RADIOBIOLOGICAL MODELING OF COMBINED TARGETED I-131 THERAPY AND TOTAL-BODY IRRADIATION FOR TREATMENT OF DISSEMINATED TUMORS OF DIFFERING RADIOSENSITIVITY

Purpose: A model is presented for calculating combinations of targeted I-131 and total body irradiation, followed by bone marrow rescue, in the treatment of tumors of different radiosensitivity. The model is used to evaluate the role of the total body irradiation component in the optimal combination regime as a function of the radiosensitivity of the tumor cells. Methods and Materials: A microdosimetric model was used to calculate absorbed dose in small tumors and micrometastases when uniformly targeted by the radionuclide I-131. ( ell kill was calculated from absorbed dose using an extended version of the linear quadratic model. The addition of varying total doses of total body irradiation, assuming 2 Gy fractions, was also calculated using the linear quadratic model. The net cell kill from combined modality (targeted I-131 and total body irradiation) was computed for varying proportions of the two components, for a range of tumor sizes, restricting the total radiation dose to within tolerance for a full-course TBI regime (approximately 14 Gy total) in all cases. The calculations were repeated for a range of presumed tumor uptakes of the targeting agent and for a range of tumor radiosensitivities, typical of those reported for tumor cells of differing type in culture. Optimal regimes were identified as those predicted to yield a high probable tumor cure rate (evaluated using a Poisson statistical model) for all tumor sizes. Results: The analysis supports earlier model studies which predicted that systemic combination treatment with targeted I-131 and total body irradiation would be superior to either component used alone. The intrinsic tumor radiosensitivity is found to be a factor which influences the optimal combination of the I-131 and external beam total body irradiation components. The total body irradiation component is greater in optimal regimes treating radioresistant than radiosensitive tumors. However, an obligatory total body irradiation component is also predicted for more radiosensitive tumors; the analysis suggests that the total body irradiation component should in no circumstances be less than 2 X 2 Gy, whilst practical arguments exist in favor of higher doses. Conclusion: Total body irradiation is an obligatory component for effective systemic treatment of disseminated malignant tumors to which I-131 can be selectively targeted. Clinical studies applying this strategy to the treatment of neuroblastoma by I-131 targeted by meta-iodo-benguanidine (mIBG), total body irradiation and bone marrow rescue are now in progress.