min immediately after docetaxel administration significantly increased mean tumor growth time (P = 0.0435) when compared to tumors treated with docetaxel at room temperature. Treatment for 30 min had no effect. Application of hyperthermia immediately and immediately plus 3 hr following docetaxel was effective in delaying tumor growth. Treatment at 3 hr only had no effect. No significant difference in mean tumor growth time was observed with docetaxel and one half hour of hyperthermia at 41.5 or 43.5 degrees C. For larger tumors, hyperthermia alone caused a significant delay in tumor growth time. Docetaxel at 41.5 degrees C for 30 min did not significantly increase mean tumor growth time compared to large tumors treated with docetaxel at room temperature.

Docetaxel shows a moderate increase in anti-tumor activity with hyperthermia. At 41.5 degrees C the thermal enhancement of docetaxel is time dependent if hyperthermia is applied immediately following drug administration. With large tumors docetaxel alone or docetaxel plus hyperthemia showed the greatest delays in tumor growth time in the experiments.