Proliferation and the advantage of longer-lived radionuclides in radioimmunotherapy

In our previous study we used the linear-quadratic model [J. Nucl. Med. 35, 1861 (1994)] to confirm our initial finding, based on the time-dose-fractionation model [J. Nucl. Med. 34, 1801 (1993)], that longer-lived radionuclides (e.g., 32P, 91Y) can offer a substantial therapeutic advantage over the shorter-lived radionuclides presently used in radioimmunotherapy (e.g., 90Y). The original calculations using the linear-quadratic (LQ) model did not account for proliferation of the tumor and critical bone marrow tissues. It has been suggested that inclusion of a proliferation term in the LQ model can have a substantial impact on the biologically effective dose (BED). With this in mind, we have reexamined the therapeutic efficacy of longer versus short-lived radionuclides using the LQ model replete with proliferation terms for tumor and bone marrow. Relative advantage factors (RAF), which quantify the overall therapeutic advantage of a long-lived compared to short-lived radionuclide, were calculated accordingly. While the extrapolated initial dose rate required to achieve a given BED can be affected by the inclusion of proliferation terms for both the tumor and marrow, the relative advantage factors for the longer-lived radionuclides were not significantly affected. Longer-lived radionuclides such as (114m)In and 91Y are about three times more therapeutically effective than the shorter-lived 90Y which is currently used in RIT. In other words, for a given therapeutic effect in the tumor, a longer-lived radionuclide can result in a lower deleterious effect to the bone marrow than a short-lived radionuclide. Given that bone marrow is generally considered to be the dose-limiting organ, these results have important implications for radioimmunotherapy.