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A Rationale for Carboplatin Treatment and Abdominal Hyperthermia in Cancers Restricted to the Peritoneal Cavity¹

Divisions of Experimental Therapy [G. L., M. J. H. v. V., M. v. d. V., H. M. P.] and Chemical Carcinogenesis [L. d. E.], The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, and Department of Radiotherapy, University of Amsterdam, Academic Medical Center, Amsterdam [O. A. G. S.], The Netherlands, and Cancer Research Campaign, London, England [J. G. M.]

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°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°C, indicating that carboplatin-DNA adduct formation and consequently cytotoxicity could be enhanced by mild hyperthermia (temperatures in the range of 39–41.5°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°C for 1 h). The mean temperature was 41.5 ± 0.3°C (SD) in the peritoneal cavity and 40.5 ± 0.3°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°C and 41.5°C were 69 and 210 µM/h, respectively; for ultrafiltered platinum these values were 47 and 173 µM/h. This may have been due to a slower elimination of platinum from the blood at the higher temperature (tß for total platinum 99 and 156 min at 37 and 41.5°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°C than at 37°C (576 µM/h versus 1255 µM/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.

¹ This work was supported by Grant NK1 90-19 from the Dutch Cancer Society (Koningën Wilhelmina Fonds).

² To whom all correspondence should be addressed.

Received 9/ 9/91. Accepted 12/16/91.

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