The critical influence of timing of combined modality cytoreductive regimens.

When sequential high dose drug-radiation cytoreductive regimens are employed, the interval between chemotherapy and total body irradiation (TBI) can markedly influence both toxicity in rapid cell renewal systems and the probability of successfully ablating normal and malignant hemopoietic stem cells. This is primarily due to the intense regenerative responses manifested by cells of these tissues that survive the first cytoreductive insult. Since the total doses of chemotherapy and radiation used are limited by toxicity to slowly or non-proliferating tissues, the best therapeutic effect should be obtained when the interval between chemotherapy and TBI is the shortest consistent with acceptable toxicity to rapid cell renewal systems, provided adequate time for drug metabolism and excretion is allowed to minimize the risk of interactive toxicity. In mice treated with piperazinedione 50 mg/m2 and fractionated TBI, the optimal interval between drug administration and irradiation is 3-4 days.