Toward CT-Equivalent Image Quality in Low-Dose Radiotherapy Planning: Conditional Diffusion-Based CBCT-to-CT Synthesis and the Impact of CBCT Input Representation

Cone-beam CT (CBCT) is routinely acquired during radiotherapy for patient setup, but its quantitative reliability is degraded by scatter, noise, and reconstruction artifacts, limiting Hounsfield Unit (HU) accuracy. We propose EPC-3D-Diff, a novel conditional 3D latent diffusion framework for volumetric CBCT to CT synthesis that introduces a projection domain equivariance loss derived from acquisition physics. Unlike common image domain equivariance, we exploit the fact that an in plane rotation of the volume corresponds to an angular shift in its projections. During training, we enforce this relationship by forward projecting rotated synthesized CT volumes and matching them to appropriately angle shifted projections of the paired target CT, yielding a physics consistent equivariance constraint integrated into the diffusion objective. To capture full 3D context efficiently, conditional diffusion is performed in a compact latent space learnt by a lightweight 3D autoencoder, preserving axial depth while downsampling in plane resolution for stable training. We validate on a paired head CBCT/CT phantom dataset, including repeat scans, and paired clinical data using patient wise splits, and perform single and mixed domain training, ablations, and comparisons with diffusion and CycleGAN. EPC-3D-Diff generalizes well and achieved substantial improvements, +7.4 dB (phantom) and +1.8 dB (clinical data) in PSNR compared to state of the art methods, alongside improved SSIM and HU accuracy, within tissue boundaries. Overall, EPC-3D-Diff improves robustness and physics consistency, supporting HU aware synthesis for downstream radiotherapy workflows. The open source code for EPC-3D-Diff is available at https://github.com/ALZAHRAALTALIB/EPC-3D-Diff.

Radiation therapy (RT) requires precise dose delivery over multiple fractions, with CT fundamental for treatment planning due to its electron density information. Repeated CT acquisitions impose radiation exposure and logistical burdens, MRI lacks electron density, and cone-beam CT (CBCT) requires correction for dose calculation. Synthetic CT (sCT) generation addresses these by converting MRI or CBCT into CT-equivalent images with accurate Hounsfield Unit (HU) values, enabling MRI-only RT and CBCT-based adaptive workflows. Building on SynthRAD2023, SynthRAD2025 benchmarked sCT methods on 2,362 patients from five European centers across head and neck, thorax, and abdomen. Two tasks: MRI-to-CT (890 cases) and CBCT-to-CT (1,472 cases), evaluated via image similarity (MAE, PSNR, MS-SSIM), segmentation (Dice, HD95), and dosimetric metrics from photon and proton plans. With 803 participants and 12/13 valid submissions, Task 1 top performance reached MAE $64.8\pm21.3$ HU, PSNR $\sim$30 dB, MS-SSIM $\sim$0.936, Dice 0.79, photon $γ_{2\%/2\text{mm}}>98\%$, proton $γ\approx85\%$. Task 2 improved: MAE $48.3\pm13.4$ HU, PSNR 32.6 dB, MS-SSIM 0.968, Dice 0.86, photon $γ>99\%$, proton $γ\approx89\%$. Strong image--segmentation correlations ($ρ=0.78$--$0.79$) but moderate dose correlations confirmed image quality is insufficient as a dosimetric surrogate. Head-and-neck cases were most consistent; thoracic and abdominal cases showed greater variability. Residual errors at tissue interfaces propagate along beam paths, affecting proton dose more than photon. SynthRAD2025 demonstrates that deep learning yields clinically relevant sCTs, especially for CBCT-to-CT, while identifying persistent MRI-to-CT challenges and underscoring dose-based evaluation as essential for clinical validation.

Generating CT volumes from MRI and CBCT can improve treatment planning in adaptive radiotherapy while avoiding additional radiation exposure. However, direct regression of CT intensities is challenged by the inherently high dynamic range and long-tailed distributions, thereby averaging out sparse yet clinically important structures. To alleviate this issue, we reformulate the regression target into multiple windowed representations, leveraging the inductive prior that CT intensities are structure-deterministic and window-separable. These windowed views exhibit smoother distributions and admit structured fusion back to the full-range CT. Building on this reformulation, we introduce WING, a WINdow-prior-based Generative network comprising: 1) a new Gated Inception Generator to produce multi-window predictions, enabling multi-shape kernel interactions to capture cross-modality correspondence; 2) a Fuse-and-Refine Transformer to aggregate the windowed outputs and learn residuals for detail refinement; and 3) a joint adversarial training objective to enhance window-conditioned realism. Extensive experiments demonstrate that our compact WING achieves state-of-the-art performance on the MRI-to-CT and CBCT-to-CT benchmarks, while supporting multi-anatomy synthesis with a single model.