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 41.5ºC at dose levels of 5 and 50% cell kill. Carboplatin-DNA adduct formation and cytotoxicity, however, were already increased at temperatures of about 40ºC, indicating that carboplatin-DNA adduct formation and consequently cytotoxicity could be enhanced by mild hyperthermia (temperatures in the range of 39-41.5ºC).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 (41.5ºC for 1 h). The mean temperature was 41.5 ± 0.3ºC (SD) in the peritoneal cavity and 40.5 ± 0 JºC 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 37ºC and 41.5ºC were 69 and 210 jxM/h, respectively; for ultrafiltered platinum these values were 47 and 173 MM/1I. This may have been due to a slower elimination of platinum from the blood at the higher temperature (tvjl for total platinum 99 and 156 min at 37 and 41.5ºC, 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 41.5ºC than at 37ºC (576 uM/h versus 1255 UM/YL, 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. © 1992, American Association for Cancer Research. All rights reserved.