Comparing 90-Day Postoperative Mortality After Neoadjuvant Proton-Based Versus Photon-Based Chemoradiotherapy for Esophageal Cancer.

Purpose: Evidence suggests that proton-beam therapy (PBT) results in less toxicity and postoperative complications compared to photon-based radiotherapy in patients who receive chemoradiotherapy followed by esophagectomy for cancer. Ninety-day mortality (90DM) is an important measure of the postoperative (nononcologic) outcome as proxy of quality-of-care. We hypothesize that PBT could reduce 90DM compared to photon-based radiotherapy. Materials and Methods: From a single-center retrospective database patients treated with chemoradiotherapy before esophagectomy for cancer were selected (1998-2022). Univariable logistic regression was used to study the association of radiotherapy modality with 90DM. Three separate methods were applied to adjust for confounding bias, including multivariable logistic regression, propensity score matching, and inverse probability of treatment weighting. Stratified analysis for the age threshold that maximized the difference in 90DM (ie, ≥67 vs <67 years) was performed. Results: A total of 894 eligible patients were included and 90DM was 5/202 (2.5%) in the PBT versus 29/692 (4.2%) in the photon-based radiotherapy group (P = .262). After adjustment for age and tumor location, PBT versus photon-based radiotherapy was not significantly associated with 90DM (P = .491). The 90DM was not significantly different for PBT versus photon-based radiotherapy in the propensity score matching (P = .379) and inverse probability of treatment weighting cohort (P = .426). The stratified analysis revealed that in patients aged ≥67 years, PBT was associated with decreased 90DM (1.3% vs 8.8%; P = .026). Higher age significantly increased 90DM risk within the photon-based radiotherapy (8.8% vs 2.7%; P = .001), but not within the PBT group (1.3% vs 3.2%; P = .651). Conclusion: No statistically significant difference was observed in postoperative 90DM after esophagectomy for cancer between PBT and photon-based neoadjuvant chemoradiotherapy. However, among older patients a signal was observed that PBT may reduce 90DM risk.

Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy.

PURPOSE: Lymphocytes play an important role in antitumor immunity; however, they are also especially vulnerable to depletion during chemoradiation therapy (CRT). The purpose of this study was to compare the incidence of grade 4 lymphopenia (G4L) between proton beam therapy (PBT) and intensity modulated photon radiation therapy (IMRT) in patients with esophageal cancer treated with CRT in a completed randomized trial and to ascertain patient heterogeneity to G4L risk based on treatment and established prognostic factors. METHODS AND MATERIALS: Between April 2012 and March 2019, a single-institution, open-label, nonblinded, phase 2 randomized trial (NCT01512589) was conducted at the University of Texas MD Anderson Cancer Center. Patients were randomly assigned to IMRT or PBT, either definitively or preoperatively. This secondary analysis of the randomized trial was G4L during concurrent CRT according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Among 105 patients evaluable for analysis, 44 patients (42%) experienced G4L at a median of 28 days after the start date of concurrent CRT. Induction chemotherapy (P = .003), baseline absolute lymphocyte count (P < .001), radiation therapy modality (P = .002), and planning treatment volume (P = .033) were found to be significantly associated with G4L. Multivariate classification analysis partitioned patients into 5 subgroups for whom the incidence of G4L was observed in 0%, 14%, 35%, 70%, and 100% of patients. The benefit of PBT over IMRT was most pronounced in patients with an intermediate baseline absolute lymphocyte count and large planning treatment volume (P = .011). CONCLUSIONS: This is the first prospective evidence that limiting dose scatter by PBT significantly reduced the incidence of G4L, especially in the intermediate-risk patients. The implication of this immune-sparing effect of PBT, especially in the context of standard adjuvant immunotherapy, needs further examination in the current phase 3 randomized trials.

Incorporating variable RBE in IMPT optimization for ependymoma.

PURPOSE: To study the dosimetric impact of incorporating variable relative biological effectiveness (RBE) of protons in optimizing intensity-modulated proton therapy (IMPT) treatment plans and to compare it with conventional constant RBE optimization and linear energy transfer (LET)-based optimization. METHODS: This study included 10 pediatric ependymoma patients with challenging anatomical features for treatment planning. Four plans were generated for each patient according to different optimization strategies: (1) constant RBE optimization (ConstRBEopt) considering standard-of-care dose requirements; (2) LET optimization (LETopt) using a composite cost function simultaneously optimizing dose-averaged LET (LETd ) and dose; (3) variable RBE optimization (VarRBEopt) using a recent phenomenological RBE model developed by McNamara et al.; and (4) hybrid RBE optimization (hRBEopt) assuming constant RBE for the target and variable RBE for organs at risk. By normalizing each plan to obtain the same target coverage in either constant or variable RBE, we compared dose, LETd , LET-weighted dose, and equivalent uniform dose between the different optimization approaches. RESULTS: We found that the LETopt plans consistently achieved increased LET in tumor targets and similar or decreased LET in critical organs compared to other plans. On average, the VarRBEopt plans achieved lower mean and maximum doses with both constant and variable RBE in the brainstem and spinal cord for all 10 patients. To compensate for the underdosing of targets with 1.1 RBE for the VarRBEopt plans, the hRBEopt plans achieved higher physical dose in targets and reduced mean and especially maximum variable RBE doses compared to the ConstRBEopt and LETopt plans. CONCLUSION: We demonstrated the feasibility of directly incorporating variable RBE models in IMPT optimization. A hybrid RBE optimization strategy showed potential for clinical implementation by maintaining all current dose limits and reducing the incidence of high RBE in critical normal tissues in ependymoma patients.

Quantifying the Effect of 4-Dimensional Computed Tomography-Based Deformable Dose Accumulation on Representing Radiation Damage for Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Standard-Fractionated Intensity-Modulated Radiation Therapy.

PURPOSE: The aim of this study was to investigate the dosimetric and clinical effects of 4-dimensional computed tomography (4DCT)-based longitudinal dose accumulation in patients with locally advanced non-small cell lung cancer treated with standard-fractionated intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Sixty-seven patients were retrospectively selected from a randomized clinical trial. Their original IMRT plan, planning and verification 4DCTs, and ∼4-month posttreatment follow-up CTs were imported into a commercial treatment planning system. Two deformable image registration algorithms were implemented for dose accumulation, and their accuracies were assessed. The planned and accumulated doses computed using average-intensity images or phase images were compared. At the organ level, mean lung dose and normal-tissue complication probability (NTCP) for grade ≥2 radiation pneumonitis were compared. At the region level, mean dose in lung subsections and the volumetric overlap between isodose intervals were compared. At the voxel level, the accuracy in estimating the delivered dose was compared by evaluating the fit of a dose versus radiographic image density change (IDC) model. The dose-IDC model fit was also compared for subcohorts based on the magnitude of NTCP difference (|ΔNTCP|) between planned and accumulated doses. RESULTS: Deformable image registration accuracy was quantified, and the uncertainty was considered for the voxel-level analysis. Compared with planned doses, accumulated doses on average resulted in <1-Gy lung dose increase and <2% NTCP increase (up to 8.2 Gy and 18.8% for a patient, respectively). Volumetric overlap of isodose intervals between the planned and accumulated dose distributions ranged from 0.01 to 0.93. Voxel-level dose-IDC models demonstrated a fit improvement from planned dose to accumulated dose (pseudo-R2 increased 0.0023) and a further improvement for patients with ≥2% |ΔNTCP| versus for patients with <2% |ΔNTCP|. CONCLUSIONS: With a relatively large cohort, robust image registrations, multilevel metric comparisons, and radiographic image-based evidence, we demonstrated that dose accumulation more accurately represents the delivered dose and can be especially beneficial for patients with greater longitudinal response.

Dosimetric response of Gafchromic™ EBT-XD film to therapeutic protons.

EBT-XD model of Gafchromic™ films has a broader optimal dynamic dose range, up to 40 Gy, compared to its predecessor models. This characteristic has made EBT-XD films suitable for high-dose applications such as stereotactic body radiotherapy and stereotactic radiosurgery, as well as ultra-high dose rate FLASH radiotherapy. The purpose of the current study was to characterize the dependence of EBT-XD film response on linear energy transfer (LET) and dose rate of therapeutic protons from a synchrotron. A clinical spot-scanning proton beam was used to study LET dependence at three dose-averaged LET (LETd) values of 1.0 keV/µm, 3.6 keV/µm, and 7.6 keV/µm. A research proton beamline was used to study dose rate dependence at 150 Gy/second in the FLASH mode and 0.3 Gy/second in the non-FLASH mode. Film response data from LETd values of 0.9 keV/µm and 9.0 keV/µm of the proton FLASH beam were also compared. Film response data from a clinical 6 MV photon beam were used as a reference. Both gray value method and optical density (OD) method were used in film calibration. Calibration results using a specific OD calculation method and a generic OD calculation method were compared. The four-parameter NIH Rodbard function and three-parameter rational function were compared in fitting the calibration curves. Experimental results showed that the response of EBT-XD film is proton LET dependent but independent of dose rate. Goodness-of-fit analysis showed that using the NIH Rodbard function is superior for both protons and photons. Using the "specific OD + NIH Rodbard function" method for EBT-XD film calibration is recommended.

Declarations of Independence: How Embedded Multicollinearity Errors Affect Dosimetric and Other Complex Analyses in Radiation Oncology.

The statistical technique of multiple regression, commonly referred to as "multivariable regression," is often used in clinical research to quantify the relationships between multiple predictor variables and a single outcome variable of interest. The foundational theory underpinning multivariable regression assumes that all predictor variables are independent of one another. In other words, the effect of each independent variable is measured by its contribution to the regression equation while all other variables remain unchanged. In the presence of correlations between two or more variables, however, it is impossible to change one variable without a consequent change in the variable(s) it is linked to. This condition, known as "multicollinearity," can introduce errors into multivariable regression models by affecting estimates of the regression coefficients that quantify the relationship between individual predictor variables and the outcome variable. Errors that arise due to violations of the multicollinearity assumption are of special interest to radiation oncology researchers. Because of high levels of correlation among variables derived from points along individual organ dose-volume histogram (DVH) curves, as well as strong intercorrelations among dose-volume parameters in neighboring organs, dosimetric analyses are particularly subject to multicollinearity errors. For example, dose-volume parameters for the heart are strongly correlated not only with other points along the heart DVH curve but are likely also correlated with dose-volume parameters in neighboring organs such as the lung. In this paper, we describe the problem of multicollinearity in accessible terms and discuss examples of violations of the multicollinearity assumption within the radiation oncology literature. Finally, we provide recommendations regarding best practices for identifying and managing multicollinearity in complex data sets.

GPU-accelerated calculation of proton microdosimetric spectra as a function of target size, proton energy, and bounding volume size.

Objective.Shortcomings of dose-averaged linear energy transfer (LETD), the quantity which is most commonly used to quantify proton relative biological effectiveness, have long been recognized. Microdosimetric spectra may overcome the limitations of LETDbut are extremely computationally demanding to calculate. A systematic library of lineal energy spectra for monoenergetic protons could enable rapid determination of microdosimetric spectra in a clinical environment. The objective of this work was to calculate and validate such a library of lineal energy spectra.Approach. SuperTrack, a GPU-accelerated CUDA/C++ based application, was developed to superimpose tracks calculated using Geant4 onto targets of interest and to compute microdosimetric spectra. Lineal energy spectra of protons with energies from 0.1 to 100 MeV were determined in spherical targets of diameters from 1 nm to 10µm and in bounding voxels with side lengths of 5µm and 3 mm.Main results.Compared to an analogous Geant4-based application, SuperTrack is up to 3500 times more computationally efficient if each track is resampled 1000 times. Dose spectra of lineal energy and dose-mean lineal energy calculated with SuperTrack were consistent with values published in the literature and with comparison to a Geant4 simulation. Using SuperTrack, we developed the largest known library of proton microdosimetric spectra as a function of primary proton energy, target size, and bounding volume size.Significance. SuperTrack greatly increases the computational efficiency of the calculation of microdosimetric spectra. The elevated lineal energy observed in a 3 mm side length bounding volume suggests that lineal energy spectra determined experimentally or computed in small bounding volumes may not be representative of the lineal energy spectra in voxels of a dose calculation grid. The library of lineal energy spectra calculated in this work could be integrated with a treatment planning system for rapid determination of lineal energy spectra in patient geometries.

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.

Intensity-modulated radiation therapy - you can have your cake and eat it too!

PURPOSE: Arguably, intensity-modulated radiotherapy (IMRT) is one of the most important contributions by physicists in medicine to the treatment of cancer. It enabled the achievement of dose distributions that allowed treatment of targets to high doses and yet spared normal tissues to degrees previously considered virtually impossible. The concept underlying IMRT for photons, originally called "inverse planning," was introduced by Anders Brahme in the early 1980s. Since then, many physicists have been conducting research to advance the state of the art, to overcome obstacles discovered and to develop tools and techniques to translate it clinically. IMRT was first implemented clinically the early 1990's. Soon thereafter, it was also incorporated into intensity modulated particle therapy (IMPT), initially for protons and eventually for ions heavier than protons. METHODS: In IMRT, intensities of small segments or beamlets of multiple incident beams are optimized to produce the best approximation of desired dose distributions that deliver the requisite tumor dose and maximally spare normal tissues. Such dose distributions are delivered using dynamic multi-leaf collimators whose leaves move continuously while the radiation is on or in a step-and-shoot fashion. For IMPT, there is an extra degree of freedom, that of energies of particle beamlets, which are part of the optimization process. IMPT dose distributions allow substantial additional sparing of normal tissues. They are delivered using scanning beams. RESULTS: IMRT and IMPT represents a true paradigm shift in the way cancer patients are treated. Their evolution, especially that of IMPT, is still ongoing, with new advancements being added continually. With the improving understanding of the immunomodulatory effects of radiotherapy, it is quite plausible that a combination of IMPT and immunotherapy will mature into one of the most effective ways of treating not just localized cancers but also systemic disease.

Optimization of mesh generation for geometric accuracy, robustness, and efficiency of biomechanical-model-based deformable image registration.

BACKGROUND: Successful generation of biomechanical-model-based deformable image registration (BM-DIR) relies on user-defined parameters that dictate surface mesh quality. The trial-and-error process to determine the optimal parameters can be labor-intensive and hinder DIR efficiency and clinical workflow. PURPOSE: To identify optimal parameters in surface mesh generation as boundary conditions for a BM-DIR in longitudinal liver and lung CT images to facilitate streamlined image registration processes. METHODS: Contrast-enhanced CT images of 29 colorectal liver cancer patients and end-exhale four-dimensional CT images of 26 locally advanced non-small cell lung cancer patients were collected. Different combinations of parameters that determine the triangle mesh quality (voxel side length and triangle edge length) were investigated. The quality of DIRs generated using these parameters was evaluated with metrics for geometric accuracy, robustness, and efficiency. Metrics for geometric accuracy included target registration error (TRE) of internal vessel bifurcations, dice similar coefficient (DSC), mean distance to agreement (MDA), Hausdorff distance (HD) for organ contours, and number of vertices in the triangle mesh. American Association of Physicists in Medicine Task Group 132 was used to ensure parameters met TRE, DSC, MDA recommendations before the comparison among the parameters. Robustness was evaluated as the success rate of DIR generation, and efficiency was evaluated as the total time to generate boundary conditions and compute finite element analysis. RESULTS: Voxel side length of 0.2 cm and triangle edge length of 3 were found to be the optimal parameters for both liver and lung, with success rate of 1.00 and 0.98 and average DIR computation time of 100 and 143 s, respectively. For this combination, the average TRE, DSC, MDA, and HD were 0.38-0.40, 0.96-0.97, 0.09-0.12, and 0.87-1.17 mm, respectively. CONCLUSION: The optimal parameters were found for the analyzed patients. The decision-making process described in this study serves as a recommendation for BM-DIR algorithms to be used for liver and lung. These parameters can facilitate consistence in the evaluation of published studies and more widespread utilization of BM-DIR in clinical practice.

Coronary artery calcium score on standard of care oncologic CT scans for the prediction of adverse cardiovascular events in patients with non-small cell lung cancer treated with concurrent chemoradiotherapy.

Introduction: Chemoradiotherapy (CRT) has been associated with increased incidence of cardiovascular (CV) adverse events (CVAE). Coronary artery calcium scoring (CAC) has shown to predict coronary events beyond the traditional CV risk factors. This study examines whether CAC, measured on standard of care, non-contrast chest CT (NCCT) imaging, predicts the development of CVAE in patients with non-small cell lung cancer (NSCLC) treated with CRT. Methods: Patients with NSCLC treated with CRT at MD Anderson Cancer Center from 7/2009 until 4/2014 and who had at least one NCCT scan within 6 months from their first CRT were identified. CAC scoring was performed on NCCT scans by an expert cardiologist and a cardiac radiologist following the 2016 SCCT/STR guidelines. CVAE were graded based on the most recent Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CVAE were also grouped into (i) coronary/vascular events, (ii) arrhythmias, or (iii) heart failure. All CVAE were adjudicated by a board-certified cardiologist. Results: Out of a total of 193 patients, 45% were female and 91% Caucasian. Mean age was 64 ± 9 years and mean BMI 28 ± 6 kg/m2. Of 193 patients, 74% had CAC >0 Agatston units (AU), 49% CAC ≥100 AU and 36% CAC ≥300 AU. Twenty-nine patients (15%) developed a grade ≥2 CVAE during a median follow-up of 24.3 months (IQR: 10.9-51.7). Of those, 11 (38%) were coronary/vascular events. In the multivariate cox regression analysis, controlling for mean heart dose and pre-existing CV disease, higher CAC score was independently associated with development of a grade ≥2 CVAE [HR: 1.04 (per 100 AU), 95% CI: 1.01-1.08, p = 0.022] and with worse overall survival (OS; CAC ≥100 vs. <100 AU, HR: 1.64, 95% CI: 1.11-2.44, p = 0.013). In a sub-analysis evaluating the type of the CVAE, it was the coronary/vascular events that were significantly associated with higher baseline CAC (median: 676 AU vs. 73 AU, p = 0.035). Discussion: Cardiovascular adverse events are frequent in patients with NSCLC treated with CRT. CAC calculated on "standard of care" NCCT can predict the development of CVAEs and specifically coronary/vascular events, as well as OS, independently from other traditional risk factors and radiation mean heart dose. Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT00915005], identifier [NCT00915005].

A Review of Proton Therapy - Current Status and Future Directions.

The original rationale for proton therapy was the highly conformal depth-dose distributions that protons are able to produce, compared to photons, which allow greater sparing of normal tissues and escalation of tumor doses, thus potentially improving outcomes. Additionally, recent research, which is still ongoing, has revealed previously unrecognized advantages of proton therapy. For instance, the higher relative biological effectiveness (RBE) near the end of the proton range can be exploited to increase the difference in biologically effective dose in tumors vs. normal tissues. Moreover, the smaller "dose bath", i.e., the compact nature of proton dose distributions has been found to reduce exposure of circulating lymphocytes and the immune organs at risk. There is emerging evidence that the resulting sparing of the immune system has the potential to improve outcomes. Protons, accelerated to therapeutic energies ranging from 70 to 250 MeV, are transported to the treatment room where they enter the treatment head mounted on a rotating gantry. The initially narrow beams of protons are spread laterally and longitudinally and shaped appropriately to deliver treatments. Spreading and shaping can be achieved by electro-mechanically for "passively-scattered proton therapy' (PSPT); or using magnetic scanning of thin "beamlets" of protons of a sequence of initial energies. The latter technique is used to treat patients with optimized intensity modulated proton therapy (IMPT), the most powerful proton therapy modality, which is rapidly supplanting PSPT. Treatment planning and plan evaluation for proton therapy require different techniques compared to photon therapy due, in part, to the greater vulnerability of protons to uncertainties, especially those introduced by inter- and intra-fractional variations in anatomy. In addition to anatomic variations, other sources of uncertainty in the treatments delivered include the approximations and assumptions of models used for computing dose distributions and the current practice of proton therapy of assuming the RBE to have a constant value of 1.1. In reality, the RBE is variable and a complex function of proton energy, dose per fraction, tissue and cell type, end point, etc. Despite the high theoretical potential of proton therapy, the clinical evidence supporting its broad use has so far been mixed. The uncertainties and approximations mentioned above, and the technological limitations of proton therapy may have diminished its true clinical potential. It is generally acknowledged that proton therapy is safe, effective and recommended for many types of pediatric cancers, ocular melanomas, chordomas and chondrosarcomas. Promising results have been and continue to be reported for many other types of cancers as well; however, they are based on small studies. At the same time, there have been reports of unforeseen toxicities. Furthermore, because of the high cost of establishing and operating proton therapy centers, questions are often raised about the value of proton therapy. The general consensus is that there is a need for continued improvement in the state of the art of proton therapy. There is also a need to conduct randomized trials and/or collect outcomes data in multi-institutional registries to generate high level evidence of the advantages of protons. Fortuitously, such efforts are taking currently place. Ongoing research is aimed at better understanding the biological and immunomodulatory effects of proton therapy and the consequences of the physical uncertainties on proton therapy and reducing them through image-guidance and adaptive radiotherapy. Since residual uncertainties will remain despite our best efforts, in order to increase the resilience of dose distributions in the face of uncertainties and improve our confidence in dose distributions seen on treatment plans, robust optimization techniques are being developed and implemented and continue to be perfected. Such research and continuing technological advancements in planning and delivery methods are likely to help demonstrate the superiority of protons.

Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC.

Introduction: Durvalumab after concurrent chemoradiation (CCRT) for NSCLC improves survival, but only in a subset of patients. We investigated the effect of severe radiation-induced lymphopenia (sRIL) on survival in these patients. Methods: Outcomes after CCRT (2010-2019) or CCRT followed by durvalumab (2018-2019) were reviewed. RIL was defined by absolute lymphocyte count (ALC) nadir in samples collected at end of CCRT; sRIL was defined as nadir ALC less than 0.23 × 109/L (the lowest tertile). Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Cox proportional hazard modeling evaluated associations between clinical variables and survival. Results: Of 309 patients, 192 (62%) received CCRT only and 117 (38%) CCRT plus durvalumab. Multivariable logistic regression analysis indicated that sRIL was associated with planning target volume (OR = 1.002, p = 0.001), stage IIIB disease (OR = 2.77, p = 0.04), and baseline ALC (OR = 0.36, p < 0.01). Durvalumab extended median PFS (23.3 versus 14.1 mo, p = 0.003) and OS (not reached versus 30.8 mo, p < 0.01). sRIL predicted poorer PFS and OS in both treatment groups. Among patients with sRIL, durvalumab did not improve survival (median = 24.6 mo versus 18.1 mo CCRT only, p = 0.079). On multivariable analyses, sRIL (OR = 1.81, p < 0.01) independently predicted poor survival. Conclusions: Severe RIL compromises survival benefits from durvalumab after CCRT for NSCLC. Measures to mitigate RIL after CCRT may be warranted to enhance the benefit of consolidation durvalumab.

Personalized mid-course FDG-PET based adaptive treatment planning for non-small cell lung cancer using machine learning and optimization.

Objective. Traditional radiotherapy (RT) treatment planning of non-small cell lung cancer (NSCLC) relies on population-wide estimates of organ tolerance to minimize excess toxicity. The goal of this study is to develop a personalized treatment planning based on patient-specific lung radiosensitivity, by combining machine learning and optimization.Approach. Sixty-nine non-small cell lung cancer patients with baseline and mid-treatment [18]F-fluorodeoxyglucose (FDG)-PET images were retrospectively analyzed. A probabilistic Bayesian networks (BN) model was developed to predict the risk of radiation pneumonitis (RP) at three months post-RT using pre- and mid-treatment FDG information. A patient-specific dose modifying factor (DMF), as a surrogate for lung radiosensitivity, was estimated to personalize the normal tissue toxicity probability (NTCP) model. This personalized NTCP was then integrated into a NTCP-based optimization model for RT adaptation, ensuring tumor coverage and respecting patient-specific lung radiosensitivity. The methodology was employed to adapt the treatment planning of fifteen NSCLC patients.Main results. The magnitude of the BN predicted risks corresponded with the RP severity. Average predicted risk for grade 1-4 RP were 0.18, 0.42, 0.63, and 0.76, respectively (p< 0.001). The proposed model yielded an average area under the receiver-operating characteristic curve (AUROC) of 0.84, outperforming the AUROCs of LKB-NTCP (0.77), and pre-treatment BN (0.79). Average DMF for the radio-tolerant (RP grade = 1) and radiosensitive (RP grade ≥ 2) groups were 0.8 and 1.63,p< 0.01. RT personalization resulted in five dose escalation strategies (average mean tumor dose increase = 6.47 Gy, range = [2.67-17.5]), and ten dose de-escalation (average mean lung dose reduction = 2.98 Gy [0.8-5.4]), corresponding to average NTCP reduction of 15% [4-27].Significance. Personalized FDG-PET-based mid-treatment adaptation of NSCLC RT could significantly lower the RP risk without compromising tumor control. The proposed methodology could help the design of personalized clinical trials for NSCLC patients.

Lymphocyte Depletion Rate as a Biomarker of Radiation Dose to Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy.

Purpose: Radiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes. Methods and Materials: Patient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of the radiation plan that determine circulating blood dose. Results: During partial-body radiation, lymphocyte loss rates are determined by physical parameters of the radiation plan that reflect radiation exposure to circulating cells, including target volume size, dose per fraction squared, and anatomic site treated. Differences in observed versus predicted lymphocyte loss rates may be partly explained by variations in concurrent chemotherapy regimens. Conclusions: We describe a novel method of using patient-specific lymphocyte loss kinetics to approximate the effective radiation dose to circulating lymphocytes during focal fractionated photon radiation therapy. Clinical applications of these findings include the early identification of patients at particularly high risk of severe radiation-induced lymphopenia based on physical parameters of the radiation therapy plan.

Optimization of FLASH proton beams using a track-repeating algorithm.

BACKGROUND: Radiation with high dose rate (FLASH) has shown to reduce toxicities to normal tissues around the target and maintain tumor control with the same amount of dose compared to conventional radiation. This phenomenon has been widely studied in electron therapy, which is often used for shallow tumor treatment. Proton therapy is considered a more suitable treatment modality for deep-seated tumors. The feasibility of FLASH proton therapy has recently been demonstrated by a series of pre- and clinical trials. One of the challenges is to efficiently generate wide enough dose distributions in both lateral and longitudinal directions to cover the entire tumor volume. The goal of this paper is to introduce a set of automatic FLASH proton beam optimization algorithms developed recently. PURPOSE: To develop a fast and efficient optimizer for the design of a passive scattering proton FLASH radiotherapy delivery at The University of Texas MD Anderson Proton Therapy Center, based on the fast dose calculator (FDC). METHODS: A track-repeating algorithm, FDC, was validated versus Geant4 simulations and applied to calculate dose distributions in various beamline setups. The design of the components was optimized to deliver homogeneous fields with well-defined diameters between 11.0 and 20.5 mm, as well as a spread-out Bragg peak (SOBP) with modulations between 8.5 and 39.0 mm. A ridge filter, a high-Z material scatterer, and a collimator with range compensator were inserted in the beam path, and their shapes and sizes were optimized to spread out the Bragg peak, widen the beam, and reduce the penumbra. The optimizer was developed and tested using two proton energies (87.0 and 159.5 MeV) in a variety of beamline arrangements. Dose rates of the optimized beams were estimated by scaling their doses to those of unmodified beams. RESULTS: The optimized 87.0-MeV beams, with a distance from the beam pipe window to the phantom surface (window-to-surface distance [WSD]) of 550 mm, produced an 8.5-mm-wide SOBP (proximal 90% to distal 90% of the maximum dose); 14.5, 12.0, and 11.0-mm lateral widths at the 50%, 80%, and 90% dose location, respectively; and a 2.5-mm penumbra from 80% to 20% in the lateral profile. The 159.5-MeV beam had an SOBP of 39.0 mm and lateral widths of 20.5, 15.0, and 12.5 mm at 50%, 80%, and 90% dose location, respectively, when the WSD was 550 mm. Wider lateral widths were obtained with increased WSD. The SOBP modulations changed when the ridge filters with different characteristics were inserted. Dose rates on the beam central axis for all optimized beams (other than the 87.0-MeV beam with 2000-mm WSD) were above that needed for the FLASH effect threshold (40 Gy/s) except at the very end of the depth dose profile scaling with a dose rate of 1400 Gy/s at the Bragg peak in the unmodified beams. The optimizer was able to instantly design the individual beamline components for each of the beamline setups, without the need of time intensive iterative simulations. CONCLUSION: An efficient system, consisting of an optimizer and an FDC have been developed and validated in a variety of beamline setups, comprising two proton energies, several WSDs, and SOBPs. The set of automatic optimization algorithms produces beam shaping element designs efficiently and with excellent quality.

National Effort to Re-Establish Heavy Ion Cancer Therapy in the United States.

In this review, we attempt to make a case for the establishment of a limited number of heavy ion cancer research and treatment facilities in the United States. Based on the basic physics and biology research, conducted largely in Japan and Germany, and early phase clinical trials involving a relatively small number of patients, we believe that heavy ions have a considerably greater potential to enhance the therapeutic ratio for many cancer types compared to conventional X-ray and proton radiotherapy. Moreover, with ongoing technological developments and with research in physical, biological, immunological, and clinical aspects, it is quite plausible that cost effectiveness of radiotherapy with heavier ions can be substantially improved.

Adaptation and dosimetric commissioning of a synchrotron-based proton beamline for FLASH experiments.

Objective. Irradiation with ultra-high dose rates (>40 Gy s-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length and size of accelerating cycles, repurposing the reference monitor for dose control, and expanding the field size with a custom double-scattering system. We performed the dosimetric commissioning with measurements using an Advanced Markus chamber and EBT-XD films as well as with Monte Carlo simulations.Main results. Through adaptations, we have successfully achieved FLASH irradiation conditions, with an average dose rate of up to 375 Gy s-1. The Advanced Markus chamber was shown to be appropriate for absolute dose calibration under our FLASH conditions with a recombination factor ranging from 1.002 to 1.006 because of the continuous nature of our synchrotron-based proton delivery within a spill. Additionally, the absolute dose measured using the Advanced Markus chamber and EBT-XD films agreed well, with average and maximum differences of 0.32% and 1.63%, respectively. We also performed a comprehensive temporal analysis for FLASH spills produced by our system, which helped us identify a unique relationship between the average dose rate and the dose in our FLASH irradiation.Significance.We have established a synchrotron-based proton FLASH irradiation platform with accurate and precise dosimetry that is suitable for pre-clinical biology experiments. The unique time structure of the FLASH irradiation produced by our synchrotron-based system may shed new light onto the mechanism behind the FLASH effect.