Development of an algorithm for proton dose calculation in magnetic fields.

BACKGROUND: The advantages of proton therapy can be further enhanced with online magnetic resonance imaging (MRI) guidance. One of the challenges in the realization of MRI-guided proton therapy (MRPT) is accurately calculating the radiation dose in the presence of magnetic fields. PURPOSE: This study aims to develop an efficient and accurate proton dose calculation algorithm adapted to the presence of magnetic fields. METHODS: An analytical-numerical radiation dose calculation algorithm, Proton and Ion Dose Engine (PRIDE), was developed. The algorithm combines the pencil beam algorithm (PBA) with a novel iterative voxel-based ray-tracing algorithm. The new ray-tracing method uses fewer assumptions and ensures broader applicability for proton beam trajectory prediction in magnetic fields, and has been compared to Wolf's method and Schellhammer's method. The accuracy of PRIDE algorithm was validated on three phantoms and two practical plans (one single-field water plan and one prostate tumor plan) in different magnetic field strengths up to 3.0 T. The validation was performed by comparing the results against the Monte Carlo (MC) simulations, using the global gamma index criteria of 2%/2 mm and 3%/3 mm with a 10% threshold. RESULTS: PRIDE showed good agreement with MC in homogeneous and slab heterogeneous phantom, achieving gamma passing rates (%GPs) above 99% for 2%/2 mm criteria when magnetic field strength is not greater than 1.5 T. Although the agreement decreased for scenarios involving high proton energy (240 MeV) and strong magnetic field (3.0 T), the 2%/2 mm %GPs still remained above 98%. In lateral heterogeneous phantom, the accuracy of PRIDE decreased due to the PBA's limitation. For the two practical plans in different magnetic fields, %GPs exceeded 98% and 99% for 2%/2 mm and 3%/3 mm criteria, respectively. CONCLUSIONS: PRIDE can perform efficient and accurate proton dose calculation in magnetic fields up to 3.0 T, and is expected to work as a useful tool for proton dose calculation in MRPT.

Impact of iodinated oil in proton therapy on relative stopping power of liver post-cTACE.

Objective. Conventional transarterial chemoembolization (cTACE) is a common treatment for hepatocellular carcinoma (HCC), often with unsatisfactory local controls. Combining cTACE with radiotherapy shows a promise for unresectable large HCC, with proton therapy preserving healthy liver tissue. However, the proton therapy benefits are subject to the accuracy of tissue relative stopping power (RSP) prediction. The RSP values are typically derived from computed tomography (CT) images using stoichiometric calibration. Lipiodol deposition significantly increases CT numbers in liver regions of post-cTACE. Hence, it is necessary to evaluate the accuracy of RSP in liver regions of post-cTACE.Approach. Liver, water, and iodinated oil samples were prepared. Some liver samples contained iodinated oil. The water equivalent path length (WEPL) of sample was measured through the pullbacks of spread-out Bragg peak (SOBP) depth-dose profiles scanned in a water tank with and without sample in the beam path. Measured RSP values were compared to estimated RSP values derived from the CT number based on the stoichiometric calibration method.Main results. The measured RSP of water was 0.991, confirming measurement system calibration. After removing the RSP contribution from container walls, the pure iodinated oil and liver samples had RSP values of 1.12 and 1.06, while the liver samples mixed with varying oil volumes (5 ml, 10 ml, 15 ml) showed RSP values of 1.05, 1.05 and 1.06. Using the stoichiometric calibration method, pure iodinated oil and liver samples had RSP values of 2.79 and 1.06. Liver samples mixed with iodinated oil (5 ml, 10 ml, 15 ml) had calculated RSP values of 1.21, 1.34, and 1.46. The RSP discrepancy reached 149.1% for pure iodinated oil.Significance.Iodinated oil notably raises CT numbers in liver tissue. However, there is almost no effect on its RSP value. Proton treatment of post-cTACE HCC patients can therefore be overshooting if no proper measures are taken against this specific effect.

Comprehensive beam delivery latency evaluation for gated proton therapy system using customized multi-channel signal acquisition platform.

PURPOSE: Beam delivery latency in respiratory-gated particle therapy systems is a crucial issue to dose delivery accuracy. The aim of this study is to develop a multi-channel signal acquisition platform for investigating gating latencies occurring within RPM respiratory gating system (Varian, USA) and ProBeam proton treatment system (Varian, USA) individually. METHODS: The multi-channel signal acquisition platform consisted of several electronic components, including a string position sensor for target motion detection, a photodiode for proton beam sensing, an interfacing board for accessing the trigger signal between the respiratory gating system and the proton treatment system, a signal acquisition device for sampling and synchronizing signals from the aforementioned components, and a laptop for controlling the signal acquisition device and data storage. RPM system latencies were determined by comparing the expected gating phases extracted from the motion signal with the trigger signal's state turning points. ProBeam system latencies were assessed by comparing the state turning points of the trigger signal with the beam signal. The total beam delivery latencies were calculated as the sum of delays in the respiratory gating system and the cyclotron proton treatment system. During latency measurements, simulated sinusoidal motion were applied at different amplitudes and periods for complete beam delivery latency evaluation under different breathing patterns. Each breathing pattern was repeated 30 times for statistical analysis. RESULTS: The measured gating ON/OFF latencies in the RPM system were found to be 104.20 ± 13.64 ms and 113.60 ± 14.98 ms, respectively. The measured gating ON/OFF delays in the ProBeam system were 108.29 ± 0.85 ms and 1.20 ± 0.04 ms, respectively. The total beam ON/OFF latencies were determined to be 212.50 ± 13.64 ms and 114.80 ± 14.98 ms. CONCLUSION: With the developed multi-channel signal acquisition platform, it was able to investigate the gating lags happened in both the respiratory gating system and the proton treatment system. The resolution of the platform is enough to distinguish the delays at the millisecond time level. Both the respiratory gating system and the proton treatment system made contributions to gating latency. Both systems contributed nearly equally to the total beam ON latency, with approximately 100 ms. In contrast, the respiratory gating system was the dominant contributor to the total beam OFF latency.

A practical and robust method for beam blocker-based cone beam CT scatter correction.

Objective. In the traditional beam-blocker based cone beam CT (CBCT) scatter correction, the scatter measured in the region shaded by lead strips was multiplied by a correction factor to directly represent the scatter in the unblocked region. The correction factor optimization is a tedious process and lacks an objective stop criterion. To skip the optimization process, an indirect scatter estimation method was developed and validated in phantom imaging.Approach.A beam-blocker made of lead strips was mounted between the x-ray source and object for scatter estimation. The primary signal between lead strips in the blocked region was first calculated by subtracting the measured scatter, and then used to calculate the scatter signal in the unblocked region corresponding to the same attenuation path. The calculated scatter signal was smoothed via local filtration and used to correct the measured projection in the unblocked region. Finally, the CBCT was reconstructed via Feldkamp-Davis-Kress algorithm. A Catphan and a head phantom were used to verify the performance of the proposed method in both full- and half-blocker scenarios, and with and without a bow-tie filter.Main Results. For scans without the bow-tie filter, the CT number error was reduced to 3.97±2.27 and 5.51±3.90 HU in the full- and half-blocker scenarios, respectively, for the Catphan, and to 4.01±2.18 and 7.97 ± 4.05 HU for the head phantom. When the bow-tie filter was applied, the CT number error was reduced to 2.29±1.42 and 6.72±0.77 HU in the full- and half-blocker scenarios, respectively, for the Catphan, and 2.35±1.25 and 4.96 ± 1.89 HU for the head phantom.Significance. The proposed method effectively avoids the influence of the inserted beam blocker itself on the scatter intensity estimation, and proves a more practical and robust way for the beam-blocker based scatter correction in CBCT scanning.

Improvement of proton beam range uncertainty in breast treatment using tissue samples.

Objective.Proton therapy after breast-conserving surgery (BCS) can substantially reduce the dose to lung and cardiac structures. However, these dosimetric benefits are subject to beam range uncertainty in patient. The conversion of the CT-Hounsfield unit (HU) into relative stopping power (RSP) is the primary contribution to range uncertainty. Hence, an accurate HU-RSP conversion is essential.Approach.Real tissue samples, including muscle and adipose, were prepared. The water equivalent path length (WEPL) of these samples was measured under homogeneous conditions using a 12-diode detector array of our time-resolvedin vivorange verification system (IRVS). The HU-RSP conversion was improved using the measured WEPL and HU for adipose tissue. The measured WEPL values were compared with the treatment planning calculation results based on the stoichiometric CT-HU calibration technique. The effect was investigated for both with and without adipose tissue in HU-RSP conversion.Main results.The IRVS was calibrated based on the solid water phantom. The relative differences in WEPL (RSP) between measurements and calculations for muscle, adipose, and water was -1.19% (-0.75%), -4.25%(-4%), and -0.23%(-0.07%), respectively. Based on the improved HU-RSP conversion, the relative differences in WEPL was reduced to -0.97%(-0.62%), -1.50%(-1.46%), and -0.22% (0.00%), respectively.Significance.The WEPL deviation of adipose tissue is larger than the testing limit of 3.5% for beam range robustness in current clinical practice. However, the improved HU-RSP conversion reduced this deviation. The main component of breast tissue is adipose. Hence, the proton treatment of BCS can be undershooting if no proper measures are taken against this specific uncertainty.

A deep LSTM autoencoder-based framework for predictive maintenance of a proton radiotherapy delivery system.

INTRODUCTION: Unscheduled machine downtime can cause treatment interruptions and adversely impact patient treatment outcomes. Conventional Quality Assurance (QA) programs of a proton Pencil Beam Scanning (PBS) system ensure its operational performance by keeping the beam parameters within clinical tolerances but often do not reveal the underlying issues of the device prior to a machine malfunction event. In this study, we propose a Predictive Maintenance (PdM) approach that leverages an advanced analytical tool built on a deep neural network to detect treatment delivery machine issues early. METHODS: Beam delivery log file data from daily QA performed at the Burr Proton Center of Massachusetts General Hospital were collected. A novel PdM framework consisting of long short-term memory-based autoencoder (LSTM-AE) modeling of the proton PBS delivery system and a Mahalanobis distance-based error metric evaluation was constructed to detect rare anomalous machine events. These included QA beam pauses, clinical operational issues, and treatment interruptions. The model was trained in an unsupervised fashion on the QA data of normal sessions so that the model learned characteristics of normal machine operation. The anomaly is quantified as the multivariate deviation between the model predicted data and the measured data of the day using Mahalanobis distance (M-Score). Two-layer and three-layer Long short-term memory-based stacked autoencoder (LSTM-SAE) models were optimized for exploring model performance improvement. Model validation was performed with two clinical datasets and was analyzed using the area under the precision-recall curve (AUPRC) and the area under the receiver operating characteristic (AUROC). RESULTS: LSTM-SAE models showed strong performance in predicting QA beam pauses for both clinical validation datasets. Despite severe skew in the dataset, the model achieved AUPRC of 0.60 and 0.82 and AUROC of 0.75 and 0.92 in the respective 2018 and 2020 datasets. Moreover, these amount to 2.8-fold and 10.7-fold enhancement compared to the respective baseline event rates. In addition, in terms of treatment interruption events, model prediction enabled 3.88-fold and 51.2-fold detection improvement, while the detection improvement for clinical operational issues was 1.04-fold and 1.37-fold, respectively, in the 2018 and 2020 datasets. CONCLUSION: Our novel deep LSTM-SAE-based framework allows for highly discriminative prediction of anomalous machine events and demonstrates great promise for enabling PdM for proton PBS beam delivery.

Accelerate treatment planning process using deep learning generated fluence maps for cervical cancer radiation therapy.

PURPOSE: This study aims to develop a deep learning method that skips the time-consuming inverse optimization process for automatic generation of machine-deliverable intensity-modulated radiation therapy (IMRT) plans. METHODS: Ninety cervical cancer clinical IMRT plans were collected to train a two-stage convolution neural network, of which 66 plans were assigned for training, 11 for validation, and 13 for test. The neural network took patients' computed tomography (CT) anatomy as the input and predicted the fluence map for each radiation beam. The predicted fluence maps were then imported into a treatment planning system and converted to multileaf collimators motion sequences. The automatic plan was evaluated against its corresponding clinical plan, and its machine deliverability was validated by patient-specific IMRT quality assurance (QA). RESULTS: There were no significant differences in dose parameters between automatic and clinical plans for all 13 test patients, indicating a good prediction of fluence maps and a decent quality of automatic plans. The average dice similarity coefficient of isodose volumes encompassed by 0%-100% isodose lines ranged from 0.94 to 1. In patient-specific IMRT QA, the mean gamma passing rate of automatic plans achieved 99.5% under 3%/3 mm criteria, and 97.3% under 2%/2 mm criteria, with a low dose threshold of 10%. CONCLUSIONS: The proposed deep learning framework can produce machine-deliverable IMRT plans with quality similar to the clinical plans in the test set. It skips the inverse plan optimization process and provides an effective and efficient method to accelerate treatment planning process.

Technical note: Does the greater power of pencil beam scanning reduce the need for a proton gantry? A study of head-and-neck and brain tumors.

PURPOSE: Proton therapy systems without a gantry can be more compact and less expensive in terms of capital cost and therefore more available to a larger patient population. Would the advances in pencil beam scanning (PBS) and robotics make gantry-less treatment possible? In this study, we explore if the high-quality treatment plans can be obtained without a gantry. METHODS AND MATERIALS: We recently showed that proton treatments with the patient in an upright position may be feasible with a new soft robotic immobilization device and imaging which enables multiple possible patient orientations during a treatment. In this study, we evaluate if this new treatment geometry could enable high quality treatment plans without a gantry. We created PBS treatment plans for seven patients with head-and-neck or brain tumors. Each patient was planned with two scenarios: one with a gantry with the patient in supine position and the other with a gantry-less fixed horizontal beam-line with the patient sitting upright. For the treatment plans, dose-volume-histograms (DVHs), target homogeneity index (HI), mean dose, D 2 ${D_2}$ , and D 98 ${D_{98}}$ are reported. A robustness analysis of one plan was performed with ± $ \pm $ 2.5-mm setup errors and ± $ \pm $ 3.5% range uncertainties with nine scenarios. RESULTS: Most of the PBS-gantry-less plans had similar target HI and organs-at-risk mean dose as compared to PBS-gantry plans and similar robustness with respect to range uncertainties and setup errors. CONCLUSIONS: PBS provides sufficient power to deliver high quality treatment plans without requiring a gantry for head-and-neck or brain tumors. In combination with the development of the new positioning and immobilization methods required to support this treatment geometry, this work suggests the feasibility of further development of a compact proton therapy system with a fixed horizontal beam-line to treat patients in sitting and reclined positions.

Investigating beam range uncertainty in proton prostate treatment using pelvic-like biological phantoms.

This study aims to develop a method for verifying site-specific and/or beam path specific proton beam range, which could reduce range uncertainty margins and the associated treatment complications. It investigates the range uncertainties from both CT HU to relative stopping power conversion and patient positioning errors for prostate treatment using pelvic-like biological phantoms. Three 25 × 14 × 12 cm3phantoms, made of fresh animal tissues mimicking the pelvic anatomies of prostate patients, were scanned with a general electric CT simulator. A 22 cm circular passive scattering beam with 29 cm range and 8 cm modulation width was used to measure the water equivalent path lengths (WEPL) through the phantoms at multiple points using the dose extinction method with a MatriXXPT detector. The measured WEPLs were compared to those predicted by TOPAS simulations and ray-tracing WEPL calculations. For the three phantoms, the WEPL differences between measured and theoretical prediction (WDMT) are below 1.8% for TOPAS, and 2.5% for ray-tracing. WDMT varies with phantom anatomies by about 0.5% for both TOPAS and ray-tracing. WDMT also correlates with the tissue types of a specific treated region. For the regions where the proton beam path is parallel to sharp bone edges, the WDMTs of TOPAS and ray-tracing respectively reach up to 1.8% and 2.5%. For the region where proton beams pass through just soft tissues, the WDMT is mostly less than 1% for both TOPAS and ray-tracing. For prostate treatments, range uncertainty depends on the tissue types within a specific treated region, patient anatomies and the range calculation methods in the planning algorithms. Our study indicates range uncertainty is less than 2.5% for the whole treated region with both ray-tracing and TOPAS, which suggests the potential to reduce the current 3.5% range uncertainty margin used in the clinics by at least 1% even for single-energy CT data.

A proof of concept treatment planning study of gated proton radiotherapy for cardiac soft tissue sarcoma.

BACKGROUND AND PURPOSE: Few studies on radiotherapy of cardiac targets exist, and none using a gating method according to cardiac movement. This study aimed to evaluate the dose-volume advantage of using cardiac-respiratory double gating (CRDG) in terms of target location with additional ECG signals in comparison to respiratory single gating (RSG) for proton radiotherapy of targets in the heart. MATERIALS AND METHODS: Cardiac motion was modeled using a cardiac-gated four-dimensional computed tomography scan obtained at the end-expiration. Plans with the prescription dose of 50 Gy (RSG and CRDG plans at diastole and systole phases) were compared in terms of clinically relevant dose-volume criteria for various target sizes and seven cardiac subsites. Potential dose sparing by utilizing CRDG over RSG was quantified in terms of surrounding organ at risk (OAR) doses while the dose coverage to the targets was fully ensured. RESULTS: The average mean dose reductions were 28 ± 10% when gated at diastole and 21 ± 12% at systole in heart and 30 ± 17% at diastole and 8 ± 9% at systole in left ventricle compared to respiratory single gating. The diastole phase was optimal for gated treatments for all target locations except right ventricle and interventricular septum. The right ventricle target was best treated at the systole phase. However, an optimal gating phase for the interventricular septum target could not be determined. CONCLUSIONS: We have studied the dose-volume benefits of CRDG for each cardiac subsite, and demonstrated that CRDG may spare organs at risk better than RSG.

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.

Targeting the DNA replication stress phenotype of KRAS mutant cancer cells.

Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.

Clinical commissioning of intensity-modulated proton therapy systems: Report of AAPM Task Group 185.

Proton therapy is an expanding radiotherapy modality in the United States and worldwide. With the number of proton therapy centers treating patients increasing, so does the need for consistent, high-quality clinical commissioning practices. Clinical commissioning encompasses the entire proton therapy system's multiple components, including the treatment delivery system, the patient positioning system, and the image-guided radiotherapy components. Also included in the commissioning process are the x-ray computed tomography scanner calibration for proton stopping power, the radiotherapy treatment planning system, and corresponding portions of the treatment management system. This commissioning report focuses exclusively on intensity-modulated scanning systems, presenting details of how to perform the commissioning of the proton therapy and ancillary systems, including the required proton beam measurements, treatment planning system dose modeling, and the equipment needed.

A new respiratory monitor system for four-dimensional computed tomography by measuring the pressure change on the back of body.

OBJECTIVE: A novel respiratory monitoring method based on the periodical pressure change on the patient's back was proposed and assessed by applying to four-dimensional CT (4DCT) scanning. METHODS: A pressure-based respiratory monitoring system is developed and validated by comparing to real-time position management (RPM) system. The pressure change and the RPM signal are compared with phase differences and correlations calculated. The 4DCT images are reconstructed by these two signals. Internal and skin artifacts due to mismatch between CT slices and respiratory phases are evaluated. RESULTS: The pressure and RPM signals shows strong consistency (R = 0.68±0.19 (1SD)). The time shift is 0.26 ± 0.51 (1SD) s and the difference of breath cycle is 0.02 ± 0.17 (1SD) s. The quality of 4DCT images reconstructed by two signals is similar. For both methods, the number of patients with artifacts is eight and the maximum magnitudes of artifacts are 20 mm (internal) and 10 mm (skin). The average magnitudes are 8.8 mm (pressure) and 8.2 mm (RPM) for internal artifacts, and 5.2 mm (pressure) and 4.6 mm (RPM) for skin artifacts. The mean square gray value difference shows no significant difference (p = 0.52). CONCLUSION: The pressure signal provides qualified results for respiratory monitoring in 4DCT scanning, demonstrating its potential application for respiration monitoring in radiotherapy. ADVANCES IN KNOWLEDGE: Pressure change on the back of body is a novel and promising method to monitor respiration in radiotherapy, which may improve treatment comfort and provide more information about respiration and body movement.

Volumetric and actuarial analysis of brain necrosis in proton therapy using a novel mixture cure model.

BACKGROUND AND PURPOSE: High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. MATERIALS AND METHODS: All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. RESULTS: Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. CONCLUSION: In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.

Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol.

INTRODUCTION: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer. METHODS: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events. ETHICS AND DISSEMINATION: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. TRIAL REGISTRATION NUMBER: NCT02603341.

Phase II Trial of Response-Based Radiation Therapy for Patients With Localized CNS Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study.

PURPOSE: Stratum 1 of ACNS1123 (ClinicalTrials.gov identifier: NCT01602666), a Children's Oncology Group phase II trial, evaluated efficacy of reduced-dose and volume of radiotherapy (RT) in children and adolescents with localized nongerminomatous germ cell tumors (NGGCTs). The primary objective was to evaluate the impact of reduced RT on progression-free survival (PFS) with a goal of preserving neurocognitive function. PATIENTS AND METHODS: Patients received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide, as used in the Children's Oncology Group predecessor study (ACNS0122; ClinicalTrials.gov identifier: NCT00047320). Patients who achieved a complete response (CR) or partial response (PR) with or without second-look surgery were eligible for reduced RT, defined as 30.6 Gy whole ventricular field and 54 Gy tumor-bed boost, compared with 36 Gy craniospinal irradiation plus 54 Gy tumor-bed boost used in ACNS0122. RESULTS: A total of 107 eligible patients were enrolled. Median age was 10.98 years (range, 3.68 to 21.63) and 75% were male. Sixty-six of 107 (61.7%) achieved a CR or PR and proceeded to reduced RT. The 3-year PFS and overall survival and standard error values were 87.8% ± 4.04% and 92.4% ± 3.3% compared with 92% and 94.1%, respectively, in ACNS0122. There were 10 recurrences, prompting early study closure; however, after a retrospective central review, only disease in eight of 66 (12.1%) patients eligible for reduced RT subsequently progressed; six patients had distant spinal relapse alone and two had disease with combined local plus distant relapse. Serum and CSF α-fetoprotein and ß-human chorionic gonadotropin levels were not associated with PFS. CONCLUSION: Patients with localized NGGCT who achieved a CR or PR to chemotherapy and received reduced RT had encouraging PFS similar to patients in ACNS0122 who received full-dose craniospinal irradiation. However, the patterns of failure were distinct, with all patients having treatment failure in the spine.

Phase II Study of Proton Beam Radiation Therapy for Patients With Breast Cancer Requiring Regional Nodal Irradiation.

PURPOSE: To evaluate the safety and efficacy of proton beam radiation therapy (RT) for patients with breast cancer who require regional nodal irradiation. METHODS: Patients with nonmetastatic breast cancer who required postoperative RT to the breast/chest wall and regional lymphatics and who were considered suboptimal candidates for conventional RT were eligible. The primary end point was the incidence of grade 3 or higher radiation pneumonitis (RP) or any grade 4 toxicity within 3 months of RT. Secondary end points were 5-year locoregional failure, overall survival, and acute and late toxicities per Common Terminology Criteria for Adverse Events (version 4.0). Strain echocardiography and cardiac biomarkers were obtained before and after RT to assess early cardiac changes. RESULTS: Seventy patients completed RT between 2011 and 2016. Median follow-up was 55 months (range, 17 to 82 months). Of 69 evaluable patients, median age was 45 years (range, 24 to 70 years). Sixty-three patients (91%) had left-sided breast cancer, two had bilateral breast cancer, and five had right-sided breast cancer. Sixty-five (94%) had stage II to III breast cancer. Sixty-eight (99%) received systemic chemotherapy. Fifty (72%) underwent immediate reconstruction. Median dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the internal mammary nodes, 48.8 Gy (relative biological effectiveness), which indicates comprehensive coverage. Among 62 surviving patients, the 5-year rates for locoregional failure and overall survival were 1.5% and 91%, respectively. One patient developed grade 2 RP, and none developed grade 3 RP. No grade 4 toxicities occurred. The unplanned surgical re-intervention rate at 5 years was 33%. No significant changes in echocardiography or cardiac biomarkers after RT were found. CONCLUSION: Proton beam RT for breast cancer has low toxicity rates and similar rates of disease control compared with historical data of conventional RT. No early cardiac changes were observed, which paves the way for randomized studies to compare proton beam RT with standard RT.

Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience.

PURPOSE: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era. METHODS AND MATERIALS: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. RESULTS: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95% confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity. CONCLUSIONS: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV.

Iterative optimization of relative stopping power by single detector based multi-projection proton radiography.

In proton therapy, range uncertainties induced by the conversion from x-ray CT (xCT) Hounsfield units (HU) to relative stopping power (RSP) compromise the precision of dose delivery. To reduce range uncertainties induced by HU-converted RSPs, this study investigates optimizing the RSP of individual voxels in xCT iteratively based on multi-projection proton radiography (pRG) acquired using a single amorphous silicon flat panel imager. Time-resolved dose rate functions (DRF) were measured by the imager placed downstream of a test phantom consisting of tissue substitute materials. Water equivalent path lengths (WEPL) in the pRG were derived. By rotating the phantom, multiple pRG projections were acquired at angles from 0 to 358° with an increment of 2°. X-ray CT of the phantom was acquired and co-registered with the pRG acquisition coordinates. RSPs of individual xCT voxels were optimized iteratively by minimizing the difference between the measured WEPLs and the calculated WEPLs by ray tracing with HU-converted RSPs. Pixels in pRGs that exhibited severe proton range mixing were rejected for the optimization. Tikhonov regularization was applied under the assumption that HU-converted RSPs are inaccurate, but the inaccuracy is within a few percent. While ~50% of WEPL pixels were rejected due to severe range mixing in pRG, RSPs of >90% CT voxels could still be optimized if multiple pRG projections, e.g. ⩾12, around the phantom are utilized. For tissue substitute materials in a cylindrical phantom, percentage errors of RSPs were reduced from a range of -8% to +4% to be within ±2%. Further optimization, achieved by implementing a material-specific regularization parameter, reduced percent errors to be within ±0.5%. This study demonstrates the concept of optimizing RSPs of individual CT voxels with multi-projection pRGs acquired by a single flat panel imager, which could be further explored and implemented in proton therapy to reduce range uncertainties.