The Impact of Tumor Cell Proliferation in Radioimmunotherapy

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Abstract
In conventional radiotherapy, proliferation of tumor cells throughout treatment is believed to be an important cause of treatment failure. For radioimmunotherapy (RAIT), tumor cell proliferation will be a significant mechanism to consider when designing therapeutic strategies. A mathematic model, based on the irradiation of a proliferating tumor cell population by an exponentially decaying dose-rate, was used to examine the effects of proliferation during RAIT. Proliferation can give rise to dose-rate effects in tumors that are distinct from those attributable to repair or recovery from radiation damage. An equation for the therapeutic efficiency of RAIT was generated. The analysis showed that RAIT will be less effective on rapidly proliferating tumor cell populations. High radioresistance causes a radiation dose to produce less tumor cell sterilization. In addition, for RAIT, the proportion of the dose that is "wasted" because of proliferation will be greater for radioresistant tumors. Therapeutically, higher initial dose-rates are more effective, meaning that, dose for dose, shorter decay half-lives will be better than longer ones. The analysis indicates that the therapeutic efficiency depends on tumor size and dosimetric heterogeneity and implies that micrometastases and "cold spots" in tumors could be major foci of recurrence. The results of this study support the use of RAIT as part of an integrated treatment regimen featuring local radiotherapy to bulk disease, and systemic treatment with total body irradiation plus bone marrow rescue and/or chemotherapy.

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