A Multimodal Clinically Informed Coarse-to-Fine Framework for Longitudinal CT Registration in Proton Therapy

Proton therapy offers superior organ-at-risk sparing but is highly sensitive to anatomical changes, making accurate deformable image registration (DIR) across longitudinal CT scans essential. Conventional DIR methods are often too slow for emerging online adaptive workflows, while existing deep learning-based approaches are primarily designed for generic benchmarks and underutilize clinically relevant information beyond images. To address this gap, we propose a clinically scalable coarse-to-fine deformable registration framework that integrates multimodal information from the proton radiotherapy workflow to accommodate diverse clinical scenarios. The model employs dual CNN-based encoders for hierarchical feature extraction and a transformer-based decoder to progressively refine deformation fields. Beyond CT intensities, clinically critical priors, including target and organ-at-risk contours, dose distributions, and treatment planning text, are incorporated through anatomy- and risk-guided attention, text-conditioned feature modulation, and foreground-aware optimization, enabling anatomically focused and clinically informed deformation estimation. We evaluate the proposed framework on a large-scale proton therapy DIR dataset comprising 1,222 paired planning and repeat CT scans across multiple anatomical regions and disease types. Extensive experiments demonstrate consistent improvements over state-of-the-art methods, enabling fast and robust clinically meaningful registration.

Diffusion Transformer-based Universal Dose Denoising for Pencil Beam Scanning Proton Therapy

Purpose: Intensity-modulated proton therapy (IMPT) offers precise tumor coverage while sparing organs at risk (OARs) in head and neck (H&N) cancer. However, its sensitivity to anatomical changes requires frequent adaptation through online adaptive radiation therapy (oART), which depends on fast, accurate dose calculation via Monte Carlo (MC) simulations. Reducing particle count accelerates MC but degrades accuracy. To address this, denoising low-statistics MC dose maps is proposed to enable fast, high-quality dose generation. Methods: We developed a diffusion transformer-based denoising framework. IMPT plans and 3D CT images from 80 H&N patients were used to generate noisy and high-statistics dose maps using MCsquare (1 min and 10 min per plan, respectively). Data were standardized into uniform chunks with zero-padding, normalized, and transformed into quasi-Gaussian distributions. Testing was done on 10 H&N, 10 lung, 10 breast, and 10 prostate cancer cases, preprocessed identically. The model was trained with noisy dose maps and CT images as input and high-statistics dose maps as ground truth, using a combined loss of mean square error (MSE), residual loss, and regional MAE (focusing on top/bottom 10% dose voxels). Performance was assessed via MAE, 3D Gamma passing rate, and DVH indices. Results: The model achieved MAEs of 0.195 (H&N), 0.120 (lung), 0.172 (breast), and 0.376 Gy[RBE] (prostate). 3D Gamma passing rates exceeded 92% (3%/2mm) across all sites. DVH indices for clinical target volumes (CTVs) and OARs closely matched the ground truth. Conclusion: A diffusion transformer-based denoising framework was developed and, though trained only on H&N data, generalizes well across multiple disease sites.

Noisy probing dose facilitated dose prediction for pencil beam scanning proton therapy: physics enhances generalizability

Purpose: Prior AI-based dose prediction studies in photon and proton therapy often neglect underlying physics, limiting their generalizability to handle outlier clinical cases, especially for pencil beam scanning proton therapy (PBSPT). Our aim is to design a physics-aware and generalizable AI-based PBSPT dose prediction method that has the underlying physics considered to achieve high generalizability to properly handle the outlier clinical cases. Methods and Materials: This study analyzed PBSPT plans of 103 prostate and 78 lung cancer patients from our institution,with each case comprising CT images, structure sets, and plan doses from our Monte-Carlo dose engine (serving as the ground truth). Three methods were evaluated in the ablation study: the ROI-based method, the beam mask and sliding window method, and the noisy probing dose method. Twelve cases with uncommon beam angles or prescription doses tested the methods' generalizability to rare treatment planning scenarios. Performance evaluation used DVH indices, 3D Gamma passing rates (3%/2mm/10%), and dice coefficients for dose agreement. Results: The noisy probing dose method showed improved agreement of DVH indices, 3D Gamma passing rates, and dice coefficients compared to the conventional methods for the testing cases. The noisy probing dose method showed better generalizability in the 6 outlier cases than the ROI-based and beam mask-based methods with 3D Gamma passing rates (for prostate cancer, targets: 89.32%$\pm$1.45% vs. 93.48%$\pm$1.51% vs. 96.79%$\pm$0.83%, OARs: 85.87%$\pm$1.73% vs. 91.15%$\pm$1.13% vs. 94.29%$\pm$1.01%). The dose predictions were completed within 0.3 seconds. Conclusions: We've devised a novel noisy probing dose method for PBSPT dose prediction in prostate and lung cancer patients. With more physics included, it enhances the generalizability of dose prediction in handling outlier clinical cases.