Myelopathy in rats after exposure to clinically relevant ions: A predictive NTCP modeling framework

Toxicities to organs at risk adjacent to the target volume represent a critical limitation to dose escalation in radiotherapy. While external beam therapy with accelerated ions allows for a reduced dose to surrounding healthy organs, its biological effectiveness can be markedly higher than that of conventional x-rays and should be considered during treatment planning. Current biophysical models possess limitations in computing in vivo normal tissue complication probability (NTCP) curves for clinically relevant ion beams.

This study introduces and validates a novel computational framework capable of predicting NTCP curves for serial organs following ion exposures.

The proposed framework integrates the linear-quadratic model, the critical volume NTCP model, a novel two-stage fitting process of fractionated photon NTCP data, histological data, and the Mayo Clinic Florida Microdosimetric Kinetic Model (MCF MKM) of relative biological effectiveness. The model was applied to predict the NTCP for the spinal cord myelopathy of rats exposed at different depths along the spread-out Bragg peaks (SOBPs) of protons, helium, carbon, and oxygen ions. Radiation transport simulations were conducted to assess the microdosimetric pattern of energy deposition at the subcellular scale.

The two-stage photon fitting process yielded a α_photons/β_photons ratio of 2.3 ± 0.6 Gy and NTCP model parameters for calculations considering either endothelial or glial cells as the primary targets for the spinal cord myelopathy. Without using any ion data for calibration, the predicted NTCP showed an overall good agreement with the corresponding animal data. The model successfully reproduced the experimentally observed trends in the NTCP dependence with respect to fractionation, ion type, and exposure position along the SOBPs.

The model's ability to predict the NTCP curves for ion exposures, based solely on photon in vivo data, provides mechanistic insights and can guide preclinical investigations into the biological effects of different ions and fractionation schemes.