Accurate proton dose calculation using Monte Carlo (MC) is computationally demanding in workflows like robust optimisation, adaptive replanning, and probabilistic inference, which require repeated evaluations. To address this, we develop a neural surrogate that integrates Monte Carlo dropout to provide fast, differentiable dose predictions along with voxelwise predictive uncertainty. The method is validated through a series of experiments, starting with a one-dimensional analytic benchmark that establishes accuracy, convergence, and variance decomposition. Two-dimensional bone-water phantoms, generated using TOPAS Geant4, demonstrate the method's behavior under domain heterogeneity and beam uncertainty, while a three-dimensional water phantom confirms scalability for volumetric dose prediction. Across these settings, we separate epistemic (model) from parametric (input) contributions, showing that epistemic variance increases under distribution shift, while parametric variance dominates at material boundaries. The approach achieves significant speedups over MC while retaining uncertainty information, making it suitable for integration into robust planning, adaptive workflows, and uncertainty-aware optimisation in proton therapy.

Although aggregating data from different institutions could alleviate this problem, data sharing is a practical challenge due to concerns about patient data privacy and other technical obstacles. Purpose: This work aims to address this dilemma by developing FedKBP+, a comprehensive federated learning (FL) platform for predictive tasks in real-world applications in radiotherapy treatment planning. Methods: We implemented a unified communication stack based on Google Remote Procedure Call (gRPC) to support communication between participants whether located on the same workstation or distributed across multiple workstations. In addition to supporting the centralized FL strategies commonly available in existing open-source frameworks, FedKBP+ also provides a fully decentralized FL model where participants directly exchange model weights to each other through Peer-to-Peer communication. We evaluated FedKBP+ on three predictive tasks using scale-attention network (SA-Net) as the predictive model. Results: Using 340 cases (training: 200; validation: 40; testing: 100) from the OpenKBP Challenge, a 3D dose prediction model trained with FedAvg algorithm outperformed the model trained on the local data, and achieved predictive accuracy comparable to that of a centrally trained model using pooled data in both independent and identically distributed (IID) and non-IID settings. We further evaluated the performance of FedKBP+ against NVFlare on the task of brain tumor segmentation using 227 cases from eight sites in the 2021 BraTS challenge dataset (training: 152; validation: 27; testing: 48). FedKBP+ surpassed the NVFlare framework in both accuracy and training efficiency.

Targeted Radionuclide Therapy (TRT) is a modern strategy in radiation oncology that aims to administer a potent radiation dose specifically to cancer cells using cancer-targeting radiopharmaceuticals. Accurate radiation dose estimation tailored to individual patients is crucial. Deep learning, particularly with pre-therapy imaging, holds promise for personalizing TRT doses. However, current methods require large time series of SPECT imaging, which is hardly achievable in routine clinical practice, and thus raises issues of data availability. Our objective is to develop a semi-supervised learning (SSL) solution to personalize dosimetry using pre-therapy images. The aim is to develop an approach that achieves accurate results when PET/CT images are available, but are associated with only a few post-therapy dosimetry data provided by SPECT images. In this work, we introduce an SSL method using a pseudo-label generation approach for regression tasks inspired by the FixMatch framework. The feasibility of the proposed solution was preliminarily evaluated through an in-silico study using synthetic data and Monte Carlo simulation. Experimental results for organ dose prediction yielded promising outcomes, showing that the use of pseudo-labeled data provides better accuracy compared to using only labeled data.

Radiotherapy (RT) planning is complex, subjective, and time-intensive. Advances in artificial intelligence (AI) promise to improve its precision, efficiency, and consistency, but progress is often limited by the scarcity of large, standardized datasets. To address this, we introduce the Automated Iterative RT Planning (AIRTP) system, a scalable solution for generating high-quality treatment plans. This scalable solution is designed to generate substantial volumes of consistently high-quality treatment plans, overcoming a key obstacle in the advancement of AI-driven RT planning. Our AIRTP pipeline adheres to clinical guidelines and automates essential steps, including organ-at-risk (OAR) contouring, helper structure creation, beam setup, optimization, and plan quality improvement, using AI integrated with RT planning software like Eclipse of Varian. Furthermore, a novel approach for determining optimization parameters to reproduce 3D dose distributions, i.e. a method to convert dose predictions to deliverable treatment plans constrained by machine limitations. A comparative analysis of plan quality reveals that our automated pipeline produces treatment plans of quality comparable to those generated manually, which traditionally require several hours of labor per plan. Committed to public research, the first data release of our AIRTP pipeline includes nine cohorts covering head-and-neck and lung cancer sites to support an AAPM 2025 challenge. This data set features more than 10 times the number of plans compared to the largest existing well-curated public data set to our best knowledge. Repo:{https://github.com/RiqiangGao/GDP-HMM_AAPMChallenge}

Deep learning-based automated contouring and treatment planning has been proven to improve the efficiency and accuracy of radiotherapy. However, conventional radiotherapy treatment planning process has the automated contouring and treatment planning as separate tasks. Moreover in deep learning (DL), the contouring and dose prediction tasks for automated treatment planning are done independently. In this study, we applied the multi-task learning (MTL) approach in order to seamlessly integrate automated contouring and voxel-based dose prediction tasks, as MTL can leverage common information between the two tasks and be able able to increase the efficiency of the automated tasks. We developed our MTL framework using the two datasets: in-house prostate cancer dataset and the publicly available head and neck cancer dataset, OpenKBP. Compared to the sequential DL contouring and treatment planning tasks, our proposed method using MTL improved the mean absolute difference of dose volume histogram metrics of prostate and head and neck sites by 19.82% and 16.33%, respectively. Our MTL model for automated contouring and dose prediction tasks demonstrated enhanced dose prediction performance while maintaining or sometimes even improving the contouring accuracy. Compared to the baseline automated contouring model with the dice score coefficients of 0.818 for prostate and 0.674 for head and neck datasets, our MTL approach achieved average scores of 0.824 and 0.716 for these datasets, respectively. Our study highlights the potential of the proposed automated contouring and planning using MTL to support the development of efficient and accurate automated treatment planning for radiotherapy.

In contemporary radiotherapy planning (RTP), a key module leaf sequencing is predominantly addressed by optimization-based approaches. In this paper, we propose a novel deep reinforcement learning (DRL) model termed as Reinforced Leaf Sequencer (RLS) in a multi-agent framework for leaf sequencing. The RLS model offers improvements to time-consuming iterative optimization steps via large-scale training and can control movement patterns through the design of reward mechanisms. We have conducted experiments on four datasets with four metrics and compared our model with a leading optimization sequencer. Our findings reveal that the proposed RLS model can achieve reduced fluence reconstruction errors, and potential faster convergence when integrated in an optimization planner. Additionally, RLS has shown promising results in a full artificial intelligence RTP pipeline. We hope this pioneer multi-agent RL leaf sequencer can foster future research on machine learning for RTP.

Radiation therapy treatment planning requires balancing the delivery of the target dose while sparing normal tissues, making it a complex process. To streamline the planning process and enhance its quality, there is a growing demand for knowledge-based planning (KBP). Ensemble learning has shown impressive power in various deep learning tasks, and it has great potential to improve the performance of KBP. However, the effectiveness of ensemble learning heavily depends on the diversity and individual accuracy of the base learners. Moreover, the complexity of model ensembles is a major concern, as it requires maintaining multiple models during inference, leading to increased computational cost and storage overhead. In this study, we propose a novel learning-based ensemble approach named LENAS, which integrates neural architecture search with knowledge distillation for 3D radiotherapy dose prediction. Our approach starts by exhaustively searching each block from an enormous architecture space to identify multiple architectures that exhibit promising performance and significant diversity. To mitigate the complexity introduced by the model ensemble, we adopt the teacher-student paradigm, leveraging the diverse outputs from multiple learned networks as supervisory signals to guide the training of the student network. Furthermore, to preserve high-level semantic information, we design a hybrid-loss to optimize the student network, enabling it to recover the knowledge embedded within the teacher networks. The proposed method has been evaluated on two public datasets, OpenKBP and AIMIS. Extensive experimental results demonstrate the effectiveness of our method and its superior performance to the state-of-the-art methods.

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.

Estimating the uncertainty of deep learning models in a reliable and efficient way has remained an open problem, where many different solutions have been proposed in the literature. Most common methods are based on Bayesian approximations, like Monte Carlo dropout (MCDO) or Deep ensembling (DE), but they have a high inference time (i.e. require multiple inference passes) and might not work for out-of-distribution detection (OOD) data (i.e. similar uncertainty for in-distribution (ID) and OOD). In safety critical environments, like medical applications, accurate and fast uncertainty estimation methods, able to detect OOD data, are crucial, since wrong predictions can jeopardize patients safety. In this study, we present an alternative direct uncertainty estimation method and apply it for a regression U-Net architecture. The method consists in the addition of a branch from the bottleneck which reconstructs the input. The input reconstruction error can be used as a surrogate of the model uncertainty. For the proof-of-concept, our method is applied to proton therapy dose prediction in head and neck cancer patients. Accuracy, time-gain, and OOD detection are analyzed for our method in this particular application and compared with the popular MCDO and DE. The input reconstruction method showed a higher Pearson correlation coefficient with the prediction error (0.620) than DE and MCDO (between 0.447 and 0.612). Moreover, our method allows an easier identification of OOD (Z-score of 34.05). It estimates the uncertainty simultaneously to the regression task, therefore requires less time or computational resources.

Abstract: Fast and accurate dose predictions are one of the bottlenecks in treatment planning for microbeam radiation therapy (MRT). In this paper, we propose a machine learning (ML) model based on a 3D U-Net. Our approach predicts separately the large doses of the narrow high intensity synchrotron microbeams and the lower valley doses between them. For this purpose, a concept of macro peak doses and macro valley doses is introduced, describing the respective doses not on a microscopic level but as macroscopic quantities in larger voxels. The ML model is trained to mimic full Monte Carlo (MC) data.