Accounting for and harnessing RBE variability in proton therapy

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The proposed study concerns proton beam radiotherapy of cancer. In the current standard of practice, treatment planning for proton therapy is based on the assumption that the relative biological effectiveness (RBE) of protons is 1.1 for all beam energies, dose levels and locations within the treated volume. Under this assumption, optimization of a treatment plan involves optimization of the physical dose only. However, it is well known that proton RBE is not constant. Abundant experimental data show unambiguously that the RBE increases with decreasing proton energy and with decreasing dose. Both these quantities vary within the treated volume and so does the RBE. This means that achieving an optimal distribution of the physical dose does not necessarily produce a treatment plan that is optimal in terms of the expected biological outcomes. The proposed study will develop a methodology and tools that will facilitate a new treatment plan optimization strategy that accounts for RBE variability, directly optimizes expected biological effects of a treatment, and thereby maximizes the likelihood of achieving best treatment outcomes. The main hypothesis of this study is that: Variations in proton RBE caused by variations of dose and beam energy spectrum can be modelled within uncertainties not exceeding those of experimental RBEs. The model can be incorporated in the treatment planning process so that for each patient a three dimensional RBE distribution is calculated. The computed RBEs will differ significantly from the generic RBE of 1.1 in clinically relevant structures. This hypothesis will be investigated by the following specific aims: 1. To develop a phenomenological model of RBE as a function of dose and beam energy spectrum. 2. To develop a proton treatment planning methodology where in addition to dose distribution, the variable RBE distribution is computed. 3. To investigate through treatment planning studies (in-silico or “virtual” clinical trials) the feasibility of the new methodology and to determine the potential clinical significance of RBE deviations from the generic RBE of 1.1.