MIDOS: a novel stochastic model towards a treatment planning system for microsphere dosimetry in liver tumors.

PURPOSE: Transarterial radioembolization (TARE) procedures treat liver tumors by injecting radioactive microspheres into the hepatic artery. Currently, there is a critical need to optimize TARE towards a personalized dosimetry approach. To this aim, we present a novel microsphere dosimetry (MIDOS) stochastic model to estimate the activity delivered to the tumor(s), normal liver, and lung. METHODS: MIDOS incorporates adult male/female liver computational phantoms with the hepatic arterial, hepatic portal venous, and hepatic venous vascular trees. Tumors can be placed in both models at user discretion. The perfusion of microspheres follows cluster patterns, and a Markov chain approach was applied to microsphere navigation, with the terminal location of microspheres determined to be in either normal hepatic parenchyma, hepatic tumor, or lung. A tumor uptake model was implemented to determine if microspheres get lodged in the tumor, and a probability was included in determining the shunt of microspheres to the lung. A sensitivity analysis of the model parameters was performed, and radiation segmentectomy/lobectomy procedures were simulated over a wide range of activity perfused. Then, the impact of using different microspheres, i.e., SIR-Sphere®, TheraSphere®, and QuiremSphere®, on the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), and mean absorbed dose was analyzed. RESULTS: Highly vascularized tumors translated into increased TNR. Treatment results (TNR and LSF) were significantly more variable for microspheres with high particle load. In our scenarios with 1.5 GBq perfusion, TNR was maximum for TheraSphere® at calibration time in segmentectomy/lobar technique, for SIR-Sphere® at 1-3 days post-calibration, and regarding QuiremSphere® at 3 days post-calibration. CONCLUSION: This novel approach is a decisive step towards developing a personalized dosimetry framework for TARE. MIDOS assists in making clinical decisions in TARE treatment planning by assessing various delivery parameters and simulating different tumor uptakes. MIDOS offers evaluation of treatment outcomes, such as TNR and LSF, and quantitative scenario-specific decisions.

Proton vs. photon radiotherapy for MR-guided dose escalation of intraprostatic lesions.

BACKGROUND: Dose escalation has been associated with improved biochemical control for prostate cancer. Focusing the high dose on the MRI-defined intraprostatic lesions (IL) could spare the surrounding organs at risk and hence allow further escalation. We compare treatment efficacy between state-of-the-art focally-boosted proton and photon-based radiotherapy, and investigate possible predictive guidelines regarding individualized treatment prescriptions. MATERIAL AND METHODS: Ten prostate cancer patients with well-defined ILs were selected. Multiparametric MRI was used to delineate ILs, which were transferred to the planning CT via image registration. Pencil beam scanning proton therapy and volumetric modulated arc therapy treatment plans, were created for each patient. Each modality featured 6 plans: (1) moderately hypofractionated dose: 70 Gy to the prostate in 28 fractions, (2)-(6) plan 1 plus additional simultaneous-integrated-boost to ILs to 75.6, 81.2, 86.6, 98 and 112 Gy in 28 fractions. Equivalent dose to 2 Gy-per-fraction (EqD2) was used to calculate tumor control (TCP) and normal tissue complication probabilities (NTCP) for ILs and organs-at-risk. RESULTS: For both modalities, the maximum necessary dose to achieve TCP > 99% was 98 Gy for very high-risk ILs. For lower risk ILs lower doses were sufficient. NTCP was <25% and 35% for protons and photons at the maximum dose escalation, respectively. For the cases and beam characteristics considered, proton therapy was dosimetrically superior when IL was >4 cc or located <2.5 mm from the rectum. CONCLUSION: This work demonstrated the potential role for proton therapy in the setting of prostate focal dose escalation. We propose that anatomical characteristic could be used as criteria to identify patients who would benefit from proton treatment.

Can differences in linear energy transfer and thus relative biological effectiveness compromise the dosimetric advantage of intensity-modulated proton therapy as compared to passively scattered proton therapy?

PURPOSE: To investigate the effect of differences in linear energy transfer (LET) and thus the relative biological effectiveness (RBE) between passively scattered proton therapy (PS) and pencil-beam scanning intensity-modulated proton therapy (IMPT). METHODS: IMPT treatment plans were generated for six ependymoma patients, originally treated with PS, using the original plan's computed tomography image sets and beam directions, and its dose-volume values as optimization constraints. Two beam spot sizes and both single-field optimization (SFO) and multi-field optimization (MFO) techniques were used for each patient. Three-dimensional variable-RBE-weighted dose distributions were computed, using Monte Carlo calculated dose and LET distributions, and a linear dose and LET-based RBE model, and were compared between the two delivery methods. RESULTS: Increased target dose coverage and decreased mean and maximum dose to the OARs was achieved with IMPT compared to PS, for constant RBE value of 1.1. Nevertheless, the maximum variable-RBE-weighted dose to the brainstem, was increased up to 6% for the IMPT plans compared to the corresponding PS plans. CONCLUSIONS: IMPT can be dosimetrically superior to PS for ependymoma patients. However, caution should be exercised so that the increased dose conformity is not counteracted by an increase in radiobiological effect in adjacent critical structures.

Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in α/ß.

BACKGROUND: Proton therapy uses a constant relative biological effectiveness (RBE) of 1.1. The use of variable RBE values has been suggested but is currently not feasible due to uncertainties. The impact of variable RBE has solely been studied using dosimetric indices. This work elucidates the impact of RBE variations on tumor control and normal tissue complication probabilities (TCP/NTCP). METHODS: Models to estimate TCP and NTCP were used in combination with an empirical proton RBE model. Variations in outcome as a function of linear-quadratic model parameters for cellular radiosensitivity were determined for TCP in prostate and ependymoma. In addition, NTCP analysis was done for brainstem necrosis. RESULTS: Considering a variable proton RBE as a dose-modifying factor for prescription doses and dose constraints is misleading, as TCP/NTCP do not simply scale with RBE. The dependency of RBE on α/ß cannot be interpreted independent of TCP/NTCP because variations in radiosensitivity affect both photon and proton treatments. Assuming interpatient variability in radiosensitivity results in lower TCP for patients with low α/ß. In proton therapy, the magnitude of TCP variations is reduced due to an RBE increase as α/ß decreases. The TCP in proton therapy is less affected by interpatient variability in α/ß. On the other hand, patients with a lower α/ß would have a lower complication probability, which is counteracted by an increase in RBE as α/ß decreases. Toxicities in proton therapy would be more affected by α/ß variations compared to photon therapy. CONCLUSIONS: Assessment of variable RBE in proton therapy should be based on TCP and NTCP. Potential interpatient variability in radiosensitivity causes a smaller variance in TCP but a larger variance in NTCP for proton patients. The relative TCP as a function of α/ß was found to be higher than the RBE, whereas the relative NTCP was lower than a calculated RBE.

Hydrogel rectum-prostate spacers mitigate the uncertainties in proton relative biological effectiveness associated with anterior-oblique beams.

AIM: Anterior-oblique (AO) proton beams can form an attractive option for prostate patients receiving external beam radiotherapy (EBRT) as they avoid the femoral heads. For a cohort with hydrogel prostate-rectum spacers, we asked whether it was possible to generate AO proton plans robust to end-of-range elevations in linear energy transfer (LET) and modeled relative biological effectiveness (RBE). Additionally we considered how rectal spacers influenced planned dose distributions for AO and standard bilateral (SB) proton beams versus intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: We studied three treatment strategies for 10 patients with rectal spacers: (A) AO proton beams, (B) SB proton beams and (C) IMRT. For strategy (A) dose and LET distributions were simulated (using the TOPAS Monte Carlo platform) and the McNamara model was used to calculate proton RBE as a function of LET, dose per fraction, and photon α/ß. All calculations were performed on pretreatment scans: inter- and intra-fractional changes in anatomy/set-up were not considered. RESULTS: For 9/10 patients, rectal spacers enabled generation of AO proton plans robust to modeled RBE elevations: rectal dose constraints were fulfilled even when the variable RBE model was applied with a conservative α/ß = 2 Gy. Amongst a subset of patients the proton rectal doses for the planning target volume plans were remarkably low: for 2/10 SB plans and 4/10 AO plans, ≤10% of the rectum received ≥20 Gy. AO proton plans delivered integral doses a factor of approximately three lower than IMRT and spared the femoral heads almost entirely. CONCLUSION: Typically, rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modeled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear.

Time-resolved diode dosimetry calibration through Monte Carlo modeling for in vivo passive scattered proton therapy range verification.

PURPOSE: Our group previously introduced an in vivo proton range verification methodology in which a silicon diode array system is used to correlate the dose rate profile per range modulation wheel cycle of the detector signal to the water-equivalent path length (WEPL) for passively scattered proton beam delivery. The implementation of this system requires a set of calibration data to establish a beam-specific response to WEPL fit for the selected 'scout' beam (a 1 cm overshoot of the predicted detector depth with a dose of 4 cGy) in water-equivalent plastic. This necessitates a separate set of measurements for every 'scout' beam that may be appropriate to the clinical case. The current study demonstrates the use of Monte Carlo simulations for calibration of the time-resolved diode dosimetry technique. METHODS: Measurements for three 'scout' beams were compared against simulated detector response with Monte Carlo methods using the Tool for Particle Simulation (TOPAS). The 'scout' beams were then applied in the simulation environment to simulated water-equivalent plastic, a CT of water-equivalent plastic, and a patient CT data set to assess uncertainty. RESULTS: Simulated detector response in water-equivalent plastic was validated against measurements for 'scout' spread out Bragg peaks of range 10 cm, 15 cm, and 21 cm (168 MeV, 177 MeV, and 210 MeV) to within 3.4 mm for all beams, and to within 1 mm in the region where the detector is expected to lie. CONCLUSION: Feasibility has been shown for performing the calibration of the detector response for three 'scout' beams through simulation for the time-resolved diode dosimetry technique in passive scattered proton delivery.

Nuclear physics in particle therapy: a review.

Charged particle therapy has been largely driven and influenced by nuclear physics. The increase in energy deposition density along the ion path in the body allows reducing the dose to normal tissues during radiotherapy compared to photons. Clinical results of particle therapy support the physical rationale for this treatment, but the method remains controversial because of the high cost and of the lack of comparative clinical trials proving the benefit compared to x-rays. Research in applied nuclear physics, including nuclear interactions, dosimetry, image guidance, range verification, novel accelerators and beam delivery technologies, can significantly improve the clinical outcome in particle therapy. Measurements of fragmentation cross-sections, including those for the production of positron-emitting fragments, and attenuation curves are needed for tuning Monte Carlo codes, whose use in clinical environments is rapidly increasing thanks to fast calculation methods. Existing cross sections and codes are indeed not very accurate in the energy and target regions of interest for particle therapy. These measurements are especially urgent for new ions to be used in therapy, such as helium. Furthermore, nuclear physics hardware developments are frequently finding applications in ion therapy due to similar requirements concerning sensors and real-time data processing. In this review we will briefly describe the physics bases, and concentrate on the open issues.

The Role of Proton Therapy for Prostate Cancer in the Setting of Hip Prosthesis.

PURPOSE: Given that the current standard of proton therapy (PT) for prostate cancer is through bilateral beams, this modality is typically avoided when it comes to treatment of patients with hip prosthesis. The purpose of this study was to evaluate whether novel PT methods, i.e., anterior proton beams and proton arc therapy (PArc), could be feasible options to treat this patient subpopulation. We evaluate PT methods in the context of dosimetry and robustness and compare with standard of practice volumetric modulated arc therapy (VMAT) to explore any potential benefits. METHODS: Two PT and one VMAT treatment plans were retrospectively created for 10 patients who participated in a clinical trial with a weekly repeat CT (rCT) imaging component. All plans were robustly optimized and featured: (1) combination anterior oblique and lateral proton beams (AoL), (2) PArc, and (3) VMAT. All patients had hydrogel spacers in place, which enabled safe application of anterior proton beams. The planned dose was 70 Gy (RBE) to the entire prostate gland and 50 Gy (RBE) to the proximal seminal vesicles in 28 fractions. Along with plan dose-volume metrics, robustness to setup and interfractional variations were evaluated using the weekly rCT images. The linear energy transfer (LET)-weighted dose was evaluated for PArc plans to ensure urethra sparing given the typical high-LET region at the end of range. RESULTS: Both PT methods were dosimetrically feasible and provided reduction of some key OAR metrics compared to VMAT except for penile bulb, while providing equally good target coverage. Significant differences in median rectum V35 (22-25%), penile bulb Dmean (5 Gy), rectum V61 (2%), right femoral head Dmean (5 Gy), and bladder V39 (4%) were found between PT and VMAT. All plans were equally robust to variations. LET-weighted dose in urethra was equivalent to the physical dose for PArc plans and hence no added urethral toxicity was expected. CONCLUSIONS: PT for treatment of prostate cancer patients with hip prosthesis is feasible and equivalent or potentially superior to VMAT in quality in some cases. The choice of radiotherapy regimen can be personalized based on patient characteristics to achieve the best treatment outcome.

A denoising diffusion probabilistic model for metal artifact reduction in CT.

The presence of metal objects leads to corrupted CT projection measurements, resulting in metal artifacts in the reconstructed CT images. AI promises to offer improved solutions to estimate missing sinogram data for metal artifact reduction (MAR), as previously shown with convolutional neural networks (CNNs) and generative adversarial networks (GANs). Recently, denoising diffusion probabilistic models (DDPM) have shown great promise in image generation tasks, potentially outperforming GANs. In this study, a DDPM-based approach is proposed for inpainting of missing sinogram data for improved MAR. The proposed model is unconditionally trained, free from information on metal objects, which can potentially enhance its generalization capabilities across different types of metal implants compared to conditionally trained approaches. The performance of the proposed technique was evaluated and compared to the state-of-the-art normalized MAR (NMAR) approach as well as to CNN-based and GAN-based MAR approaches. The DDPM-based approach provided significantly higher SSIM and PSNR, as compared to NMAR (SSIM: p < 10-26; PSNR: p < 10-21), the CNN (SSIM: p < 10-25; PSNR: p < 10-9) and the GAN (SSIM: p < 10-6; PSNR: p < 0.05) methods. The DDPM-MAR technique was further evaluated based on clinically relevant image quality metrics on clinical CT images with virtually introduced metal objects and metal artifacts, demonstrating superior quality relative to the other three models. In general, the AI-based techniques showed improved MAR performance compared to the non-AI-based NMAR approach. The proposed methodology shows promise in enhancing the effectiveness of MAR, and therefore improving the diagnostic accuracy of CT.

Radiation Therapy for Stage IIA/B Seminoma: Modeling Secondary Cancer Risk for Protons and VMAT versus 3D Photons.

Radiation therapy (RT) is an effective treatment for stage IIA and select stage IIB seminomas. However, given the long life expectancy of seminoma patients, there are concerns about the risk of secondary cancers from RT. This study assessed differences in secondary cancer risk for stage II seminoma patients following proton pencil-beam scanning (PBS) and photon VMAT, compared to 3D conformal photon RT. Ten seminoma patients, five with a IIA staging who received 30 GyRBE and five with a IIB staging who received 36 GyRBE, had three RT plans generated. Doses to organs at risk (OAR) were evaluated, and secondary cancer risks were calculated as the Excess Absolute Risk (EAR) and Lifetime Attributable Risk (LAR). PBS reduced the mean OAR dose by 60% on average compared to 3D, and reduced the EAR and LAR for all OAR, with the greatest reductions seen for the bowel, liver, and stomach. VMAT reduced high doses but increased the low-dose bath, leading to an increased EAR and LAR for some OAR. PBS provided superior dosimetric sparing of OAR compared to 3D and VMAT in stage II seminoma cases, with models demonstrating that this may reduce secondary cancer risk. Therefore, proton therapy shows the potential to reduce acute and late side effects of RT for this population.

Dose-volume metric-based prediction of radiotherapy-induced lymphocyte loss in patients with non-small-cell lung cancer treated with modern radiotherapy techniques.

Background and Purpose: Radiation-induced lymphopenia (RIL) is a common side effect of radiotherapy (RT) that may negatively impact survival. We aimed to identify RIL predictors in patients with non-small-cell lung cancer (NSCLC) treated intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Materials and Methods: We retrospectively analysed data of 306 patients who underwent radical RT for NSCLC. Absolute lymphocyte count (ALC) loss was evaluated for each patient by fitting an exponential decay curve to data from first 45 days since treatment start, and percentage ALC loss relative to baseline was calculated based on area under the decay curve and baseline ALC. We compared IMRT and VMAT treatment plans and used linear regression to predict ALC loss. Results: ALC decreased during RT in the whole patient group, while neutrophil counts remained stable and decreased only in those treated with concurrent chemoradiotherapy (CRT). Percentage ALC loss ranged between 11 and 78 % and was more strongly than lymphocyte nadir correlated with dose-volume metrics for relevant normal structures. We found evidence for the association of high radiation dose to the lungs, heart and body with percentage ALC loss, with lung volume exposed to 20-30 Gy being most important predictors in patients treated with IMRT. A multivariable model based on CRT use, baseline ALC and first principal component (PC1) of the dose-volume predictors showed good predictive performance (bias-corrected R2 of 0.40). Conclusion: Percentage lymphocyte loss is a robust measure of RIL that is predicted by baseline ALC, CRT use and dose-volume parameters to the lungs, heart and body.

Particle arc therapy: Status and potential.

There is a rising interest in developing and utilizing arc delivery techniques with charged particle beams, e.g., proton, carbon or other ions, for clinical implementation. In this work, perspectives from the European Society for Radiotherapy and Oncology (ESTRO) 2022 physics workshop on particle arc therapy are reported. This outlook provides an outline and prospective vision for the path forward to clinically deliverable proton, carbon, and other ion arc treatments. Through the collaboration among industry, academic, and clinical research and development, the scientific landscape and outlook for particle arc therapy are presented here to help our community understand the physics, radiobiology, and clinical principles. The work is presented in three main sections: (i) treatment planning, (ii) treatment delivery, and (iii) clinical outlook.

Feasibility of Using Distal Endpoints for In-room PET Range Verification of Proton Therapy.

In an effort to verify the dose delivery in proton therapy, Positron Emission Tomography (PET) scans have been employed to measure the distribution of ß+ radioactivity produced from nuclear reactions of the protons with native nuclei. Because the dose and PET distributions are difficult to compare directly, the range verification is currently carried out by comparing measured and Monte Carlo (MC) simulation predicted PET distributions. In order to reduce the reliance on MC, simulated PET (simPET) and dose distal endpoints were compared to explore the feasibility of using distal endpoints for in-room PET range verification. MC simulations were generated for six head and neck patients with corrections for radiological decay, biological washout, and PET resolution. One-dimensional profiles of the dose and simPET were examined along the direction of the beam and covering the cross section of the beam. The chosen endpoints of the simPET (x-intercept of the linear fit to the distal falloff) and planned dose (20-50% of maximum dose) correspond to where most of the protons are below the threshold energy for the nuclear reactions. The difference in endpoint range between the distal surfaces of the dose and MC-PET were compared and the spread of range differences were assessed. Among the six patients, the mean difference between MC-PET and dose depth was found to be -1.6 mm to +0.5 mm between patients, with a standard deviation of 1.1 to 4.0 mm across the individual beams. In clinical practice, regions with deviations beyond the safety margin need to be examined more closely and can potentially lead to adjustments to the treatment plan.

A review on lymphocyte radiosensitivity and its impact on radiotherapy.

It is well known that radiation therapy causes lymphopenia in patients and that this is correlated with a negative outcome. The mechanism is not well understood because radiation can have both immunostimulatory and immunosuppressive effects. How tumor dose conformation, dose fractionation, and selective lymph node irradiation in radiation therapy does affect lymphopenia and immune response is an active area of research. In addition, understanding the impact of radiation on the immune system is important for the design and interpretation of clinical trials combining radiation with immune checkpoint inhibitors, both in terms of radiation dose and treatment schedules. Although only a few percent of the total lymphocyte population are circulating, it has been speculated that their increased radiosensitivity may contribute to, or even be the primary cause of, lymphopenia. This review summarizes published data on lymphocyte radiosensitivity based on human, small animal, and in vitro studies. The data indicate differences in radiosensitivity among lymphocyte subpopulations that affect their relative contribution and thus the dynamics of the immune response. In general, B cells appear to be more radiosensitive than T cells and NK cells appear to be the most resistant. However, the reported dose-response data suggest that in the context of lymphopenia in patients, aspects other than cell death must also be considered. Not only absolute lymphocyte counts, but also lymphocyte diversity and activity are likely to be affected by radiation. Taken together, the reviewed data suggest that it is unlikely that radiation-induced cell death in lymphocytes is the sole factor in radiation-induced lymphopenia.

The complexity of DNA damage by radiation follows a Gamma distribution: insights from the Microdosimetric Gamma Model.

Introduction: DNA damage is the main predictor of response to radiation therapy for cancer. Its Q8 quantification and characterization are paramount for treatment optimization, particularly in advanced modalities such as proton and alpha-targeted therapy. Methods: We present a novel approach called the Microdosimetric Gamma Model (MGM) to address this important issue. The MGM uses the theory of microdosimetry, specifically the mean energy imparted to small sites, as a predictor of DNA damage properties. MGM provides the number of DNA damage sites and their complexity, which were determined using Monte Carlo simulations with the TOPAS-nBio toolkit for monoenergetic protons and alpha particles. Complexity was used together with a illustrative and simplistic repair model to depict the differences between high and low LET radiations. Results: DNA damage complexity distributions were were found to follow a Gamma distribution for all monoenergetic particles studied. The MGM functions allowed to predict number of DNA damage sites and their complexity for particles not simulated with microdosimetric measurements (yF) in the range of those studied. Discussion: Compared to current methods, MGM allows for the characterization of DNA damage induced by beams composed of multi-energy components distributed over any time configuration and spatial distribution. The output can be plugged into ad hoc repair models that can predict cell killing, protein recruitment at repair sites, chromosome aberrations, and other biological effects, as opposed to current models solely focusing on cell survival. These features are particularly important in targeted alpha-therapy, for which biological effects remain largely uncertain. The MGM provides a flexible framework to study the energy, time, and spatial aspects of ionizing radiation and offers an excellent tool for studying and optimizing the biological effects of these radiotherapy modalities.

Evaluating the effect of setup uncertainty reduction and adaptation to geometric changes on normal tissue complication probability using online adaptive head and neck intensity modulated proton therapy.

Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT).Approach.A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism.Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia (mean reductions of 8.25, 5.42 and 5.12 pp respectively). While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone.SignificanceOnline adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC.

Comparing Predicted Toxicities between Hypofractionated Proton and Photon Radiotherapy of Liver Cancer Patients with Different Adaptive Schemes.

With the availability of MRI linacs, online adaptive intensity modulated radiotherapy (IMRT) has become a treatment option for liver cancer patients, often combined with hypofractionation. Intensity modulated proton therapy (IMPT) has the potential to reduce the dose to healthy tissue, but it is particularly sensitive to changes in the beam path and might therefore benefit from online adaptation. This study compares the normal tissue complication probabilities (NTCPs) for liver and duodenal toxicity for adaptive and non-adaptive IMRT and IMPT treatments of liver cancer patients. Adaptive and non-adaptive IMRT and IMPT plans were optimized to 50 Gy (RBE = 1.1 for IMPT) in five fractions for 10 liver cancer patients, using the original MRI linac images and physician-drawn structures. Three liver NTCP models were used to predict radiation-induced liver disease, an increase in albumin-bilirubin level, and a Child-Pugh score increase of more than 2. Additionally, three duodenal NTCP models were used to predict gastric bleeding, gastrointestinal (GI) toxicity with grades >3, and duodenal toxicity grades 2-4. NTCPs were calculated for adaptive and non-adaptive IMRT and IMPT treatments. In general, IMRT showed higher NTCP values than IMPT and the differences were often significant. However, the differences between adaptive and non-adaptive treatment schemes were not significant, indicating that the NTCP benefit of adaptive treatment regimens is expected to be smaller than the expected difference between IMRT and IMPT.

Neural network based ensemble model to predict radiation induced lymphopenia after concurrent chemo-radiotherapy for non-small cell lung cancer from two institutions.

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment. Multi-institutional data of 139 LA-NSCLC patients from two hospitals were collected for training and validation of our suggested model. Ensemble learning was combined with a bootstrap strategy to stabilize the model, which was evaluated internally using repeated cross validation. The performance of our proposed model was compared to conventional models using the same input features, such as Logistic Regression (LR) and Random Forests (RF), using the Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) curves. Our suggested model (AUC=0.77) outperformed the comparison models (AUC=0.72, 0.74) in terms of absolute performance, indicating that the convolutional structure of the network successfully abstracts additional information from the differential DVHs, which we studied using Gradient-weighted Class Activation Map. This study shows that clinical factors combined with dDVHs can be used to predict the risk of RIL for an individual patient and shows a path toward preventing lymphopenia using patient-specific modifications of the radiotherapy plan.

Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations.

PURPOSE: Radiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters. METHODS AND MATERIALS: We assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute lymphocyte counts (ALCs) during RT and follow-up were available. We used HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histograms for circulating lymphocytes for changing BOTs (1 second-300 seconds) and fractionations (5 fx, 15 fx). From this, we used the linear cell survival model and an exponential model to determine patient-specific lymphocyte radiation sensitivity, α, and recovery, σ, respectively. RESULTS: The in vivo-derived patient-specific α had a median of 0.65 Gy-1 (range, 0.30-1.38). Decreasing BOT to 1 second led to an increased average end-of-treatment ALC of 27.5%, increasing to 60.3% when combined with the 5-fx regimen. Decreasing to 5 fx at the conventional dose rate led to an increase of 17.0% on average. The benefit of both increasing dose rate and reducing the number of fractions was patient specificࣧpatients with highly sensitive lymphocytes benefited most from decreasing BOT, whereas patients with slow lymphocyte recovery benefited most from the shorter fractionation regimen. CONCLUSIONS: We observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High-dose-rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.