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To Kill or Not to Kill: On Fundamental Issues of Thermal Therapies in Cancer Treatment
Y. Feng1, M. N. Rylander2, I. Babuska1, K. R. Diller1, J. T. Oden1;
1The University of Texas at Austin, Austin, TX, 2Virginia Polytechnic and State University, Blacksburg, VA.
Background: The ultimate goal of any cancer treatment including thermal therapy is to kill cancerous cells completely, at least in the ideal case, while minimizing healthy tissue injury. To optimize the treatment outcome, two fundamental issues need to be addressed: (1) accurately characterizing cell death under various thermal conditions, and (2) establishing equivalent relationship between different treatment protocols. Traditionally, experimental cell viability data are fitted to a model based on the Arrhenius law with the assumption that the rate of cell damage resembles the rate of unimolecular reactions. However, this model fails to capture “break points” of activation energy in a clinically viable temperature range. It would potentially compromise the effectiveness of treatment planning based on this model. Methods: In this study, a generalized Arrhenius law is derived based on experimental data for human prostate PC3 and RWPE-1 cells. Using system biology concepts and statistical mechanics approaches, a two-state cell damage model with a feedback control term is established over the hyperthermic temperature range. In addition, a general equivalence relationship for cell damage in terms of both temperature and heating time is proposed, which generalizes the 43oC equivalent minute criterion. Results: Due to mitigation of heat shock proteins, cell viability data show that the cell damage rate is slow at the beginning before it is dominated by exponential decay. The new model can more accurately capture the important cellular injury progression over a wider hyperthermic temperature range especially at the beginning of the heat shock. The beginning rate is modeled by autoregulatory mechanisms that provide feedback control to the heat shock. A general equivalence relationship is proposed, which enables patient-specific protocol designs without compromising effectiveness of the treatment. Conclusions: Traditional Arrhenius law is unable to adequately model the injury phenomena over the entire hyperthermic temperature range especially at the beginning of injury progression when heat shock may provide protection. Generalized Arrhenius model and equivalent relationship for cell damage under various hyperthermic conditions is constructed, which enables more accurate optimal treatment planning.
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