Publications by authors named "Liyong Lin"

57 Publications

Learning-Based Stopping Power Mapping on Dual-Energy CT for Proton Radiation Therapy.

Int J Part Ther 2021 12;7(3):46-60. Epub 2021 Feb 12.

Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Purpose: Dual-energy computed tomography (DECT) has been used to derive relative stopping power (RSP) maps by obtaining the energy dependence of photon interactions. The DECT-derived RSP maps could potentially be compromised by image noise levels and the severity of artifacts when using physics-based mapping techniques. This work presents a noise-robust learning-based method to predict RSP maps from DECT for proton radiation therapy.

Materials And Methods: The proposed method uses a residual attention cycle-consistent generative adversarial network to bring DECT-to-RSP mapping close to a 1-to-1 mapping by introducing an inverse RSP-to-DECT mapping. To evaluate the proposed method, we retrospectively investigated 20 head-and-neck cancer patients with DECT scans in proton radiation therapy simulation. Ground truth RSP values were assigned by calculation based on chemical compositions and acted as learning targets in the training process for DECT datasets; they were evaluated against results from the proposed method using a leave-one-out cross-validation strategy.

Results: The predicted RSP maps showed an average normalized mean square error of 2.83% across the whole body volume and an average mean error less than 3% in all volumes of interest. With additional simulated noise added in DECT datasets, the proposed method still maintained a comparable performance, while the physics-based stoichiometric method suffered degraded inaccuracy from increased noise level. The average differences from ground truth in dose volume histogram metrics for clinical target volumes were less than 0.2 Gy for D and D with no statistical significance. Maximum difference in dose volume histogram metrics of organs at risk was around 1 Gy on average.

Conclusion: These results strongly indicate the high accuracy of RSP maps predicted by our machine-learning-based method and show its potential feasibility for proton treatment planning and dose calculation.
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http://dx.doi.org/10.14338/IJPT-D-20-00020.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886267PMC
February 2021

Synthetic dual-energy CT for MRI-only based proton therapy treatment planning using label-GAN.

Phys Med Biol 2021 Mar 9;66(6):065014. Epub 2021 Mar 9.

Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States of America.

MRI-only treatment planning is highly desirable in the current proton radiation therapy workflow due to its appealing advantages such as bypassing MR-CT co-registration, avoiding x-ray CT exposure dose and reduced medical cost. However, MRI alone cannot provide stopping power ratio (SPR) information for dose calculations. Given that dual energy CT (DECT) can estimate SPR with higher accuracy than conventional single energy CT, we propose a deep learning-based method in this study to generate synthetic DECT (sDECT) from MRI to calculate SPR. Since the contrast difference between high-energy and low-energy CT (LECT) is important, and in order to accurately model this difference, we propose a novel label generative adversarial network-based model which can not only discriminate the realism of sDECT but also differentiate high-energy CT (HECT) and LECT from DECT. A cohort of 57 head-and-neck cancer patients with DECT and MRI pairs were used to validate the performance of the proposed framework. The results of sDECT and its derived SPR maps were compared with clinical DECT and the corresponding SPR, respectively. The mean absolute error for synthetic LECT and HECT were 79.98 ± 18.11 HU and 80.15 ± 16.27 HU, respectively. The corresponding SPR maps generated from sDECT showed a normalized mean absolute error as 5.22% ± 1.23%. By comparing with the traditional Cycle GANs, our proposed method significantly improves the accuracy of sDECT. The results indicate that on our dataset, the sDECT image form MRI is close to planning DECT, and thus shows promising potential for generating SPR maps for proton therapy.
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http://dx.doi.org/10.1088/1361-6560/abe736DOI Listing
March 2021

A novel proton counting detector and method for the validation of tissue and implant material maps for Monte Carlo dose calculation.

Phys Med Biol 2021 Feb 2;66(4):045003. Epub 2021 Feb 2.

Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, United States of America.

The presence of artificial implants complicates the delivery of proton therapy due to inaccurate characterization of both the implant and the surrounding tissues. In this work, we describe a method to characterize implant and human tissue mimicking materials in terms of relative stopping power (RSP) using a novel proton counting detector. Each proton is tracked by directly measuring the deposited energy along the proton track using a fast, pixelated spectral detector AdvaPIX-TPX3 (TPX3). We considered three scenarios to characterize the RSPs. First, in-air measurements were made in the presence of metal rods (Al, Ti and CoCr) and bone. Then, measurements of energy perturbations in the presence of metal implants and bone in an anthropomorphic phantom were performed. Finally, sampling of cumulative stopping power (CSP) of the phantom were made at different locations of the anthropomorphic phantom. CSP and RSP information were extracted from energy spectra at each beam path. To quantify the RSP of metal rods we used the shift in the most probable energy (MPE) of CSP from the reference CSP without a rod. Overall, the RSPs were determined as 1.48, 2.06, 3.08, and 5.53 from in-air measurements; 1.44, 1.97, 2.98, and 5.44 from in-phantom measurements, for bone, Al, Ti and CoCr, respectively. Additionally, we sampled CSP for multiple paths of the anthropomorphic phantom ranging from 18.63 to 25.23 cm deriving RSP of soft tissues and bones in agreement within 1.6% of TOPAS simulations. Using minimum error of these multiple CSP, optimal mass densities were derived for soft tissue and bone and they are within 1% of vendor-provided nominal densities. The preliminary data obtained indicates the proposed novel method can be used for the validation of material and density maps, required by proton Monte Carlo Dose calculation, provided by competing multi-energy computed tomography and metal artifact reduction techniques.
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http://dx.doi.org/10.1088/1361-6560/abd22eDOI Listing
February 2021

Beam characteristics of the first clinical 360° rotational single gantry room scanning pencil beam proton treatment system and comparisons against a multi-room system.

J Appl Clin Med Phys 2020 Sep 13;21(9):266-271. Epub 2020 Aug 13.

Emory Proton Therapy Center, Atlanta, GA, USA.

Purpose: The purpose of this study was to present the proton beam characteristics of the first clinical single-room ProBeam Compact™ proton therapy system (SRPT) and comparison against multi-room ProBeam™ system (MRPT).

Materials And Methods: A newly designed SRPT with proton beam energies ranging from 70 to 220 MeV was commissioned in late 2019. Integrated depth doses (IDDs) were scanned using 81.6 mm diameter Bragg peak chambers and normalized by outputs at 15 mm WET and 1.1 RBE offset, following the methodology of TRS 398. The in-air beam spot profiles were acquired by a planar scintillation device, respectively, at ISO, upper and down streams, fitted with single Gaussian distribution for beam modeling in Eclipse v15.6. The field size effect was adjusted for the best overall accuracy of clinically relevant field QAs. The halo effects at near surface were quantified by a pinpoint ionization chamber. Its major dosimetric characteristics were compared against MRPT comparable beam dataset.

Results: Contrast to MRPT, an increased proton straggling in the Bragg peak region was found with widened beam distal falloffs and elevated proximal transmission dose values. Integrated depth doses showed 0.105-0.221 MeV (energy sigma) or 0.30-0.94 mm broader Bragg peak widths (R -R ) for 130 MeV or higher energy beams and up to 0.48-0.79 mm extended distal falloffs (R -R ). Minor differences were identified in beam spot sizes, spot divergences, proton particles/MU, and field size output effects. High passing scores are reported for independent end-to-end dosimetry checks by IROC and for initial 108 field-specific QAs at 3%/3 mm Gamma index with fields regardless with or without range shifters.

Conclusions: The author highlighted the dosimetry differences in IDDs mainly caused by the shortened beam transport system of SRPT, for which new acceptance criteria were adapted. This report offers a unique reference for future commissioning, beam modeling, planning, and analysis of QA and clinical studies.
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http://dx.doi.org/10.1002/acm2.12984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497910PMC
September 2020

Predicted Secondary Malignancies following Proton versus Photon Radiation for Oropharyngeal Cancers.

Int J Part Ther 2020 22;6(4):1-10. Epub 2020 Apr 22.

Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Purpose: There has been a recent epidemic of human papillomavirus (HPV)-positive oropharyngeal cancer, accounting for 70% to 80% of diagnosed cases. These patients have an overall favorable prognosis and are typically treated with a combination of surgery, chemotherapy, and radiation. Because these patients live longer, they are at risk of secondary malignant neoplasms (SMNs) associated with radiation therapy. Therefore, we assessed the predicted risk of SMNs after adjuvant radiation therapy with intensity-modulated proton therapy (IMPT) compared with intensity modulated photon radiation therapy (IMRT) in patients with HPV- positive oropharyngeal cancers after complete resection.

Materials And Methods: Thirteen consecutive patients with HPV-positive oropharyngeal cancers treated with postoperative radiation alone were selected. All patients were treated with pencil beam scanning IMPT to a total dose of 60 Gy in 2 Gy fractions. The IMRT plans were generated for clinical backup and were used for comparative purposes. The SMN risk was calculated based on an organ equivalent dose model for the linear-exponential dose-response curve.

Results: Median age of the patient cohort was 63 years (range, 47-73 years). There was no difference in target coverage between IMPT and IMRT plans. We noted significant reductions in mean mandible, contralateral parotid, lung and skin organ equivalent doses with IMPT compared with IMRT plans ( < .001). Additionally, a significant decrease in the risk of SMNs with IMPT was observed for all the evaluated organs. Per our analysis, for patients with oropharyngeal cancers diagnosed at a national median age of 54 years with an average life expectancy of 27 years (per national Social Security data), 4 excess SMNs per 100 patients could be avoided by treating them with IMPT versus IMRT.

Conclusions: Treatment with IMPT can achieve comparable target dose coverage while significantly reducing the dose to healthy organs, which can lead to fewer predicted SMNs compared with IMRT.
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http://dx.doi.org/10.14338/IJPT-19-00076.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302732PMC
April 2020

Optimization of hexagonal-pattern minibeams for spatially fractionated radiotherapy using proton beam scanning.

Med Phys 2020 Aug 11;47(8):3485-3495. Epub 2020 May 11.

Medical Physics Program, Georgia Institute of Technology, Atlanta, GA, 30332, USA.

Purpose: In this study, we investigated computationally and experimentally a hexagonal-pattern array of spatially fractionated proton minibeams produced by proton pencil beam scanning (PBS) technique. Spatial fractionation of dose delivery with millimeter or submillimeter beam size has proven to be a promising approach to significantly increase the normal tissue tolerance. Our goals are to obtain an optimized minibeam design and to show that it is feasible to implement the optimized minibeams at the existing proton clinics.

Methods: An optimized minibeam arrangement is one that would produce high peak-to-valley dose ratios (PVDRs) in normal tissues and a PVDR approaching unity at the Bragg peak. Using Monte Carlo (MC) code TOPAS we simulated proton pencil beams that mimic those available at the existing proton therapy facilities and obtained a hexagonal-pattern array of minibeams by collimating the proton pencil beams through the 1-3 mm diameter pinholes of a collimator. We optimized the minibeam design by considering different combinations of parameters including collimator material and thickness (t), center-to-center (c-t-c) distance, and beam size. The optimized minibeam design was then evaluated for normal tissue sparing against the uniform pencil beam scanning (PBS) by calculating the therapeutic advantage (TA) in terms of cell survival fraction. Verification measurements using radiochromic films were performed at the Emory proton therapy center (EPTC).

Results: Optimized hexagonal-pattern minibeams having PVDRs of >10 at phantom surface and of >3 at depths up to 6 cm were achieved with 2 mm diameter modulated proton minibeams (with proton energies between 120 and 140 MeV) corresponding to a spread-out-Bragg-peak (SOBP) over the depth of 10-14 cm. The results of the film measurements agree with the MC results within 10%. The TA of the 2 mm minibeams against the uniform PBS is >3 from phantom surface to the depth of 5 cm and then smoothly drops to ~1.5 as it approaches the proximal edge of the SOBP. For 2 mm minibeams and 6 mm c-t-c distance, we delivered 1.72 Gy at SOBP for 7.2 × 7.2 × 4 cm volume in 48 s.

Conclusions: We conclude that it is feasible to implement the optimized hexagonal-pattern 2 mm proton minibeam radiotherapy at the existing proton clinics, because desirable PVDRs and TAs are achievable and the treatment time is reasonable.
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http://dx.doi.org/10.1002/mp.14192DOI Listing
August 2020

Technical Note: Integrating an open source Monte Carlo code "MCsquare" for clinical use in intensity-modulated proton therapy.

Med Phys 2020 Jun 13;47(6):2558-2574. Epub 2020 Apr 13.

Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, 85054, USA.

Purpose: To commission an open source Monte Carlo (MC) dose engine, "MCsquare" for a synchrotron-based proton machine, integrate it into our in-house C++-based I/O user interface and our web-based software platform, expand its functionalities, and improve calculation efficiency for intensity-modulated proton therapy (IMPT).

Methods: We commissioned MCsquare using a double Gaussian beam model based on in-air lateral profiles, integrated depth dose of 97 beam energies, and measurements of various spread-out Bragg peaks (SOBPs). Then we integrated MCsquare into our C++-based dose calculation code and web-based second check platform "DOSeCHECK." We validated the commissioned MCsquare based on 12 different patient geometries and compared the dose calculation with a well-benchmarked GPU-accelerated MC (gMC) dose engine. We further improved the MCsquare efficiency by employing the computed tomography (CT) resampling approach. We also expanded its functionality by adding a linear energy transfer (LET)-related model-dependent biological dose calculation.

Results: Differences between MCsquare calculations and SOBP measurements were <2.5% (<1.5% for ~85% of measurements) in water. The dose distributions calculated using MCsquare agreed well with the results calculated using gMC in patient geometries. The average 3D gamma analysis (2%/2 mm) passing rates comparing MCsquare and gMC calculations in the 12 patient geometries were 98.0 ± 1.0%. The computation time to calculate one IMPT plan in patients' geometries using an inexpensive CPU workstation (Intel Xeon E5-2680 2.50 GHz) was 2.3 ± 1.8 min after the variable resolution technique was adopted. All calculations except for one craniospinal patient were finished within 3.5 min.

Conclusions: MCsquare was successfully commissioned for a synchrotron-based proton beam therapy delivery system and integrated into our web-based second check platform. After adopting CT resampling and implementing LET model-dependent biological dose calculation capabilities, MCsquare will be sufficiently efficient and powerful to achieve Monte Carlo-based and LET-guided robust optimization in IMPT, which will be done in the future studies.
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http://dx.doi.org/10.1002/mp.14125DOI Listing
June 2020

A standardized commissioning framework of Monte Carlo dose calculation algorithms for proton pencil beam scanning treatment planning systems.

Med Phys 2020 Apr 4;47(4):1545-1557. Epub 2020 Feb 4.

Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.

Purpose: Treatment planning systems (TPSs) from different vendors can involve different implementations of Monte Carlo dose calculation (MCDC) algorithms for pencil beam scanning (PBS) proton therapy. There are currently no guidelines for validating non-water materials in TPSs. Furthermore, PBS-specific parameters can vary by 1-2 orders of magnitude among different treatment delivery systems (TDSs). This paper proposes a standardized framework on the use of commissioning data and steps to validate TDS-specific parameters and TPS-specific heterogeneity modeling to potentially reduce these uncertainties.

Methods: A standardized commissioning framework was developed to commission the MCDC algorithms of RayStation 8A and Eclipse AcurosPT v13.7.20 using water and non-water materials. Measurements included Bragg peak depth-dose and lateral spot profiles and scanning field outputs for Varian ProBeam. The phase-space parameters were obtained from in-air measurements and the number of protons per MU from output measurements of 10 × 10 cm square fields at a 2 cm depth. Spot profiles and various PBS field measurements at additional depths were used to validate TPS. Human tissues in TPS, Gammex phantom materials, and artificial materials were used for the TPS benchmark and validation.

Results: The maximum differences of phase parameters, spot sigma, and divergence between MCDC algorithms are below 4.5 µm and 0.26 mrad in air, respectively. Comparing TPS to measurements at depths, both MC algorithms predict the spot sigma within 0.5 mm uncertainty intervals, the resolution of the measurement device. Beam Configuration in AcurosPT is found to underestimate number of protons per MU by ~2.5% and requires user adjustment to match measured data, while RayStation is within 1% of measurements using Auto model. A solid water phantom was used to validate the range accuracy of non-water materials within 1% in AcurosPT.

Conclusions: The proposed standardized commissioning framework can detect potential issues during PBS TPS MCDC commissioning processes, and potentially can shorten commissioning time and improve dosimetric accuracies. Secondary MCDC can be used to identify the root sources of disagreement between primary MCDC and measurement.
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http://dx.doi.org/10.1002/mp.14021DOI Listing
April 2020

Nuclear halo measurements for accurate prediction of field size factor in a Varian ProBeam proton PBS system.

J Appl Clin Med Phys 2020 Jan 2;21(1):197-204. Epub 2019 Dec 2.

Department of Radiation Oncology, Emory University, Atlanta, GA, USA.

Purpose: For pencil-beam scanning proton therapy systems, in-air non-Gaussian halo can significantly impact output at small field sizes and low energies. Since the low-intensity tail of spot profile (halo) is not necessarily modeled in treatment planning systems (TPSs), this can potentially lead to significant differences in patient dose distribution. In this work, we report such impact for a Varian ProBeam system.

Methods: We use a pair magnification technique to measure two-dimensional (2D) spot profiles of protons from 70 to 242 MeV at the treatment isocenter and 30 cm upstream of the isocenter. Measurements are made with both Gafchromic film and a scintillator detector coupled to a CCD camera (IBA Lynx). Spot profiles are measured down to 0.01% of their maximum intensity. Field size factors (FSFs) are compared among calculation using measured 2D profiles, calculation using a clinical treatment planning algorithm (Raystation 8A clinical Monte Carlo), and a CC04 small-volume ion chamber. FSFs were measured for square fields of proton energies ranging from 70 to 242 MeV.

Results: All film and Lynx measurements agree within 1 mm for full width at half maximum beam intensity. The measured radial spot profiles disagree with simple Gaussian approximations, which are used for modeling in the TPS. FSF measurements show the magnitude of disagreements between beam output in reality and in the TPS without modeling halo. We found that the clinical TPS overestimated output by as much as 6% for small field sizes of 2 cm at the lowest energy of 70 MeV while the film and Lynx measurements agreed within 4% and 1%, respectively, for this FSF.

Conclusions: If the in-air halo for low-energy proton beams is not fully modeled by the TPS, this could potentially lead to under-dosing small, shallow treatment volumes in PBS treatment plans.
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http://dx.doi.org/10.1002/acm2.12783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964762PMC
January 2020

MRI-based treatment planning for proton radiotherapy: dosimetric validation of a deep learning-based liver synthetic CT generation method.

Phys Med Biol 2019 07 16;64(14):145015. Epub 2019 Jul 16.

Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States of America.

Magnetic resonance imaging (MRI) has been widely used in combination with computed tomography (CT) radiation therapy because MRI improves the accuracy and reliability of target delineation due to its superior soft tissue contrast over CT. The MRI-only treatment process is currently an active field of research since it could eliminate systematic MR-CT co-registration errors, reduce medical cost, avoid diagnostic radiation exposure, and simplify clinical workflow. The purpose of this work is to validate the application of a deep learning-based method for abdominal synthetic CT (sCT) generation by image evaluation and dosimetric assessment in a commercial proton pencil beam treatment planning system (TPS). This study proposes to integrate dense block into a 3D cycle-consistent generative adversarial networks (cycle GAN) framework in an effort to effectively learn the nonlinear mapping between MRI and CT pairs. A cohort of 21 patients with co-registered CT and MR pairs were used to test the deep learning-based sCT image quality by leave-one-out cross validation. The CT image quality, dosimetric accuracy and the distal range fidelity were rigorously checked, using side-by-side comparison against the corresponding original CT images. The average mean absolute error (MAE) was 72.87  ±  18.16 HU. The relative differences of the statistics of the PTV dose volume histogram (DVH) metrics between sCT and CT were generally less than 1%. Mean 3D gamma analysis passing rate of 1 mm/1%, 2 mm/2%, 3 mm/3% criteria with 10% dose threshold were 90.76%  ±  5.94%, 96.98%  ±  2.93% and 99.37%  ±  0.99%, respectively. The median, mean and standard deviation of absolute maximum range differences were 0.170 cm, 0.186 cm and 0.155 cm. The image similarity, dosimetric and distal range agreement between sCT and original CT suggests the feasibility of further development of an MRI-only workflow for liver proton radiotherapy.
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http://dx.doi.org/10.1088/1361-6560/ab25bcDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635951PMC
July 2019

Clinical significance of pretreatment tumor growth rate for locally advanced non-small cell lung cancer.

Ann Transl Med 2019 Mar;7(5):95

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.

Background: Locally advanced non-small cell lung cancer (NSCLC) may exhibit significant tumor growth before the initiation of definitive chemoradiation therapy (CRT). We thus investigated the prognostic value of pretreatment tumor growth rate as measured by specific growth rate (SGR).

Methods: We conducted a retrospective review of 42 patients with locally advanced NSCLC treated with definitive concurrent CRT. For each patient, we contoured the primary gross tumor volume (GTV) on the pretreatment diagnostic chest computed tomography (CT) scan and the radiation therapy (RT) planning CT scan. We then calculated SGR based on the primary GTV from each scan and the time interval between scans. We used log-rank tests and univariate Cox regression models to quantify differences in progression-free survival (PFS), overall survival (OS) and recurrence based on SGR.

Results: We divided patients into two groups for analysis: those with an SGR greater than or equal to the upper tercile value of 0.94%/day (high SGR) and those with SGR less than 0.94%/day (low SGR). Patients with high SGRs versus low SGRs experienced inferior PFS (median, 5.6 13.6 months, P=0.016), without a significant difference in OS. The inferior PFS in the high SGR group persisted on multivariate analysis [adjusted hazard ratio (HR) 2.37, 95% confidence interval (CI): 1.07-5.25, P=0.034]. The risk of distant recurrence was higher in the high SGR group (HR 2.62, 95% CI: 1.08-6.38, P=0.033), but there was no difference in the risk of locoregional recurrence between groups.

Conclusions: Pretreatment SGR was associated with inferior PFS and distant control among patients with locally advanced NSCLC treated with concurrent CRT. Further studies in larger populations may aid in elucidating optimal SGR cut-off points for risk stratification.
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http://dx.doi.org/10.21037/atm.2019.02.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462644PMC
March 2019

Validation and application of a fast Monte Carlo algorithm for assessing the clinical impact of approximations in analytical dose calculations for pencil beam scanning proton therapy.

Med Phys 2018 Dec 26;45(12):5631-5642. Epub 2018 Oct 26.

Department of Radiation Oncology, University of Pennsylvania, 3400 Civic Central Blvd, Philadelphia, PA, 19104, USA.

Purpose: Monte Carlo (MC) dose calculation is generally superior to analytical dose calculation (ADC) used in commercial TPS to model the dose distribution especially for heterogeneous sites, such as lung and head/neck patients. The purpose of this study was to provide a validated, fast, and open-source MC code, MCsquare, to assess the impact of approximations in ADC on clinical pencil beam scanning (PBS) plans covering various sites.

Methods: First, MCsquare was validated using tissue-mimicking IROC lung phantom measurements as well as benchmarked with the general purpose Monte Carlo TOPAS for patient dose calculation. Then a comparative analysis between MCsquare and ADC was performed for a total of 50 patients with 10 patients per site (including liver, pelvis, brain, head-and-neck, and lung). Differences among TOPAS, MCsquare, and ADC were evaluated using four dosimetric indices based on the dose-volume histogram (target Dmean, D95, homogeneity index, V95), a 3D gamma index analysis (using 3%/3 mm criteria), and estimations of tumor control probability (TCP).

Results: Comparison between MCsquare and TOPAS showed less than 1.8% difference for all of the dosimetric indices/TCP values and resulted in a 3D gamma index passing rate for voxels within the target in excess of 99%. When comparing ADC and MCsquare, the variances of all the indices were found to increase as the degree of tissue heterogeneity increased. In the case of lung, the D95s for ADC were found to differ by as much as 6.5% from the corresponding MCsquare statistic. The median gamma index passing rate for voxels within the target volume decreased from 99.3% for liver to 75.8% for lung. Resulting TCP differences can be large for lung (≤10.5%) and head-and-neck (≤6.2%), while smaller for brain, pelvis and liver (≤1.5%).

Conclusions: Given the differences found in the analysis, accurate dose calculation algorithms such as Monte Carlo simulations are needed for proton therapy, especially for disease sites with high heterogeneity, such as head-and-neck and lung. The establishment of MCsquare can facilitate patient plan reviews at any institution and can potentially provide unbiased comparison in clinical trials given its accuracy, speed and open-source availability.
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http://dx.doi.org/10.1002/mp.13231DOI Listing
December 2018

Validation and clinical implementation of an accurate Monte Carlo code for pencil beam scanning proton therapy.

J Appl Clin Med Phys 2018 Sep 30;19(5):558-572. Epub 2018 Jul 30.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Monte Carlo (MC)-based dose calculations are generally superior to analytical dose calculations (ADC) in modeling the dose distribution for proton pencil beam scanning (PBS) treatments. The purpose of this paper is to present a methodology for commissioning and validating an accurate MC code for PBS utilizing a parameterized source model, including an implementation of a range shifter, that can independently check the ADC in commercial treatment planning system (TPS) and fast Monte Carlo dose calculation in opensource platform (MCsquare). The source model parameters (including beam size, angular divergence and energy spread) and protons per MU were extracted and tuned at the nozzle exit by comparing Tool for Particle Simulation (TOPAS) simulations with a series of commissioning measurements using scintillation screen/CCD camera detector and ionization chambers. The range shifter was simulated as an independent object with geometric and material information. The MC calculation platform was validated through comprehensive measurements of single spots, field size factors (FSF) and three-dimensional dose distributions of spread-out Bragg peaks (SOBPs), both without and with the range shifter. Differences in field size factors and absolute output at various depths of SOBPs between measurement and simulation were within 2.2%, with and without a range shifter, indicating an accurate source model. TOPAS was also validated against anthropomorphic lung phantom measurements. Comparison of dose distributions and DVHs for representative liver and lung cases between independent MC and analytical dose calculations from a commercial TPS further highlights the limitations of the ADC in situations of highly heterogeneous geometries. The fast MC platform has been implemented within our clinical practice to provide additional independent dose validation/QA of the commercial ADC for patient plans. Using the independent MC, we can more efficiently commission ADC by reducing the amount of measured data required for low dose "halo" modeling, especially when a range shifter is employed.
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http://dx.doi.org/10.1002/acm2.12420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123159PMC
September 2018

Proton Beam Therapy for Bronchogenic Adenoid Cystic Carcinoma: Dosimetry, Toxicities, and Outcomes.

Int J Part Ther 2018 26;4(4):1-9. Epub 2018 Jul 26.

Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, USA.

Purpose: Bronchogenicadenoid cystic carcinoma (ACC) is a rare malignancy particularly challenging to irradiate, largely owing to anatomic location and associated toxicities. Proton beam therapy (PBT) can reduce doses to nearby organs at risk, but only one case report has been published detailing PBT for this neoplasm.

Patients And Methods: This study was an institutional review board-approved retrospective chart review of all patients at one institution with bronchogenic ACC treated with PBT. Toxicities were assessed per Common Toxicity Criteria for Adverse Events, version 4.0.

Results: Five patients, median age 67 years (range = 40-97 years), were all symptomatic before PBT. Two patients were debulked before PBT, which was delivered at a median 66.6 Gy (RBE) (range, 57.5-80 Gy (RBE)). Two patients received concurrent platinum-based chemotherapy. Symptoms improved in all patients. Acute toxicities included the following: grade 1 fatigue (n = 3), grade 1 dermatitis (n = 2), grade 1 esophagitis (n = 1), grade 2 fatigue (n = 1), grade 2 dermatitis (n = 1), grade 2 esophagitis (n = 2). There was one case of late radiation fibrosis causing bronchial stenosis and requiring a stent, and another of late grade 1 dysphagia. All grade 2 toxicities occurred in patients receiving concurrent chemoradiotherapy. At median follow-up of 10 months (range = 5-47 months), no patient experienced tumor recurrence and none had symptoms impairing daily functioning or quality of life. Although statistically nonsignificant owing to low sample sizes, dosimetric data revealed that PBT numerically reduced doses, most notably to the heart and to low-dose volumes of the lung.

Conclusions: This is the largest series to date evaluating PBT for bronchogenic ACC. PBT is associated with low rates of acute and late toxicities and excellent early local control.
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http://dx.doi.org/10.14338/IJPT-17-00014.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871572PMC
July 2018

First Ever Use of Proton Stereotactic Body Radiation Therapy Delivered with Curative Intent to Bilateral Synchronous Primary Renal Cell Carcinomas.

Cureus 2017 10 24;9(10):e1799. Epub 2017 Oct 24.

Department of Radiation Oncology, University of Maryland Medical Center.

Limited therapeutic options exist for inoperable bilateral kidney tumors. We report the first ever use of proton therapy to treat primary renal cell carcinoma (RCC) and the first report of proton stereotactic body radiation therapy (SBRT) for RCC in an inoperable patient with synchronous RCCs treated with proton SBRT. The patient is a 47-year-old 450-pound female with multiple medical comorbidities, including Stage 3 chronic kidney disease (CKD), who was found to have bilateral renal masses during work-up for cellulitis and sepsis. Following resolution of her sepsis, subsequent cross-sectional imaging demonstrated interval growth of the left renal mass to 4.4 x 4.8 cm and the right renal mass to 2.0 x 2.6 cm. Bilateral biopsies were performed, with pathology revealing Furhman Grade 1-2 clear cell RCC on both sides. A customized SBRT plan delivered a total dose of 3,000 cGy in five fractions to the bilateral kidneys every other day using proton beam therapy. The patient experienced no grade > 1 acute adverse toxicities from proton therapy, and now at one year after treatment, she has had no clinical symptoms of late radiation-induced toxicities. Although a marginal decline in post-treatment glomerular filtration rate (GFR) was observed (baseline 34 mL/min/1.73m, one-year post-SBRT 29 mL/min/1.73m), the patient remains asymptomatic and without a requirement for intervention. In presenting a case in which proton SBRT was performed safely and effectively for a medically complex patient with inoperable synchronous bilateral RCC, we suggest that proton therapy is a promising therapeutic approach for even unilateral primary RCC where preservation of renal function is of importance and should be considered for medically inoperable patients. Further experience is needed to determine the optimal dose and fractionation regimen for renal SBRT with proton therapy.
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http://dx.doi.org/10.7759/cureus.1799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741276PMC
October 2017

Superiority in Robustness of Multifield Optimization Over Single-Field Optimization for Pencil-Beam Proton Therapy for Oropharynx Carcinoma: An Enhanced Robustness Analysis.

Int J Radiat Oncol Biol Phys 2017 11 20;99(3):738-749. Epub 2017 Jun 20.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: To compare the difference in robustness of single-field optimized (SFO) and robust multifield optimized (rMFO) proton plans for oropharynx carcinoma patients by an improved robustness analysis.

Methods And Materials: We generated rMFO proton plans for 11 patients with oropharynx carcinoma treated with SFO intensity modulated proton therapy with simultaneous integrated boost prescription. Doses from both planning approaches were compared for the initial plans and the worst cases from 20 optimization scenarios of setup errors and range uncertainties. Expected average dose distributions per range uncertainty were obtained by weighting the contributions from the respective scenarios with their expected setup error probability, and the spread of dose parameters for different range uncertainties were quantified. Using boundary dose distributions created from 56 combined setup error and range uncertainty scenarios and considering the vanishing influence of setup errors after 30 fractions, we approximated realistic worst-case values for the total treatment course. Error bar metrics derived from these boundary doses are reported for the clinical target volumes (CTVs) and organs at risk (OARs).

Results: The rMFO plans showed improved CTV coverage and homogeneity while simultaneously reducing the average mean dose to the constrictor muscles, larynx, and ipsilateral middle ear by 5.6 Gy, 2.0 Gy, and 3.9 Gy, respectively. We observed slightly larger differences during robustness evaluation, as well as a significantly higher average brainstem maximum and ipsilateral parotid mean dose for SFO plans. For rMFO plans, the range uncertainty-related spread in OAR dose parameters and many error bar metrics were found to be superior. The SFO plans showed a lower global maximum dose for single-scenario worst cases and a slightly lower mean oral cavity dose throughout.

Conclusions: An enhanced robustness analysis has been proposed and implemented into clinical systems. The benefit of better CTV coverage and OAR dose sparing in oropharynx carcinoma patients by rMFO compared with SFO proton plans is preserved in a robustness analysis with consideration of setup error and range uncertainty.
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http://dx.doi.org/10.1016/j.ijrobp.2017.06.017DOI Listing
November 2017

Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage.

Int J Mol Sci 2017 Nov 25;18(12). Epub 2017 Nov 25.

Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Stemmler Hall, Office Suite 227, Philadelphia, PA 19104, USA.

Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.
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http://dx.doi.org/10.3390/ijms18122525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751128PMC
November 2017

Consensus Guidelines for Implementing Pencil-Beam Scanning Proton Therapy for Thoracic Malignancies on Behalf of the PTCOG Thoracic and Lymphoma Subcommittee.

Int J Radiat Oncol Biol Phys 2017 09 19;99(1):41-50. Epub 2017 May 19.

Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT. Four-dimensional computed tomography-based motion management and robust optimization and evaluation are crucial for minimizing uncertainties associated with beam range and organ motion. Rigorous quality assurance is required to validate dose delivery both before and during the course of treatment. Active motion management (eg, breath hold), beam gating, rescanning, tracking, or adaptive planning may be needed for cases involving significant motion or changes in motion or anatomy over the course of treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2017.05.014DOI Listing
September 2017

Prospective study of proton-beam radiation therapy for limited-stage small cell lung cancer.

Cancer 2017 Nov 5;123(21):4244-4251. Epub 2017 Jul 5.

Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.

Background: Existing data supporting the use of proton-beam therapy (PBT) for limited-stage small cell lung cancer (LS-SCLC) are limited to a single 6-patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS-SCLC.

Methods: This study prospectively analyzed patients with primary, nonrecurrent LS-SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to 2016. Clinical backup intensity-modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates and toxicities.

Results: Thirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, 45-66.6 cobalt gray equivalents) in 33 to 37 fractions delivered daily (n = 18 [60.0%]) or twice daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow-up of 14 months, the 1-/2-year LC and RFS rates were 85%/69% and 63%/42%, respectively. The median OS was 28.2 months, and the 1-/2-year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively.

Conclusions: In the first prospective registry study and largest analysis to date of PBT for LS-SCLC, PBT was found to be safe with a limited incidence of high-grade toxicities. Cancer 2017;123:4244-4251. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30870DOI Listing
November 2017

A study of the beam-specific interplay effect in proton pencil beam scanning delivery in lung cancer.

Acta Oncol 2017 Apr 25;56(4):531-540. Epub 2017 Feb 25.

a Department of Radiation Oncology , University of Pennsylvania , Philadelphia , PA , USA.

Background: For lung tumors with large motion amplitudes, the use of proton pencil beam scanning (PBS) can produce large dose errors. In this study, we assess under what circumstances PBS can be used to treat lung cancer patients who exhibit large tumor motion, based on the quantification of tumor motion and the dose interplay.

Material And Methods: PBS plans were optimized on average 4DCT datasets using a beam-specific PTV method for 10 consecutive patients with locally advanced non-small-cell-lung-cancer (NSCLC) treated with proton therapy to 6660/180 cGy. End inhalation (CT0) and end exhalation (CT50) were selected as the two extreme scenarios to acquire the relative stopping power ratio difference (Δrsp) for a respiration cycle. The water equivalent difference (ΔWET) per radiological path was calculated from the surface of patient to the iCTV by integrating the Δrsp of each voxel. The magnitude of motion of voxels within the target follows a quasi-Gaussian distribution. A motion index (MI (>5mm WET)), defined as the percentage of target voxels with an absolute integral ΔWET larger than 5 mm, was adopted as a metric to characterize interplay. To simulate the treatment process, 4D dose was calculated by accumulating the spot dose on the corresponding respiration phase to the reference phase CT50 by deformable image registration based on spot timing and patient breathing phase.

Results: The study indicated that the magnitude of target underdose in a single fraction plan is proportional to the MI (p < .001), with larger motion equating to greater dose degradation and standard deviations. The target homogeneity, minimum, maximum and mean dose in the 4D dose accumulations of 37 fractions varied as a function of MI.

Conclusions: This study demonstrated that MI can predict the level of dose degradation, which potentially serves as a clinical decision tool to assess whether lung cancer patients are potentially suitable to receive PBS treatment.
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http://dx.doi.org/10.1080/0284186X.2017.1293287DOI Listing
April 2017

Risk of major cardiac events following adjuvant proton versus photon radiation therapy for patients with thymic malignancies.

Acta Oncol 2017 Aug 24;56(8):1060-1064. Epub 2017 Mar 24.

a Department of Radiation Oncology , Hospital of the University of Pennsylvania , Philadelphia , PA , USA.

Background: While often managed with surgery alone, patients with thymic malignancies with high-risk features may benefit from adjuvant radiation therapy but are at risk for late toxicities. Previously, the risk of major cardiac events (MCEs) was reported to increase by 7% per one Gray (Gy) to the heart. In this study, we compare dose to organs at risk (OARs) with intensity-modulated (IMRT) versus proton beam therapy (PBT). We hypothesize a decrease risk of predicted MCEs with PBT.

Material And Methods: Patients requiring adjuvant therapy for thymic malignancies were treated with double scattered proton beam therapy (DS-PBT). Clinical backup IMRT plans were generated. Predicted MCEs were calculated based on median dose to the heart. A Wilcoxon rank sum test was used for statistical comparisons.

Results: Twenty-two consecutive patients were evaluated. DS-PBT resulted in statistically significant decreases in dose to the heart, lungs, left ventricle, esophagus, and spinal cord (all p ≤ .01). The increase in risk of MCEs from 0 to ≥20 years was lower with PBT (74% versus 135%, p = .04).

Discussion: DS-PBT results in decreased dose to OARs and may reduce the risk of MCEs compared with IMRT. Long-term follow-up is required to assess for clinical benefit from DS-PBT.
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http://dx.doi.org/10.1080/0284186X.2017.1302097DOI Listing
August 2017

A benchmarking method to evaluate the accuracy of a commercial proton monte carlo pencil beam scanning treatment planning system.

J Appl Clin Med Phys 2017 Mar 2;18(2):44-49. Epub 2017 Feb 2.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

AcurosPT is a Monte Carlo algorithm in the Eclipse 13.7 treatment planning system, which is designed to provide rapid and accurate dose calculations for proton therapy. Computational run-time in minimized by simplifying or eliminating less significant physics processes. In this article, the accuracy of AcurosPT was benchmarked against both measurement and an independent MC calculation, TOPAS. Such a method can be applied to any new MC calculation for the detection of potential inaccuracies. To validate multiple Coulomb scattering (MCS) which affects primary beam broadening, single spot profiles in a Solidwater phantom were compared for beams of five selected proton energies between AcurosPT, measurement and TOPAS. The spot Gaussian sigma in AcurosPT was found to increase faster with depth than both measurement and TOPAS, suggesting that the MCS algorithm in AcurosPT overestimates the scattering effect. To validate AcurosPT modeling of the halo component beyond primary beam broadening, field size factors (FSF) were compared for multi-spot profiles measured in a water phantom. The FSF for small field sizes were found to disagree with measurement, with the disagreement increasing with depth. Conversely, TOPAS simulations of the same FSF consistently agreed with measurement to within 1.5%. The disagreement in absolute dose between AcurosPT and measurement was smaller than 2% at the mid-range depth of multi-energy beams. While AcurosPT calculates acceptable dose distributions for typical clinical beams, users are cautioned of potentially larger errors at distal depths due to overestimated MCS and halo implementation.
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http://dx.doi.org/10.1002/acm2.12043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689961PMC
March 2017

Evaluation of motion mitigation using abdominal compression in the clinical implementation of pencil beam scanning proton therapy of liver tumors.

Med Phys 2017 Feb 30;44(2):703-712. Epub 2017 Jan 30.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To determine whether individual liver tumor patients can be safely treated with pencil beam scanning proton therapy. This study reports a planning preparation workflow that can be used for beam angle selection and the evaluation of the efficacy of abdominal compression (AC) to mitigate motion.

Methods: Four-dimensional computed tomography scans (4DCT) with and without AC were available from 10 liver tumor patients with fluoroscopy-proven motion reduction by AC, previously treated using photons. For each scan, the motion amplitudes and the motion-induced variation of water-equivalent thickness (ΔWET) in each voxel of the target volume were evaluated during treatment plan preparation. Optimal proton beam angles were selected after volume analysis of the respective beam-specific planning target volume (BSPTV). M and ΔWET derived from the 80th percentiles of perpendicular motion amplitude (M ) and ΔWET were compared with and without AC. Proton plans were created on the average CT to achieve target coverage similar to that of the conventional photon treatments. 4D dynamic dose calculation was performed postplan by synchronizing proton beam delivery timing patterns to the 4DCT phases to assess interplay and fractionation effects, and to determine motion criteria for subsequent patient treatment.

Results: Selected coplanar beam angles ranged between 180° and 39°, primarily from right lateral (oblique) and posterior (oblique) directions. While AC produced a significant reduction in mean Liver-GTV dose, any reduction in mean heart dose was patient dependent and not significant. Similarly, AC resulted in reductions in M , ΔWET, and BSPTV volumes and improved dose degradation (ΔD and ΔD ) within the CTV. For small motion (M < 7 mm and ΔWET < 5 mm), motion mitigation was not needed. For moderate motion (M 7-10 mm or ΔWET 5-7 mm), AC produced a modest improvement. For large motion (M > 10 mm or ΔWET > 7 mm), AC and/or some other form of mitigation strategies were required.

Conclusion: A workflow for screening patients' motion characteristics and optimizing beam angle selection was established for the pencil beam scanning proton therapy treatment of liver tumors. Abdominal compression was found to be useful at mitigation of moderate and large motion.
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http://dx.doi.org/10.1002/mp.12040DOI Listing
February 2017

Technical Note: A treatment plan comparison between dynamic collimation and a fixed aperture during spot scanning proton therapy for brain treatment.

Med Phys 2016 Aug;43(8):4693

Department of Radiation Oncology, University of Iowa, 200 Hawkins Drive, Iowa City, Iowa 52242.

Purpose: To quantitatively assess the advantages of energy-layer specific dynamic collimation system (DCS) versus a per-field fixed aperture for spot scanning proton therapy (SSPT).

Methods: Five brain cancer patients previously planned and treated with SSPT were replanned using an in-house treatment planning system capable of modeling collimated and uncollimated proton beamlets. The uncollimated plans, which served as a baseline for comparison, reproduced the target coverage and organ-at-risk sparing of the clinically delivered plans. The collimator opening for the fixed aperture-based plans was determined from the combined cross sections of the target in the beam's eye view over all energy layers which included an additional margin equivalent to the maximum beamlet displacement for the respective energy of that energy layer. The DCS-based plans were created by selecting appropriate collimator positions for each row of beam spots during a Raster-style scanning pattern which were optimized to maximize the dose contributions to the target and limited the dose delivered to adjacent normal tissue.

Results: The reduction of mean dose to normal tissue adjacent to the target, as defined by a 10 mm ring surrounding the target, averaged 13.65% (range: 11.8%-16.9%) and 5.18% (2.9%-7.1%) for the DCS and fixed aperture plans, respectively. The conformity index, as defined by the ratio of the volume of the 50% isodose line to the target volume, yielded an average improvement of 21.35% (19.4%-22.6%) and 8.38% (4.7%-12.0%) for the DCS and fixed aperture plans, respectively.

Conclusions: The ability of the DCS to provide collimation to each energy layer yielded better conformity in comparison to fixed aperture plans.
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http://dx.doi.org/10.1118/1.4955117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360163PMC
August 2016

Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC.

Radiat Oncol 2016 May 4;11:66. Epub 2016 May 4.

University of Pennsylvania, Philadelphia, PA, USA.

Background: To establish the feasibility of the dosimetric compliance criteria of the RTOG 1308 trial through testing against Intensity Modulation Radiation Therapy (IMRT) and Passive Scattering Proton Therapy (PSPT) plans.

Methods: Twenty-six lung IMRT and 26 proton PSPT plans were included in the study. Dose Volume Histograms (DVHs) for targets and normal structures were analyzed. The quality of IMRT plans was assessed using a knowledge-based engineering tool.

Results: Most of the RTOG 1308 dosimetric criteria were achieved. The deviation unacceptable rates were less than 10 % for most criteria; however, a deviation unacceptable rate of more than 20 % was computed for the planning target volume minimum dose compliance criterion. Dose parameters for the target volume were very close for the IMRT and PSPT plans. However, the PSPT plans led to lower dose values for normal structures. The dose parameters in which PSPT plans resulted in lower values than IMRT plans were: lung V5Gy (%) (34.4 in PSPT and 47.2 in IMRT); maximum spinal cord dose (31.7 Gy in PSPT and 43.5 Gy in IMRT); heart V5Gy (%) (19 in PSPT and 47 in IMRT); heart V30Gy (%) (11 in PSPT and 19 in IMRT); heart V45Gy (%) (7.8 in PSPT and 12.1 in IMRT); heart V50% (Gy) (7.1 in PSPT and 9.8 in IMRT) and mean heart dose (7.7 Gy in PSPT and 14.9 Gy in IMRT).

Conclusions: The revised RTOG 1308 dosimetric compliance criteria are feasible and achievable.
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http://dx.doi.org/10.1186/s13014-016-0640-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855766PMC
May 2016

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer.

Int J Radiat Oncol Biol Phys 2016 May 4;95(1):549-559. Epub 2016 Feb 4.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Purpose: An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning.

Methods And Materials: The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the target's distal surface.

Results: The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology.

Conclusions: A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.
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http://dx.doi.org/10.1016/j.ijrobp.2016.01.055DOI Listing
May 2016

Toward improved target conformity for two spot scanning proton therapy delivery systems using dynamic collimation.

Med Phys 2016 Mar;43(3):1421-7

Department of Radiation Oncology, University of Iowa, 200 Hawkins Drive, Iowa City, Iowa 52242.

Purpose: To quantify improvement in target conformity in brain and head and neck tumor treatments resulting from the use of a dynamic collimation system (DCS) with two spot scanning proton therapy delivery systems (universal nozzle, UN, and dedicated nozzle, DN) with median spot sizes of 5.2 and 3.2 mm over a range of energies from 100 to 230 MeV.

Methods: Uncollimated and collimated plans were calculated with both UN and DN beam models implemented within our in-house treatment planning system for five brain and ten head and neck datasets in patients previously treated with spot scanning proton therapy. The prescription dose and beam angles from the clinical plans were used for both the UN and DN plans. The average reduction of the mean dose to the 10-mm ring surrounding the target between the uncollimated and collimated plans was calculated for the UN and the DN. Target conformity was analyzed using the mean dose to 1-mm thickness rings surrounding the target at increasing distances ranging from 1 to 10 mm.

Results: The average reductions of the 10-mm ring mean dose for the UN and DN plans were 13.7% (95% CI: 11.6%-15.7%; p < 0.0001) and 11.5% (95% CI: 9.5%-13.5%; p < 0.0001) across all brain cases and 7.1% (95% CI: 4.4%-9.8%; p < 0.001) and 6.3% (95% CI: 3.7%-9.0%; p < 0.001), respectively, across all head and neck cases. The collimated UN plans were either more conformal (all brain cases and 60% of the head and neck cases) than or equivalent (40% of the head and neck cases) to the uncollimated DN plans. The collimated DN plans offered the highest conformity.

Conclusions: The DCS added either to the UN or DN improved the target conformity. The DCS may be of particular interest for sites with UN systems looking for a more economical solution than upgrading the nozzle to improve the target conformity of their spot scanning proton therapy system.
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http://dx.doi.org/10.1118/1.4942375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360164PMC
March 2016

Improving Head and Neck Cancer Treatments Using Dynamic Collimation in Spot Scanning Proton Therapy.

Int J Part Ther 2016 Mar 24;2(4):544-554. Epub 2016 Mar 24.

Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

Purpose: Interest in using collimation for spot scanning proton therapy has recently increased in an attempt to improve the lateral penumbra. To investigate the advantages of such an approach for complex targets, a plan comparison between uncollimated and collimated beam spots was performed for patients with head and neck cancer.

Patients And Methods: For 10 patients with head and neck cancer, previously treated with spot scanning proton therapy, uncollimated and collimated treatment plans were created using an in-house treatment-planning system capable of modeling asymmetric-beamlet dose distributions resulting from the use of a dynamic collimation system. Both uncollimated and collimated plans reproduced clinically delivered plans in terms of target coverage. A relative plan comparison was performed using both physical and radiobiological metrics on the organs at risk.

Results: The dynamic collimation system improved dose-distribution conformity while preserving target coverage. The median reduction of the mean dose to the esophagus, uninvolved larynx, and uninvolved parotids were -11.9% (minimum to maximum, -6.4% to -24.1%), -7.2% (-0.8% to -60.1%), and -5.2% (-0.2% to -21.5%), respectively, and depended on the organ location relative to the target and radiation beam angle. The collimation did not improve dose to some organs at risk surrounded by the target or located upstream of Bragg peaks because of the priority on the target coverage.

Conclusion: In spot scanning proton therapy, the dynamic collimation system generally affords better target conformity, which results in improvement in organ-at-risk sparing in the head and neck region while preserving target coverage. However, the benefits of collimation and the increased complexity should be considered for each patient. Patients with large bilateral targets or organs at risk surrounded by the target showed the least benefit.
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http://dx.doi.org/10.14338/IJPT-15-00026.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871640PMC
March 2016

Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: Early response and toxicity assessment.

Radiother Oncol 2016 Mar 16;118(3):504-9. Epub 2016 Feb 16.

Hospital of the University of Pennsylvania, Department of Radiation Oncology, Philadelphia, United States.

Background And Purpose: Radiation is an important modality in treatment of thymic tumors. However, toxicity may reduce its overall benefit. We hypothesized that double-scattering proton beam therapy (DS-PT) can achieve excellent local control with limited toxicity in patients with thymic malignancies.

Methods And Materials: Patients with thymoma or thymic carcinoma treated with DS-PT between 2011 and 2015 were prospectively analyzed for toxicity and patterns of failure on an IRB-approved study.

Results: Twenty-seven consecutive patients were evaluated. Patients were a median of 56 years and had thymoma (85%). They were treated with definitive (22%), salvage (15%) or adjuvant (63%) DS-PT to a median of 61.2/1.8 Gy [CGE]. No patient experienced grade ⩾3 toxicity. Acute grade 2 toxicities included dermatitis (37%), fatigue (11%), esophagitis (7%), and pneumonitis (4%). Late grade 2 toxicity was limited to a single patient with chronic dyspnea. At a median follow-up of 2 years, 100% local control was achieved. Three-year regional control, distant control, and overall survival rates were 96% (95% CI 76-99%), 74% (95% CI 41-90%), and 94% (95% CI 63-99%), respectively.

Conclusions: This is the first cohort and prospective series of proton therapy to treat thymic tumors, demonstrating low rates of early toxicity and excellent initial outcomes.
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http://dx.doi.org/10.1016/j.radonc.2016.02.003DOI Listing
March 2016

Beam-specific planning target volumes incorporating 4D CT for pencil beam scanning proton therapy of thoracic tumors.

J Appl Clin Med Phys 2015 11 8;16(6):5678. Epub 2015 Nov 8.

University of Pennsylvania.

The purpose of this study is to determine whether organ sparing and target coverage can be simultaneously maintained for pencil beam scanning (PBS) proton therapy treatment of thoracic tumors in the presence of motion, stopping power uncertainties, and patient setup variations. Ten consecutive patients that were previously treated with proton therapy to 66.6/1.8 Gy (RBE) using double scattering (DS) were replanned with PBS. Minimum and maximum intensity images from 4D CT were used to introduce flexible smearing in the determination of the beam specific PTV (BSPTV). Datasets from eight 4D CT phases, using ± 3% uncertainty in stopping power and ± 3 mm uncertainty in patient setup in each direction, were used to create 8 × 12 × 10 = 960 PBS plans for the evaluation of 10 patients. Plans were normalized to provide identical coverage between DS and PBS. The average lung V20, V5, and mean doses were reduced from 29.0%, 35.0%, and 16.4 Gy with DS to 24.6%, 30.6%, and 14.1 Gy with PBS, respectively. The average heart V30 and V45 were reduced from 10.4% and 7.5% in DS to 8.1% and 5.4% for PBS, respectively. Furthermore, the maximum spinal cord, esophagus, and heart doses were decreased from 37.1 Gy, 71.7 Gy, and 69.2 Gy with DS to 31.3 Gy, 67.9 Gy, and 64.6 Gy with PBS. The conformity index (CI), homogeneity index (HI), and global maximal dose were improved from 3.2, 0.08, 77.4 Gy with DS to 2.8, 0.04, and 72.1 Gy with PBS. All differences are statistically significant, with p-values <0.05, with the exception of the heart V45 (p = 0.146). PBS with BSPTV achieves better organ sparing and improves target coverage using a repainting method for the treatment of thoracic tumors. Incorporating motion-related uncertainties is essential.
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http://dx.doi.org/10.1120/jacmp.v16i6.5678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691001PMC
November 2015