Radiobiologic optimization of combination radiopharmaceutical therapy applied to myeloablative treatment of non-Hodgkin lymphoma.

Abstract

Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid-1990s, such treatment strategies have only been implemented clinically recently and without a rigorous methodology for treatment optimization. Radiobiologic and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiologic normal-organ tolerance while optimizing the ratio of 2 different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-Hodgkin lymphoma (NHL) patients using (131)I-tositumomab and (90)Y-ibritumomab tiuxetan. The range of potential administered activities (AAs) is limited by the normal-organ maximum-tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose-limiting normal organs are expected to be the lungs for (131)I-tositumomab and the liver for (90)Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal-organ constraints as a function of the AAs and calculating tumor biologic effective dose (BED) along the normal-organ MTBED limits, we obtained the optimal combination of activities. The model was tested using previously acquired patient normal-organ and tumor kinetic data and MTBED values taken from the literature. The average AA value based solely on normal-organ constraints was 19.0 ± 8.2 GBq (range, 3.9-36.9 GBq) for (131)I-tositumomab and 2.77 ± 1.64 GBq (range, 0.42-7.54 GBq) for (90)Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal-organ kinetics for the 2 radiopharmaceuticals. Results included AA ranges that would deliver 95% of the maximum tumor BED, allowing for informed inclusion of clinical considerations, such as a maximum-allowable (131)I administration. A rational approach for combination radiopharmaceutical treatment has been developed within the framework of a proven 3-dimensional (3D) personalized dosimetry software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate that combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single-agent chemotherapy.