Schedule-dependent therapeutic gain from the combination of fractionated irradiation and cis-diamminedichloroplatinum (II) in C3H/Km mouse model systems.

The interaction of cis-diamminedichloroplatinum(II) (c-DDP) with daily fractionated radiotherapy was studied in the SCCVII tumor, the duodenum, and the lungs of C3H/Km mice. The experimental end points were the time required for treated tumors to reach 3 times their treatment size, the survival of stem cells in the duodenal crypts, and the breathing rate measured early (19-23 weeks) and late (41-46 weeks) after treatment. In the 8 treatment schedules that were evaluated, radiation was delivered in 5 daily doses of 2-7 Gy, for total doses of 10-35 Gy; and c-DDP was administered either daily (2.4 or 1.6 mg/kg/day) or as a single bolus (8 or 12 mg/kg). Schedule 2, in which 2.4 mg/kg c-DDP was administered immediately before X-ray on 5 consecutive days produced the highest degree of enhancement of radiation effect (expressed as dose-effect factor); and the next greatest enhancement was produced by 12 mg/kg c-DDP administered 24 h before the start of fractionated daily radiotherapy. Those schedules also caused some enhancement in the normal tissues, but the dose-effect factors for those tissues were lower than for the tumor, which was reflected in the finding of maximal therapeutic gain factors for those same schedules. There was little or no enhancement nor were the therapeutic gain factors significantly greater than 1.00 when the 2 modalities were administered more than 24 h apart. Thus, for both normal tissue toxicity and antitumor effect there is striking schedule dependence with respect to both sequence and timing of these 2 modalities. This is of major relevance in clinical treatment planning.