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.