Minimizing normal tissue toxicity can enhance the therapeutic gain of thermochemotherapy. For this purpose, we investigated the optimal duration of whole body hyperthermia (WBH) (41.5 degrees C) when administered simultaneously with carboplatin (CBDCA). Using a transplantable fibrosarcoma in Fischer 344 rats, we measured tumor growth delay (TGD) as well as normal tissue toxicities (body weight loss, thrombocytopenia) induced by various durations of WBH (0.5, 1.0, 1.5, 2.0 or 2.5 hours) when combined with CBDCA (30 mg/kg, i.v.). When combined with CBDCA, 1.0 hour WBH increased the TGD compared to 0.5 hour of WBH, but with WBH durations greater than 1.0 hour, the TGD did not further significantly increase. Measuring CBDCA-induced myelosuppression, the platelet count on day 6 post-treatment decreased from a control mean of 6.8 x 10(8)/ml to 1.8 x 10(8)/ml after 2.5 hour WBH exposure in a duration-dependent manner (p < 0.001). To estimate the specific therapeutic efficacy (STE), we calculated a ratio of TGD to myelosuppression (thrombocytopenia). Compared to other WBH exposure times, 1.0 hour duration of WBH combined with CBDCA produced the highest STE (2.8) and over 1.5 hour duration of WBH did not result in any additional increase in STE. We conclude that 1.0 hour WBH exposure is optimal when combined with CBDCA in order to maximize the therapeutic gain.
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