Secondary neutron dosimetry for conformal FLASH proton therapy.

BACKGROUND: Cyclotron-based proton therapy systems utilize the highest proton energies to achieve an ultra-high dose rate (UHDR) for FLASH radiotherapy. The deep-penetrating range associated with this high energy can be modulated by inserting a uniform plate of proton-stopping material, known as a range shifter, in the beam path at the nozzle to bring the Bragg peak within the target while ensuring high proton transport efficiency for UHDR. Aluminum has been recently proposed as a range shifter material mainly due to its high compactness and its mechanical properties. A possible drawback lies in the fact that aluminum has a larger cross-section of producing secondary neutrons compared to conventional plastic range shifters. Accordingly, an increase in secondary neutron contamination was expected during the delivery of range-modulated FLASH proton therapy, potentially heightening neutron-induced carcinogenic risks to the patient. PURPOSE: We conducted neutron dosimetry using simulations and measurements to evaluate excess dose due to neutron exposure during UHDR proton irradiation with aluminum range shifters compared to plastic range shifters. METHODS: Monte Carlo simulations in TOPAS were performed to investigate the secondary neutron production characteristics with aluminum range shifter during 225 MeV single-spot proton irradiation. The computational results were validated against measurements with a pair of ionization chambers in an out-of-field region ( ≤ $\le$ 30 cm) and with a Proton Recoil Scintillator-Los Alamos rem meter in a far-out-of-field region (0.5-2.5 m). The assessments were repeated with solid water slabs as a surrogate for the conventional range shifter material to evaluate the impact of aluminum on neutron yield. The results were compared with the International Electrotechnical Commission (IEC) standards to evaluate the clinical acceptance of the secondary neutron yield. RESULTS: For a range modulation up to 26 cm in water, the maximum simulated and measured values of out-of-field secondary neutron dose equivalent per therapeutic dose with aluminum range shifter were found to be ( 0.57 ± 0.02 ) mSv/Gy $(0.57\pm 0.02)\ \text{mSv/Gy}$ and ( 0.46 ± 0.04 ) mSv/Gy $(0.46\pm 0.04)\ \text{mSv/Gy}$ , respectively, overall higher than the solid water cases (simulation: ( 0.332 ± 0.003 ) mSv/Gy $(0.332\pm 0.003)\ \text{mSv/Gy}$ ; measurement: ( 0.33 ± 0.03 ) mSv/Gy $(0.33\pm 0.03)\ \text{mSv/Gy}$ ). The maximum far out-of-field secondary neutron dose equivalent was found to be ( 8.8 ± 0.5 $8.8 \pm 0.5$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ and ( 1.62 ± 0.02 $1.62 \pm 0.02$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ for the simulations and rem meter measurements, respectively, also higher than the solid water counterparts (simulation: ( 3.3 ± 0.3 $3.3 \pm 0.3$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ ; measurement: ( 0.63 ± 0.03 $0.63 \pm 0.03$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ ). CONCLUSIONS: We conducted simulations and measurements of secondary neutron production under proton irradiation at FLASH energy with range shifters. We found that the secondary neutron yield increased when using aluminum range shifters compared to conventional materials while remaining well below the non-primary radiation limit constrained by the IEC regulations.

ACR benchmark testing of a novel high-speed ring-gantry linac kV-CBCT system.

A new generation cone-beam computed tomography (CBCT) system with new hardware design and advanced image reconstruction algorithms is available for radiation treatment simulation or adaptive radiotherapy (HyperSight CBCT imaging solution, Varian Medical Systems-a Siemens Healthineers company). This study assesses the CBCT image quality metrics using the criteria routinely used for diagnostic CT scanner accreditation as a first step towards the future use of HyperSight CBCT images for treatment planning and target/organ delineations. Image performance was evaluated using American College of Radiology (ACR) Program accreditation phantom tests for diagnostic computed tomography systems (CTs) and compared HyperSight images with a standard treatment planning diagnostic CT scanner (Siemens SOMATOM Edge) and with existing CBCT systems (Varian TrueBeam version 2.7 and Varian Halcyon version 2.0).  Image quality performance for all Varian HyperSight CBCT vendor-provided imaging protocols were assessed using ACR head and body ring CT phantoms, then compared to existing imaging modalities. Image quality analysis metrics included contrast-to-noise (CNR), spatial resolution, Hounsfield number (HU) accuracy, image scaling, and uniformity. All image quality assessments were made following the recommendations and passing criteria provided by the ACR. The Varian HyperSight CBCT imaging system demonstrated excellent image quality, with the majority of vendor-provided imaging protocols capable of passing all ACR CT accreditation standards. Nearly all (8/11) vendor-provided protocols passed ACR criteria using the ACR head phantom, with the Abdomen Large, Pelvis Large, and H&N vendor-provided protocols produced HU uniformity values slightly exceeding passing criteria but remained within the allowable minor deviation levels (5-7 HU maximum differences). Compared to other existing CT and CBCT imaging modalities, both HyperSight Head and Pelvis imaging protocols matched the performance of the SOMATOM CT scanner, and both the HyperSight and SOMATOM CT substantially surpassed the performance of the Halcyon 2.0 and TrueBeam version 2.7 systems. Varian HyperSight CBCT imaging system could pass almost all tests for all vendor-provided protocols using ACR accreditation criteria, with image quality similar to those produced by diagnostic CT scanners and significantly better than existing linac-based CBCT imaging systems.

Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

The effective radiation dose to immune cells predicts lymphopenia and inferior cancer control in locally advanced NSCLC.

PURPOSE: To explore the association of the effective dose to immune cells (EDIC) with disease control, lymphopenia, and toxicity in patients with non-small cell lung cancer (NSCLC) and identify methods to reduce EDIC. METHODS: We abstracted data from all patients with locally advanced NSCLC treated with chemoradiation with or without consolidative immunotherapy over a ten-year period. Associations between EDIC and progression-free survival (PFS) and overall survival (OS) were modeled with Cox proportional hazards and Kaplan-Meier method. Logistic regression was used to model predictors of lymphopenia and higher EDIC. Analyses were performed with EDIC as a continuous and categorical variable. Lymphopenia was graded per CTCAE v5.0. RESULTS: Overall, 786 patients were included (228 of which received consolidative immunotherapy); median EDIC was 4.7 Gy. Patients with EDIC < 4.7 Gy had a longer median PFS (15.3 vs. 9.0 months; p < 0.001) and OS (34.2 vs. 22.4 months; p < 0.001). On multivariable modeling, EDIC correlated with inferior PFS (HR 1.08, 95 % CI 1.01-1.14, p = 0.014) and OS (HR 1.10, 95 % CI 1.04-1.18, p = 0.002). EDIC was predictive of grade 4 lymphopenia (OR 1.16, 95 % CI 1.02-1.33, p = 0.026). EDIC ≥ 4.7 Gy was associated with increased grade 2 + pneumonitis (6-month incidence: 26 % vs 20 %, p = 0.04) and unplanned hospitalizations (90-day incidence: 40 % vs 30 %, p = 0.002). Compared to protons, photon therapy was associated with EDIC ≥ 4.7 Gy (OR 5.26, 95 % CI 3.71-7.69, p < 0.001) in multivariable modeling. CONCLUSIONS: EDIC is associated with inferior disease outcomes, treatment-related toxicity, and the development of severe lymphopenia. Proton therapy is associated with lower EDIC. Further investigations to limit radiation dose to the immune system appear warranted.

Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging in Radiation Therapy Treatment Planning: A Review of PET Imaging Tracers and Methods to Incorporate PET/CT.

Purpose: Positron emission tomography (PET)/computed tomography (CT) has become a critical tool in clinical oncology with an expanding role in guiding radiation treatment planning. As its application and availability grows, it is increasingly important for practicing radiation oncologists to have a comprehensive understanding of how molecular imaging can be incorporated into radiation planning and recognize its potential limitations and pitfalls. The purpose of this article is to review the major approved positron-emitting radiopharmaceuticals clinically being used today along with the methods used for their integration into radiation therapy including methods of image registration, target delineation, and emerging PET-guided protocols such as biologically-guided radiation therapy and PET-adaptive therapy. Methods and Materials: A review approach was utilized using collective information from a broad review of the existing scientific literature sourced from PubMed search with relevant keywords and input from a multidisciplinary team of experts in medical physics, radiation treatment planning, nuclear medicine, and radiation therapy. Results: A number of radiotracers imaging various targets and metabolic pathways of cancer are now commercially available. PET/CT data can be incorporated into radiation treatment planning through cognitive fusion, rigid registration, deformable registration, or PET/CT simulation techniques. PET imaging provides a number of benefits to radiation planning including improved identification and delineation of the radiation targets from normal tissue, potential automation of target delineation, reduction of intra- and inter-observer variability, and identification of tumor subvolumes at high risk for treatment failure which may benefit from dose intensification or adaptive protocols. However, PET/CT imaging has a number of technical and biologic limitations that must be understood when guiding radiation treatment. Conclusion: For PET guided radiation planning to be successful, collaboration between radiation oncologists, nuclear medicine physicians, and medical physics is essential, as well as the development and adherence to strict PET-radiation planning protocols. When performed properly, PET-based radiation planning can reduce treatment volumes, reduce treatment variability, improve patient and target selection, and potentially enhance the therapeutic ratio accessing precision medicine in radiation therapy.

A comparative study of machine-learning approaches in proton radiography using energy-resolved dose function.

PURPOSE: The feasibility of machine learning (ML) techniques and their performance compared to the conventional χ2-minimization technique in the context of the proton energy-resolved dose imaging method are presented. MATERIALS AND METHOD: Various geometries resembling a wedge and varying gradients are simulated in GATE to obtain energy-resolved dose functions (ERDF) from proton beams of different energies. These ERDFs are used to predict the WEPL using a conventional technique and other ML-based methods. The results are compared to gain an understanding of the performance of ML models in proton radiography. RESULTS: The results obtained from the χ2-minimization technique indicate that it is robust and more reliable compared to the ML-based techniques. It is also observed that the ML-based techniques did not mitigate the effect of range-mixing but seem to be more affected by it compared to the χ2-minimization technique. Substantial data reduction was required in order to make the results of ML-based methods comparable to that of χ2-minimization. We also note that such data reduction might not be possible in a clinical setting. The only advantage in using the ML-based technique is the computational time required to generate a WEPL map which, in our case study, is 10-30 times shorter than the time required for the conventional χ2-minimization technique. CONCLUSIONS: The first results from this preliminary study indicate that the ML techniques failed to be on par with the conventional χ2-minimization technique in terms of the achievable accuracy in the predictions of WEPL and in the mitigation of range-mixing effects in the WEPL image. Modern strategies like the GAN-based models may be suitable for such applications.

Dosimetric Results for Adjuvant Proton Radiation Therapy of HPV-Associated Oropharynx Cancer.

Purpose: One significant advantage of proton therapy is its ability to improve normal tissue sparing and toxicity mitigation, which is relevant in the treatment of oropharyngeal squamous cell carcinoma (OPSCC). Here, we report our institutional experience and dosimetric results with adjuvant proton radiation therapy (PRT) versus intensity-modulated radiotherapy (IMRT) for Human Papilloma Virus (HPV)-associated OPSCC. Materials and Methods: This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved equivalent IMRT plan to serve as a reference. Endpoints included dosimetric outcomes to the organs at risk (OARs), local regional control (LRC), progression-free survival (PFS), and overall survival (OS). Descriptive statistics, a 2-tailed paired t test for dosimetric comparisons, and the Kaplan-Meier method for disease outcomes were used. Results: Fifty-three patients were identified. Doses delivered to OARs compared favorably for PRT versus IMRT, particularly for the pharyngeal constrictors, esophagus, larynx, oral cavity, and submandibular and parotid glands. The achieved normal tissue sparing did not negatively impact disease outcomes, with 2-year LRC, PFS, and OS of 97.0%, 90.3%, and 97.5%, respectively. Conclusion: Our study suggests that meaningful normal tissue sparing in the postoperative setting is achievable with PRT, without impacting disease outcomes.

Tubarial salivary gland sparing with proton therapy.

The recently identified bilateral macroscopic tubarial salivary glands present a potential opportunity for further toxicity mitigation for patients receiving head and neck radiotherapy. Here, we show superior dosimetric sparing of the tubarial salivary glands with proton radiation therapy (PRT) compared to intensity-modulated radiotherapy (IMRT) for patients treated postoperatively for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved, equivalent IMRT plan to serve as a reference. The main end point was dose delivered to the tubarial salivary glands by modality, assessed via a 2-tailed, paired t-test. We also report disease outcomes for the entire cohort, via the Kaplan-Meier method. Sixty-four patients were identified. The mean RT dose to the tubarial salivary glands was 23.6 Gy (95% confidence interval (CI) 21.7 to 25.5) and 30.4 Gy (28.6 to 32.2) for PRT and IMRT plans (p < 0.0001), respectively. With a median follow-up of 25.2 months, the two-year locoregional control, progression-free survival and overall survival were 97.8% (95% CI 85.6% to 99.7%), 94.1% (82.8% to 98.1%) and 98.1% (87.4% to 99.7%), respectively. Our study suggests that meaningful normal tissue sparing of the recently identified tubarial salivary glands is achievable with PRT. The apparent gains with PRT did not impact disease outcomes, with only 1 observed locoregional recurrence (0 local, 1 regional). Further studies are warranted to explore the impact of the improved dosimetric sparing of the tubarial salivary glands conveyed by PRT on patient toxicity and quality of life.

Stricter Postoperative Oropharyngeal Cancer Radiation Therapy Normal Tissue Dose Constraints Are Feasible.

PURPOSE: Although dose de-escalation is one proposed strategy to mitigate long-term toxicity in human papillomavirus associated oropharyngeal cancer, applying more stringent normal tissue constraints may be a complementary approach to further reduce toxicity. Our study demonstrates that in a postoperative setting, improving upon nationally accepted constraints is achievable and leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease control. METHODS AND MATERIALS: We identified 92 patients at our institution between 2015 and 2019 with p16+ oropharyngeal cancer who were treated with adjuvant volumetric modulated arc therapy. We included patients treated to postoperative doses and standard volumes (including bilateral neck). Doses delivered to organs at risk were compared with recommended dose constraints from a recent cooperative group head and neck cancer trial of radiation therapy to 60 Gy. We applied validated and published NTCP models for dysphagia, dysgeusia, esophagitis, oral mucositis, and xerostomia relevant to oropharyngeal cancer. RESULTS: Achievable and delivered mean doses to most normal head and neck tissues were well below national recommended constraints. This translates to notable absolute NTCP reductions for salivary flow (10% improvement in contralateral parotid, 35% improvement in submandibular gland), grade ≥ 2 esophagitis (23% improvement), grade ≥ 3 mucositis (17% improvement), dysgeusia (10% improvement), and dysphagia (8% improvement). Locoregional control at a median follow-up of 26.3 months was 96.7%, with only 3 patients experiencing locoregional recurrence (1 local, 2 regional). CONCLUSIONS: Modern radiation therapy planning techniques allow for improved normal tissue sparing compared with currently established dose constraints without compromising disease control. These improvements may lead to reduced toxicity in a patient population expected to have favorable long-term outcomes. Stricter constraints can be easily achieved and should be used in conjunction with other evolving efforts to mitigate toxicity.

A proof-of-concept study of an in-situ partial-ring time-of-flight PET scanner for proton beam verification.

Development of a PET system capable of in-situ imaging requires a design that can accommodate the proton treatment beam nozzle. Among the several PET instrumentation approaches developed thus far, the dual-panel PET scanner is often used as it is simpler to develop and integrate within the proton therapy gantry. Partial-angle coverage of these systems can however lead to limited-angle artefacts in the reconstructed PET image. We have previously demonstrated via simulations that time-of-flight (TOF) reconstruction reduces the artifacts accompanying limited-angle data, and permits proton range measurement with 1-2 mm accuracy and precision. In this work we show measured results from a small proof-of-concept dual-panel PET system that uses TOF information to reconstruct PET data acquired after proton irradiation. The PET scanner comprises of two detector modules, each comprised of an array of 4×4×30 mm3 lanthanum bromide scintillator. Measurements are performed with an oxygen-rich gel-water, an adipose tissue equivalent material, and in vitro tissue phantoms. For each phantom measurement, 2 Gy dose was deposited using 54 - 100 MeV proton beams. For each phantom, a Monte Carlo simulation generating the expected distribution of PET isotope from the corresponding proton irradiation was also performed. Proton range was calculated by drawing multiple depth-profiles over a central region encompassing the proton dose deposition. For each profile, proton range was calculated using two techniques (a) 50% pick-off from the distal edge of the profile, and (b) comparing the measured and Monte Carlo profile to minimize the absolute sum of differences over the entire profile. A 10 min PET acquisition acquired with minimal delay post proton-irradiation is compared with a 10 min PET scan acquired after a 20 min delay. Measurements show that PET acquisition with minimal delay is necessary to collect 15O signal, and maximize 11C signal collection with a short PET acquisition. In comparison with the 50% pick-off technique, the shift technique is more robust and offers better precision in measuring the proton range for the different phantoms. Range measurements from PET images acquired with minimal delay, and the shift technique demonstrate the ability to achieve <1.5 mm accuracy and precision in estimating proton range.

Dual-Energy Computed Tomography Proton-Dose Calculation with Scripting and Modified Hounsfield Units.

PURPOSE: To describe an implementation of dual-energy computed tomography (DECT) for calculation of proton stopping-power ratios (SPRs) in a commercial treatment-planning system. The process for validation and the workflow for safe deployment of DECT is described, using single-energy computed tomography (SECT) as a safety check for DECT dose calculation. MATERIALS AND METHODS: The DECT images were acquired at 80 kVp and 140 kVp and were processed with computed tomography scanner software to derive the electron density and effective atomic number images. Reference SPRs of tissue-equivalent plugs from Gammex (Middleton, Wisconsin) and CIRS (Computerized Imaging Reference Systems, Norfolk, Virginia) electron density phantoms were used for validation and comparison of SECT versus DECT calculated through the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, California) application programming interface scripting tool. An in-house software was also used to create DECT SPR computed tomography images for comparison with the script output. In the workflow, using the Eclipse system application programming interface script, clinical plans were optimized with the SECT image set and then forward-calculated with the DECT SPR for the final dose distribution. In a second workflow, the plans were optimized using DECT SPR with reduced range-uncertainty margins. RESULTS: For the Gammex phantom, the root mean square error in SPR was 1.08% for DECT versus 2.29% for SECT for 10 tissue-surrogates, excluding the lung. For the CIRS Phantom, the corresponding results were 0.74% and 2.27%. When evaluating the head and neck plan, DECT optimization with 2% range-uncertainty margins achieved a small reduction in organ-at-risk doses compared with that of SECT plans with 3.5% range-uncertainty margins. For the liver case, DECT was used to identify and correct the lipiodol SPR in the SECT plan. CONCLUSION: It is feasible to use DECT for proton-dose calculation in a commercial treatment planning system in a safe manner. The range margins can be reduced to 2% in some sites, including the head and neck.

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer.

PURPOSE: To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). METHODS AND MATERIALS: In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. RESULTS: The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. CONCLUSIONS: With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.

Per-fraction positional and dosimetric performance of prone breast tangential radiotherapy on Halcyon™ linear accelerator assessed with daily rapid kilo-voltage cone beam computed tomography: a single-institution pilot study.

BACKGROUND: This study investigates daily breast geometry and delivered dose to prone-positioned patients undergoing tangential whole breast radiation therapy (WBRT) on an O-ring linear accelerator with 6X flattening filter free mode (6X-FFF), planned with electronic compensation (ECOMP) method. Most practices rely on skin marks or daily planar image matching for prone breast WBRT. This system provides low dose daily CBCT, which was used to study daily robustness of delivered dose parameters for prone-positioned WBRT. METHODS: Eight patients treated with 16-fraction prone-breast WBRT were retrospectively studied. Planning CTs were deformed to daily CBCT to generate daily synthetic CTs, on which delivered dose distributions were calculated. A total of 8 × 16 = 128 synthetic CTs were generated. Consensus ASTRO definition was used to contour Breast PTV Eval for each daily deformed CT. Breast PTV Eval coverage (V90%) and hotspot (V105% and Dmax) were monitored daily to compare prescription dose with daily delivered dose. Various predictors including patient weight, breast width diameter (BWD), and Dice similarity coefficient (DSC) were fit into an analysis of covariance model predicting V90% and V105% deviation from prescribed (ΔV90%, ΔV105%). Statistical significance is indicated with asterisks (* for p < 0.05; ** for p < 0.001). RESULTS: Daily delivered Breast PTV Eval V90% was moderately smaller than prescribed (median ΔV90% = - 0.1%*), while V105% was much larger (median ΔV105% = + 10.1%** or + 92.4 cc**). Patient's weight loss correlated with significantly increased ΔV105% (+ 4.6%/ - 1% weight, R2 = 0.4**) and moderately decreased ΔV90% (- 0.071%/ - 1% wt., R2 = 0.2**). Comprehensive ANCOVA models indicated three factors affect ΔV90% and ΔV105% the most: (1) BWD decrease (- 0.09%* and + 10%**/ - 1 cm respectively), (2) PTV Eval volume decrease (- 0.4%** and + 9%**/ - 100 cc), and for ΔV105% only, (3) the extent of breast deformation (+ 10%**/ - 0.01 DSC). Breast PTV Eval volume also decreased with time (- 2.21*cc/fx), possibly indicating seroma resolution and increase in V105% over time. CONCLUSIONS: Daily CBCT revealed key delivered dose parameters vary significantly for patients undergoing tangential prone breast WBRT planned with ECOMP using 6X-FFF. Patient weight, BWD, and breast shape deformation could be used to predict dosimetric variations from prescribed. Preliminary findings suggest an adaptive plan based on daily CBCT could reduce excessive dose to the breast.

Higher Dose Volumes May Be Better for Evaluating Radiation Pneumonitis in Lung Proton Therapy Patients Compared With Traditional Photon-Based Dose Constraints.

PURPOSE: The dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. METHODS AND MATERIALS: In the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. RESULTS: The multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. CONCLUSIONS: In addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.

Prompt gamma imaging for the identification of regional proton range deviations due to anatomic change in a heterogeneous region.

OBJECTIVES: Prompt gamma (PG) imaging has previously been demonstrated for use in proton range verification of a brain treatment with a homogeneous target region. In this study, the feasibility of PG imaging to detect anatomic change within a heterogeneous region is presented. METHODS: A prompt gamma camera recorded several fractions of a patient treatment to the base of skull. An evaluation CT revealed a decrease in sinus cavity filling during the treatment course. Comparison of PG profiles between measurement and simulation was performed to investigate range variations between planned and measured pencil beam spot positions. RESULTS: For one field, an average over range of 3 mm due to the anatomic change could be detected for a subset of spots traversing the sinus cavity region. The two other fields appeared less impacted by the change but predicted range variations could not be detected. These results were partially consistent with the simulations of the evaluation CT. CONCLUSION: We report the first clinical application of PG imaging that detected some of the expected small regional proton range deviations due to anatomic change in a heterogeneous region. However, several limitations exist with the technology that may limit its sensitivity to detect range deviations in heterogeneous regions. ADVANCES IN KNOWLEDGE: We report on the first detection of range variations due to anatomic change in a heterogeneous region using PGI. The results confirm the feasibility of using PG-based range verification in highly heterogeneous target regions to identify deviations from the treatment plan.

Techniques for and uncertainties of MRI-based reconstruction of titanium tandem and ring brachytherapy applicators.

PURPOSE: Eliminating patient computed tomography (CT) scans for tandem and ring (T&R) brachytherapy can reduce overall procedure time and eliminates imaging dose. However, reconstructing titanium applicators in magnetic resonance imaging (MRI) is challenging. We evaluated the uncertainty of different applicator reconstruction workflows in MR-guided brachytherapy, and assessed the clinical impact of reconstruction uncertainties. METHODS AND MATERIALS: Titanium MRI-compatible T&Rs with aqueous gel in the buildup cap were reconstructed on CTs and MRIs to assess the uncertainties of four different workflows. Reconstruction was performed using (1) proton density-weighted MRIs with solid applicator from a library, (2) applicator-only reference CT fused with MRIs, (3) T2-weighted (T2W) MRIs following GEC-ESTRO guidelines, and (4) patient CTs fused with patient MRIs with in situ applicators. We evaluated dwell positions and plan quality differences using high-risk clinical target volume coverage, and EQD2 D2cc of rectum, sigmoid, bladder, and small bowel. RESULTS: The 2σ uncertainty for dwell positions for each workflow were (1) 2.7 mm for both ring and tandem, (2) 1.4 mm ring and 0.8 mm tandem, (3) 0.2 mm ring and 0.8 mm tandem, and (4) 1.9 mm ring and 0.4 mm tandem. Reconstruction uncertainties resulted in dose variations within acceptable levels (below 10%) except for (1) which resulted in larger dose to the rectum (20%). Dose uncertainties were similar between reference CT and patient CT. CONCLUSIONS: Reconstruction with a reference CT results in similar uncertainty to a patient CT. T2W MRI plans have acceptable uncertainty levels for the applicator reconstruction and resulting dose distributions.

Dose to Highly Functional Ventilation Zones Improves Prediction of Radiation Pneumonitis for Proton and Photon Lung Cancer Radiation Therapy.

PURPOSE: We hypothesized that the radiation dose in high-ventilation portions of the lung better predicts radiation pneumonitis (RP) outcome for patients treated with proton radiation therapy (PR) and photon radiation therapy (PH). METHODS AND MATERIALS: Seventy-four patients (38 protons, 36 photons) with locally advanced non-small cell lung cancer treated with concurrent chemoradiation therapy were identified, of whom 24 exhibited RP (graded using Common Terminology Criteria for Adverse Events v4.0) after PR or PH, and 50 were negative controls. The inhale and exhale simulation computed tomography scans were deformed using Advanced Normalization Tools. The 3-dimensional lung ventilation maps were derived from the deformation matrix and partitioned into low- and high-ventilation zones for dosimetric analysis. Receiver operating curve analysis was used to study the power of relationship between RP and ventilation zones to determine an optimal ventilation cutoff. Univariate logistic regression was used to correlate dose in high- and low-ventilation zones with risk of RP. A nonparametric random forest process was used for multivariate importance assessment. RESULTS: The optimal high-ventilation zone definition was determined to be the higher 45% to 60% of the ventilation values. The parameter vV20Gy_high (high ventilation volume receiving ≥20 Gy) was found to be a significant indicator for RP (PH: P = .002, PR: P = .035) with improved areas under the curve compared with the traditional V20Gy for both photon and proton cohorts. The relationship of RP with dose to the low-ventilation zone of the lung was insignificant (PH: P = .123, PR: P = .661). Similar trends were observed for ventilation mean lung dose and ventilation V5Gy. Multivariate importance assessment determined that vV20Gy_high, vV5_high, and mean lung dose were the most significant parameters for the proton cohort with a combined area under the curve of 0.78. CONCLUSION: Dose to the high-ventilated regions of the lung can improve predictions of RP for both PH and PR.

Feasibility of energy-resolved dose imaging technique in pencil beam scanning mode.

Purpose:Proton energy-resolved dose imaging (pERDI) is a recently proposed technique to generate water equivalent path length (WEPL) images using a single detector. Owing to its simplicity in instrumentation, analysis and the possibility of using the in-room x-ray flat panels as detectors, this technique offers a promising avenue towards a clinically usable imaging system for proton therapy using scanned beams. The purpose of this study is to estimate the achievable accuracy in WEPL and Relative Stopping Power (RSP) using the pERDI technique and to assess the minimum dose required to achieve such accuracy. The novelty of this study is the first demonstration of the feasibility of pERDI technique in the pencil beam scanning (PBS) mode.Methods:A solid water wedge was placed in front of a 2D detector (Lynx). A library of energy-resolved dose functions (ERDF) was generated from the dose deposited in the detector by 50 PBS layers of energy varying from 100 MeV to 225 MeV. This set-up is further used to image the following configurations using the pERDI technique: stair-case shaped solid water phantom (configuration 1), electron density phantom (configuration 2) and head phantom (configuration 3). The result from configuration 1 was used to determine the achievable WEPL accuracy. The result from configuration 2 was used to estimate the relative uncertainty in RSP. Configuration 3 was used to evaluate the effect of range mixing on the WEPL. In all three cases, the variation of the accuracy with respect to dose, by varying the number of scanning layers, was also studied.Results:An accuracy of 1 mm in WEPL was achieved using the Lynx detector with an imaging field of 10 PBS layers or more, which is equivalent to a total dose of 5 cGy. The RSP is measured with a precision better than 2% for all homogeneous inserts of tissue surrogates. The pERDI technique failed for tissues surrogates with total WEPL outside the calibration window (WEPL < 70 mm) like in the case of lung exhale and lung inhale. The imaging of an anthropomorphic head phantom, in the same condition, produced a WEPL radiograph and compared to the WEPL derived from CT using gamma index analysis. The gamma index failed in the heterogeneous areas due to range mixing.Conclusions:The pERDI technique is a promising clinically usable imaging modality for reducing range uncertainties and set-up errors in proton therapy. The first results have demonstrated that WEPL and RSP can be estimated with clinically acceptable accuracy using the Lynx detector. Similar accuracy is also expected with in-room flat-panel detectors but at significantly reduced imaging dose. Though the issue of range mixing is still to be addressed, we expect that a statistical moment analysis of the ERDFs can be implemented to filter out the regions with high gradient of range mixing.