Effects of hyperthermia on the rat bladder: a pre-clinical study on thermometry and functional damage after treatment.

The rat bladder was heated using a microwave applicator which was equipped with a system of circulating deionized water. The applicator was operated at 434 MHz and was placed at the ventral side with the rats in supine position. Temperatures in the bladder and adjacent were monitored using thermocouples with single or multiple sensors. One thermocouple located most centrally in the bladder served as reference. The rats were treated at intravesical reference temperature of 41, 42, 43, 44 and 45 degrees C for 1 h. The heating time to reach the reference temperature was approximately 5 min. Temperatures inside the bladder varied within 0.5 degrees C from the reference value, while the temperatures in the urethra were approximately 1.0 degrees C lower. At the left and the right side of the outer bladder wall, temperatures were approximately 0.5 degrees C lower than the reference value, while the temperature on the dorsal and ventral sides of the bladder wall were 1.0-1.5 degrees C lower. In the rectum, located in the treatment field, the temperature reached 39.1, 40.5, 42.4 and 42.5 degrees C after 1 h of hyperthermia at intravesical reference temperatures of 41, 42, 43, 44 and 45 degrees C, respectively. Body core temperature measured in the esophagus behind the pericardium never exceeded 40.0 degrees C. The capacity of the bladder was assessed after 1 h at 43, 44 and 45 degrees C at various intervals after heat treatment. In the sham treated control group and in the animals treated at 43 degrees C, no reduction in bladder capacity was observed. The treatment group where the bladder was kept at 44 degrees C for 1 h showed a clear reduction in bladder capacity at days 1 and 3 after hyperthermia. In the 45 degrees C treatment group, four out of seven rats died, this within a few days after treatment. The three surviving rats were tested for bladder capacity and all had a reduced capacity at days 3 and 7 post-treatment. Four weeks after 44 degrees C hyperthermia, all rats had recovered. After hyperthermia, depending on the heat-dose, an increase in blood urea nitrogen (BUN) was observed. After treatment at 42, 43 and 44 degrees C, peak values were observed after approximately 1 day (16 or 24 h) followed by recovery; after 42 degrees C, BUN levels were almost back to normal after 1 week; after 43 degrees C, the level was still twice as high as control levels; and after 44 degrees C, recovery of BUN levels to normal seemed slow, 1 week after treatment it was still five times as high as control. From these results, it is concluded that temperatures in the bladder below 44 degrees C are well tolerated. After 1 h at 44 degrees C, a transient decrease in bladder capacity was observed, as well as a high level of azotemia. After 1 h at 45 degrees C, a high mortality rate was observed. These observations agree with early clinical observations and may be used as guidelines for further clinical work.

A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity.

The purpose of this study was to optimize the treatment of cancers restricted to the peritoneal cavity by combining i.p. chemotherapy with abdominal hyperthermia. In vitro experiments demonstrated that the uptake of carboplatin into CC531 tumor cells was increased at temperatures higher than 41.5 degrees C at dose levels of 5 and 50% cell kill. Carboplatin-DNA adduct formation and cytotoxicity, however, were already increased at temperatures of about 40 degrees C, indicating that carboplatin-DNA adduct formation and consequently cytotoxicity could be enhanced by mild hyperthermia (temperatures in the range of 39-41.5 degrees C). CC531 tumor bearing rats were treated i.v. and i.p. with carboplatin (6.15 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C for 1 h). The mean temperature was 41.5 +/- 0.3 degrees C (SD) in the peritoneal cavity and 40.5 +/- 0.3 degrees C in the esophagus. Enhanced platinum concentrations were found in peritoneal tumors (factor 3) and in kidney, liver, spleen, and lung (a factor 2 average), after the combined i.v. or i.p. carboplatin-hyperthermia treatment. Pharmacokinetic data of i.p. CBDCA combined with hyperthermia demonstrated an increased tumor exposure for total and ultrafiltered platinum in plasma. The areas under the concentration x time curve for total platinum at 37 degrees C and 41.5 degrees C were 69 and 210 microM/h, respectively; for ultrafiltered platinum these values were 47 and 173 microM/h. This may have been due to a slower elimination of platinum from the blood at the higher temperature (t1/2 beta for total platinum 99 and 156 min at 37 and 41.5 degrees C, respectively). The direct exposure of the tumor via the peritoneal fluid appeared to diminish, since the area under the curve for total platinum was lower at 41.5 degrees C than at 37 degrees C (576 microM/h versus 1255 microM/h, respectively). Our results indicate that the advantage of adding hyperthermia is caused by an increased drug exposure of the tumor via the circulation. This was supported by the fact that platinum concentrations in peritoneal tumors after carboplatin treatment at elevated temperatures were similar for the i.p. and i.v. routes.