Time-dose-fractionation in radioimmunotherapy: implications for selecting radionuclides

As currently practiced, the doses delivered to tumors in radioimmunotherapy are less than desirable primarily because of dose-limiting bone marrow toxicity, thus reducing the therapeutic efficacy of this modality. The biological effectiveness of internal radionuclide therapy depends on the total dose, the rate at which it is delivered, and the fractionation schedule of the radiolabeled antibodies administered. A new approach, based on time-dose-fractionation (TDF), which has been used in conventional radiotherapy, is advanced. This approach incorporates differences in dose rates, biological half-lives of the antibodies, physical half-lives of the radionuclides employed and the total doses needed for a given biological effect. The TDF concept is illustrated with several relevant examples for radioimmunotherapy. Based on the TDF approach, it is proposed that under certain biological conditions radionuclides with physical half-lives that are 1-3 times the biological half-life of the radiolabeled antibodies in the tumor are more likely to deliver sterilization doses to tumors than the shorter-lived nuclides presently in use unless precluded by specific activity considerations. Several radionuclides that meet this criteria are suggested with 32P being the most promising among them. Finally, a practical method for treatment planning in radioimmunotherapy using TDF factors is recommended.