Model prediction of treatment planning for dose-fractionated radioimmunotherapy.

Abstract

Clinical trials of radioimmunotherapy (RIT) often use dose fractionation to reduce marrow toxicity. The dosing scheme can be optimized if marrow and tumor cell kinetics following radiation exposure are known. A mathematic model of tumor clonogenic cell kinetics was combined with a previously reported marrow cell kinetics model that included marrow stromal cells, progenitor cells, megakaryocytes, and platelets. Reported values for murine tumor and marrow cellular turnover rates and radiosensitivity were used in the model calculation. Given a tolerated level of thrombocytopenia, there is a fractionation scheme in which total radioactive dose administration can be maximized. Isoeffect doses that had different numbers of fractions and total radioactivity, but induced identical platelet nadirs of 20%, were determined. Assuming identical tumor uptake for all dose fractions, six tumor types were examined: early-responding tumors, late-responding tumors, and tumors that lacked a late-responding effect, with either constant or accelerated doubling time. For most tumor types, better tumor control (tumor growth delay and nadir of survival fraction) was predicted for a dosing scheme in which total radioactive dose was maximized. For late-responding tumors with accelerated doubling time, tumor growth delay increased, but the nadir of survival fraction became shallower as the number of fractions increased. A mathematic model has been developed that allows prediction of the nadir and duration of thrombocytopenia as well as tumor clonogenic cell response to various RIT doses and fractionation schemes. Given a maximum tolerated level of thrombocytopenia, the model can be used to determine a dosing scheme for optimal tumor response.