Licentiate Thesis defense: Averaged linear energy transfer and other beam quality descriptors in relation to relative biological effectiveness

In radiotherapy with protons, a constant relative biological effectiveness (RBE) of 1.1 is traditionally applied, i.e.
protons are assumed to be 10\% more effective than photons in killing cells. This constant RBE is however being
questioned, as an abundance of in vitro studies indicate a variable RBE with particle energy, and as in vivo
studies also show unexpected toxities near proton track ends, thereby indicating that a variable RBE might also
be present clinically. Variable RBE is in turn typically described by a model. For protons, the vast majority of
suggested models are based on the linear quadratic (LQ) model, where an expression for RBE is derived by
comparing the dose from protons and a reference radiation (typically photons) to achieve a desired survival
fraction. The parameters for the model are subsequently obtained by fitting parameters of the derived expression
to in vitro data, where the survival fraction of cells has been determined as a function of dose and an averaging
over the fluence spectrum of linear energy transfer (LET). While the beam quality parameter typically is the
averaged LET, how the averaged LET value has been calculated or determined has often not been fully provided,
possibly introducing a source of error in the estimated RBE value. This can vary with respect to the averaging
method (typical dose- or track averaging), included particles (only primary, or also including secondaries) and
other aspects. Furthermore, while LET is the most commonly used beam quality descriptor, other quantities exist
such as Q and z*2/β2 , here renamed as Qeff. These alternative metrics have been shown to better correlate with
RBE across different particle species compared to LET, and can possibly also perform better for a single particle
species. However, this has so far not been systematically tested or verified. Paper I investigates which kind of
averaged LET is provided in the scientific literature for the purpose of RBE determination, for both protons and
other hadronic particles. It also attempts to quantify the corresponding impact to the calculated RBE values.
Paper II investigates which beam quality descriptor is most suitable for predicting RBE by simulating the
experimental setup of recently published high throughput in vitro cell survival studies for RBE determination by
a Monte Carlo particle transport code, and fitting parameters to a phenomenological LQ-based model based on
the cell survival data. Different variations of LET, Q and Qeff are included, to generate both linear and non linear
variable RBE models. In paper I, it is shown that averaged LET for the purpose of RBE determination is,
typically, not entirely well defined with a significant minority not mentioning which averaging method is used,
and a majority not mentioning what particles are included when averaging. The corresponding impact to the
RBE for protons is, in most cases, small, unless heavier secondary particles are included. In paper II it is shown
that Q and especially Qeff are expected to better predict RBE compared to LET by a statistically significant
margin, for both linear and non-linear models, suggesting they are likely to be more suitable beam quality
descriptors to use in a LQ based phenomenological variable RBE model.