A multi-source feature-driven deep learning method to generate linear energy transfer distribution for proton therapy

Monte Carlo (MC)-based estimation of dose-averaged linear energy transfer (LETd) in proton therapy is accurate but computationally intensive. Although deep learning (DL) models offer efficient alternatives, few have been optimized for multi-source inputs or validated on anatomically complex tumors, such as nasopharyngeal carcinoma (NPC).

This study developed and evaluated a multi-source DL framework for voxel-level LETd prediction in proton therapy for NPC, aiming to identify optimal input configurations and assess both prediction accuracy and clinical reliability.

This study analyzed 100 patients with NPC, yielding 500 proton therapy fields. Ground-truth LETd maps were generated using GPU-based Monte Carlo simulations. A deep learning model was trained with different combinations of four input features: dose distribution, CT image, beam mask, and radiological depth, resulting in eight configurations (M_dose, M_dose+ct, M_dose+beam, M_dose+depth, M_{dose+beam+depth}, M_{dose+ct+depth}, M_dose+ct+beam, and M_{dose+ct+beam+depth}). The dataset was randomly divided into training (300 fields, 60 patients), validation (100 fields, 20 patients), and testing (100 fields, 20 patients) sets. Model performance was evaluated using mean absolute error (MAE), peak signal-to-noise ratio (PSNR), normalized cross-correlation (NCC), structural similarity index measure (SSIM), and 3D Gamma analysis. A 3D U-Net baseline was retrained under identical conditions for comparison. Model interpretability was examined with Gradient-weighted Class Activation Mapping (Grad-CAM), and prediction confidence was assessed using uncertainty maps.

The M_dose+ct model achieved the best performance (MAE 0.21 ± 0.03 keV/µm, PSNR 28.99 ± 1.33, NCC 0.98 ± 0.01, SSIM 0.971 ± 0.007, Gamma 3%/3 mm: 94.69 ± 3.69%), outperforming the 3D U-Net baseline (MAE 0.38 ± 0.52 keV/µm). Grad-CAM visualizations confirmed that the model focused on physically relevant regions, while uncertainty maps highlighted high-variability zones at LETd transitions. The model generated voxel-level LETd predictions in approximately 7 s per case, which was substantially faster than GPU-based MC simulations (30 s per case).

The proposed multi-source deep learning framework enables rapid and accurate voxel-level LETd prediction for NPC. Combining dose with CT yielded the most reliable input configuration, and incorporating interpretability and uncertainty analyses enhances confidence in its suitability for biologically guided proton therapy planning.