Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

A data‐driven calibration of a nonlinear mechanistic model for DNA damage and repair: applications to radiosurgery and heavy ion irradiation treatment for glioblastoma
Russel Rockne

Last modified: 2014-06-09


Current radiation treatment options for the invasive primary brain tumor glioblastoma
multiforme (GBM), consist of two modalities which are very different in terms of the amount
of dose delivered, the distribution of dose in space, and perhaps, the biological
On one hand, the current standard of care for GBM consists of “conformal” or intensity
modulated radiation therapy (IMRT) with daily treatments of 1.8 – 2 Gy over the course of
several weeks to a total dose of approximately 60 Gy to a large treatment volume. On the
other hand is stereotactic radiosurgery (SRS), which is a secondary radiation therapy
treatment used after the disease has recurred. The spatial localization of the highly focused
“radiosurgical” dose is achieved through the composition of small 3–5 mm spherical targets,
created with multiple small beams. SRS is typically a single fraction treatment, with doses of
up to 24 Gy or higher and used primarily for small lesions. It is a matter of contemporary
debate as to whether or not biological response to radiation changes for doses higher than
10 Gy per fraction. Because of the different dose per fraction, dose delivery times, and
potentially different biological responses to these two radiation treatments, mechanistic
models of radiation‐induced DNA damage and repair are often used to quantify and
translate radiation dose into biological effect.
I present a mechanistic two‐compartment nonlinear ODE model of radiation‐induced DNA
damage and repair, which includes sub‐lethal and fatal DNA classes of damage which is
based on physically measurable quantities of the radiation treatment. Analytic solutions for
this model can be found and demonstrates orders of magnitude differences from the
linearized approximation used pervasively in the literature, particularly in the SRS high dose
range. Further, data‐driven parameterization of the fully nonlinear model reveals superior
model prediction and parameter stability across a wide range of experimental conditions
compared to current model paradigms such as the linear‐quadratic model. The doseresponse
data used to test the model includes a wide range of particles, energies, doses,
dose rates and dose‐fraction timing, motivated by current trends in radiation oncology,
including fractionated SRS and heavy ion therapy. This mechanistic modeling approach at
the DNA level is connected to a patient‐specific tissue level reaction‐diffusion model for
GBM which includes spatial and temporal delivery and response to radiation therapy to
investigate the net effect of these novel radiation treatment strategies in silico.