As part of an ongoing Phase II trial at Duke University Medical Center (DUMC), patients with Stage IIB-IVA soft tissue sarcomas (STS) potentially amenable to wide local excision were treated with preoperative hyperthermia (HT) plus radiation therapy (RT), with HT randomized to one versus two treatments per week, stratified with respect to tumor volume. 17 patients were treated and analyzed. HT was given 30-60 minutes after RT, with heating maintained for 1 hour after 42.0 degrees C was reached. In patients treated with 2 HT per week, treatments were separated by 48 hrs. Concurrent RT was given with 180-200 cGy fractions, five treatments per week, to a nominal tumor dose of 5000-5040 cGy. Surgical extirpation was performed 4 weeks after completion of HT/RT. Treatment effect was evaluated by histopathologic examination of the resected lesions, according to a previously reported system. The mean number of HT given in the 1 and 2/wk groups was 4.4 and 7.3, respectively (p less than 0.01). Tmax for the 1 and 2 HT/wk groups was 42.4 +/- 2.1 degrees C and 43.5 +/- 1.8 degrees C, and T min was 38.1 +/- 0.8 degrees C and 38.6 +/- 0.5 degrees C, respectively. The increase in T min from first to last treatment was 0.5 +/- 1.2 degrees C and 1.0 +/- 0.8 degrees C, respectively. The T min from the best treatment was 39.1 +/- 1.2 degrees C and 40.0 +/- 1.0 degrees C, and the Tmax from the best treatment was 44.5 +/- 3.4 degrees C and 45.4 +/- 2.5 degrees C for the 1 and 2 HT/wk groups, respectively. There were no statistically significant differences between the 2 treatment groups for any of the above temperature parameters. Severe histopathologic changes were found in 71% (12 of 17) of the lesions. T min and Tmax and highest T min and Tmax were between 0.4-1.1 degrees C higher in patients with severe changes (p = NS). All 9 patients in the 2 HT/wk group had extensive changes, versus only 3 of the 8 patients in the 1 HT/wk group. This difference was highly statistically significant (p = 0.009, two-tailed Fisher's exact test). These findings suggest an advantage to twice weekly, as opposed to weekly, HT in the setting of this study. Whether there is a corresponding therapeutic gain, or whether these results can be extrapolated to other settings requires further investigational efforts. It is recommended that treatment parameters, particularly temperature parameters, continue to be examined in Phase II trials.