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

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

Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

BACKGROUND: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. METHODS: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. DISCUSSION: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

Modernization of safety environment for a dedicated beamline for proton ocular therapy.

BACKGROUND: Proton therapy is an effective treatment for ocular melanoma, and other tumors of the eye. The fixed horizontal beamline dedicated to ocular treatments at Massachusetts General Hospital was originally commissioned in 2002, with much of the equipment, safety features, and practices dating back to an earlier implementation at Harvard Cyclotron in the 1970s. PURPOSE: To describe the experience of reevaluation and enhancement of the safety environment for one of the longest continuously operating proton therapy programs. METHODS: Several enhancements in quality control had been introduced throughout the years of operation, as described in this manuscript, to better align the practice with the evolving standards of proton therapy and the demands of a modern hospital. We spotlight the design and results of the failure mode and effect analysis (FMEA), and subsequent actions introduced to mitigate the modes associated with elevated risk. The findings of the FMEA informed the specifications for the new software application, which facilitated the improved management of the treatment workflow and the image-guidance aspects of ocular treatments. RESULTS: Eleven failure modes identified as having the highest risk are described. Six of these were mitigated with the clinical roll-out of a new application for image-guided radiation therapy (IGRT). Others were addressed through task automation, the broader introduction of checklists, and enhancements in pre-treatment staff-led time-out. CONCLUSIONS: Throughout the task of modernizing the safety system of our dedicated ocular beamline, FMEA proved to be an effective instrument in soliciting inputs from the staff about safety and workflow concerns, helping to identify steps associated with elevated failure risks. Risks were reduced with the clinical introduction of a new IGRT application, which integrates quality management tools widely recognized for their role in risk mitigation: automation of the data transfer and workflow steps, and with the introduction of checklists and redundancy cross-checks.

Modeling the Risk of Hearing Loss From Radiation Therapy in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

PURPOSE: The Pediatric Normal Tissue Effects in the Clinic (PENTEC) hearing loss (HL) task force reviewed investigations on cochlear radiation dose-response relationships and risk factors for developing HL. Evidence-based dose-response data are quantified to guide treatment planning. METHODS AND MATERIALS: A systematic review of the literature was performed to correlate HL with cochlear dosimetry. HL was considered present if a threshold exceeded 20 dB at any frequency. Radiation dose, ototoxic chemotherapy exposure, hearing profile including frequency spectra, interval to HL, and age at radiation therapy (RT) were analyzed. RESULTS: Literature was systematically reviewed from 1970 to 2021. This resulted in 739 abstracts; 19 met inclusion for meta-analysis, and 4 included data amenable to statistical modeling. These 4 studies included 457 cochleas at risk in patients treated with RT without chemotherapy, and 398 cochlea treated with chemotherapy. The incidence and severity of cochlear HL from RT exposure alone is related to dose and age. Risk of HL was <5% in cochlea receiving a mean dose ≤35 Gy but increased to 30% at 50 Gy. HL risk ranged from 25% to 40% in children under the age of 5 years at diagnosis, declining to 10% in older children for any radiation dose. Probability of similar severe HL occurred at doses 18.3 Gy higher for children <3 versus >3 years of age. High-frequency HL was most common, with average onset occurring 3.6 years (range, 0.4-13.2 years) after RT. Exposure to platinum-based chemotherapies added to the rates of HL at a given cochlear dose level, with 300 mg/m2 shifting the dose response by 7 Gy. CONCLUSIONS: In children treated with RT alone, risk of HL was low for cochlear dose <35 Gy and rose when dose exceeded 35 Gy without clear RT dose dependence. High-frequency HL was most prevalent, but all frequencies were affected. Children younger than 5 years were at highest risk of developing HL, although independent effects of dose and age were not fully elucidated. Future reports with more granular data are needed to better delineate time to onset of HL and the effects of chemoradiotherapy.

Alliance for Clinical Trials in Oncology (Alliance) trial A022101/NRG-GI009: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

Background: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. Methods: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. Discussion: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.

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

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

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

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

AAPM Task Group Report 290: Respiratory motion management for particle therapy.

Dose uncertainty induced by respiratory motion remains a major concern for treating thoracic and abdominal lesions using particle beams. This Task Group report reviews the impact of tumor motion and dosimetric considerations in particle radiotherapy, current motion-management techniques, and limitations for different particle-beam delivery modes (i.e., passive scattering, uniform scanning, and pencil-beam scanning). Furthermore, the report provides guidance and risk analysis for quality assurance of the motion-management procedures to ensure consistency and accuracy, and discusses future development and emerging motion-management strategies. This report supplements previously published AAPM report TG76, and considers aspects of motion management that are crucial to the accurate and safe delivery of particle-beam therapy. To that end, this report produces general recommendations for commissioning and facility-specific dosimetric characterization, motion assessment, treatment planning, active and passive motion-management techniques, image guidance and related decision-making, monitoring throughout therapy, and recommendations for vendors. Key among these recommendations are that: (1) facilities should perform thorough planning studies (using retrospective data) and develop standard operating procedures that address all aspects of therapy for any treatment site involving respiratory motion; (2) a risk-based methodology should be adopted for quality management and ongoing process improvement.

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

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

Semi-automated IGRT QA using a cone-shaped scintillator screen detector for proton pencil beam scanning treatments.

To promote accurate image-guided radiotherapy (IGRT) for a proton pencil beam scanning (PBS) system, a new quality assurance (QA) procedure employing a cone-shaped scintillator detector has been developed for multiple QA tasks in a semi-automatic manner. The cone-shaped scintillator detector (XRV-124, Logos Systems, CA) is sensitive to both x-ray and proton beams. It records scintillation on the cone surface as a 2D image, from which the geometry of the radiation field that enters and exits the cone can be extracted. Utilizing this feature, QA parameters that are essential to PBS IGRT treatment were measured and analyzed. The first applications provided coincidence checks of laser, imaging and radiation isocenters, and dependencies on gantry angle and beam energies. The analysis of the Winston-Lutz test was made available by combining the centricity measurements of the x-ray beam and the pencil beam. The accuracy of the gantry angle was validated against console readings provided by the digital encoder and an agreement of less than 0.2° was found. The accuracy of the position measurement was assessed with a robotic patient positioning system (PPS) and an agreement of less than 0.5 mm was obtained. The centricity of the two onboard x-ray imaging systems agreed well with that from the routinely used Digital Imaging Positioning System (DIPS), up to a consistent small shift of (-0.5 mm, 0.0 mm, -0.3 mm). The pencil beam spot size, in terms of σ of Gaussian fitting, agreed within 0.2 mm for most energies when compared to the conventional measurements by a 2D ion-chamber array (MatriXX-PT, IBA Dosimetry, Belgium). The cone-shaped scintillator system showed advantages in making multi-purpose measurements with a single setup. The in-house algorithms were successfully implemented to measure and analyze key QA parameters in a semi-automatic manner. This study presents an alternative and more efficient approach for IGRT QA for PBS and potentially for linear accelerators.

Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors.

PURPOSE: Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS). METHODS AND MATERIALS: We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n = 757) and ES (n = 314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8 Gy vs <55.8 Gy) × disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS. RESULTS: The median follow-up for surviving patients was 97 months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8 Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P = .015), and there was a significant radiation dose × disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; Pinteraction < .001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8 Gy radiation therapy to the pelvis or spine was 5.0% (95% CI, 0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS. CONCLUSIONS: Patients with osteosarcoma and ES receiving ≥55.8 Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.

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

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

A single detector energy-resolved proton radiography system: a proof of principle study by Monte Carlo simulations.

Taking advantage of Bragg peak and small spot size, pencil beam scanning proton therapy can deliver a highly conformal dose distribution to target while sparing normal tissues. However, such dose distributions can be highly sensitive to the proton range uncertainty which can reach 5% or higher in lung tissue. One proposed method for reducing range uncertainty is to measure the water equivalent path length (WEPL) by proton radiography. In this study, we followed a newly proposed proton beam radiography technique based on energy resolved dose functions (ERDF) to construct a Monte Carlo model for a single detector energy-resolved proton radiography system (SDPRS). This SDPRS model was constructed in the Monte Carlo software package TOPAS (TOol for PArticle Simulation) and it includes the Mevion HYPERSCAN™ pencil beam scanning treatment head and a 2D dose detector positioned downstream as the imager. A calibration phantom containing a number of tissue equivalent materials was simulated to evaluate the accuracy in WEPL measurement by SDPRS. The mean deviation of the obtained relative stopping power (RSP) from the reference values was 0.31%. Proton radiographs of an anthropomorphic head phantom were also generated to demonstrate the clinical relevance of the technique. Effects of different energy layer spacing and measurement noise were also studied.

What Is the Effect of High-dose Radiation on Bone in Patients With Sacral Chordoma? A CT Study.

BACKGROUND: Effects of high-dose radiation using protons and photons on bone are relatively unexplored, but high rates of insufficiency fractures are reported, and the causes of this are incompletely understood. Imaging studies with pre- and postradiation scans can help one understand the effect of radiation on bone. QUESTIONS/PURPOSES: The purpose of this study was to assess the effects of high-dose radiation on the trabecular density of bone in the sacrum using CT-derived Hounsfield units (HU). METHODS: Between 2009 and 2015, we treated 57 patients (older then 18 years) with sacral chordoma. Fourteen (25%) of them were treated with radiation only. The general indication for this approach is inoperability resulting from tumor size. Forty-two (74%) patients were treated with transverse sacral resections and high-dose radiotherapy (using either protons or photons or a combination) before surgery and after surgery. During this time period, our indication for this approach generally was symptomatic sacral chordoma in which resection would prevent further growth and reasonable sacrifice of nerve roots was possible. Of those patients, 21 (50%) had CT scans both before and after radiation treatment. We used HU as a surrogate for bone density. CT uses HU to derive information on tissue and bone quantity. A recent study presented reference HU values for normal (mean 133 ± 38 HU), osteoporotic (101 ± 25 HU), and osteopenic bone (79 ± 32 HU). To adjust for scanning protocol-induced changes in HU, we calculated the ratio between bone inside and outside the radiation field rather than using absolute values. To assess the effect of radiation, we tested whether there was a difference in ratio (sacrum/L1) before and after radiation. A control measurement was performed (L2/L1) and also tested for a difference before and after radiation. Statistical analyses were performed using the paired t-test. RESULTS: The effects of radiation appeared confined to the intended field, because the bone density outside the treated field was not observed to decrease. The ratio of HU (a surrogate for bone density) in L2 relative to L1 did not change after radiotherapy (preradiation mean: 0.979 ± 0.009, postradiation mean: 0.980 ± 0.009, mean difference outside the radiation field: -0.001, 95% confidence interval [CI], -0.009 to 0.007, p = 0.799). The ratio of HU within the radiation field relative to L1 decreased after radiotherapy (preradiation mean: 0.895 ± 0.050, postradiation mean: 0.658 ± 0.050, mean difference inside the radiation field: 0.237, 95% CI, 0.187-0.287, p < 0.001), suggesting the bone density stayed the same outside the radiation field but decreased inside the radiation field. CONCLUSIONS: Trabecular bone density decreased after high-dose radiation therapy in a small group of patients with sacral chordoma. High-dose radiation is increasingly gaining acceptance for treating sacral malignancies; further long-term prospective studies using calibrated CT scanners and preferably bone biopsies are needed. LEVEL OF EVIDENCE: Level IV, therapeutic study.

A minimum-phase Shinnar-Le Roux spectral-spatial excitation RF pulse for simultaneous water and lipid suppression in 1H-MRSI of body extremities.

PURPOSE: To develop a spectral-spatial (SPSP) excitation RF pulse for simultaneous water and lipid suppression in proton (1H) magnetic resonance spectroscopic imaging (MRSI) of body extremities. METHODS: An SPSP excitation pulse is designed to excite Creatine (Cr) and Choline (Cho) metabolite signals while suppressing the overwhelming water and lipid signals. The SPSP pulse is designed using a recently proposed multidimensional Shinnar-Le Roux (SLR) RF pulse design method. A minimum-phase spectral selectivity profile is used to minimize signal loss from T2⁎ decay. RESULTS: The performance of the SPSP pulse is evaluated via Bloch equation simulations and phantom experiments. The feasibility of the proposed method is demonstrated using three-dimensional, short repetition-time, free induction decay-based 1H-MRSI in the thigh muscle at 3T. CONCLUSION: The proposed SPSP excitation pulse is useful for simultaneous water and lipid suppression. The proposed method enables new applications of high-resolution 1H-MRSI in body extremities.

Experimental validation of two dual-energy CT methods for proton therapy using heterogeneous tissue samples.

PURPOSE: The purpose of this work is to evaluate the performance of dual-energy CT (DECT) for determining proton stopping power ratios (SPRs) in an experimental environment and to demonstrate its potential advantages over conventional single-energy CT (SECT) in clinical conditions. METHODS: Water equivalent range (WER) measurements of 12 tissue-equivalent plastic materials and 12 fresh animal tissue samples are performed in a 195 MeV broad proton beam using the dose extinction method. SECT and DECT scans of the samples are performed with a dual-source CT scanner (Siemens SOMATOM Definition Flash). The methods of Schneider et al. (1996), Bourque et al. (2014), and Lalonde et al. (2017) are used to predict proton SPR on SECT and DECT images. From predicted SPR values, the WER of the proton beam through the sample is predicted for SECT and DECT using Monte Carlo simulations and compared to the measured WER. RESULTS: For homogeneous tissue-equivalent plastic materials, results with DECT are consistent with experimental measurements and show a systematic reduction of SPR uncertainty compared to SECT, with root-mean-square errors of 1.59% versus 0.61% for SECT and DECT, respectively. Measurements with heterogeneous animal samples show a clear reduction of the bias on range predictions in the presence of bones, with -0.88% for SECT versus -0.58% and -0.14% for both DECT methods. An uncertainty budget allows isolating the effect of CT number conversion to SPR and predicts improvements by DECT over SECT consistently with theoretical predictions, with 0.34% and 0.31% for soft tissues and bones in the experimental setup compared to 0.34% and 1.14% with the theoretical method. CONCLUSIONS: The present work uses experimental measurements in a realistic clinical environment to show potential benefits of DECT for proton therapy treatment planning. Our results show clear improvements over SECT in tissue-equivalent plastic materials and animal tissues. Further work towards using Monte Carlo simulations for treatment planning with DECT data and a more detailed investigation of the uncertainties on I-value and limitations on the Bragg additivity rule could potentially further enhance the benefits of this imaging technology for proton therapy.

Improvement of single detector proton radiography by incorporating intensity of time-resolved dose rate functions.

Proton radiography, which images patients with the same type of particles as those with which they are to be treated, is a promising approach to image guidance and water equivalent path length (WEPL) verification in proton radiation therapy. We have shown recently that proton radiographs could be obtained by measuring time-resolved dose rate functions (DRFs) using an x-ray amorphous silicon flat panel. The WEPL values were derived solely from the root-mean-square (RMS) of DRFs, while the intensity information in the DRFs was filtered out. In this work, we explored the use of such intensity information for potential improvement in WEPL accuracy and imaging quality. Three WEPL derivation methods based on, respectively, the RMS only, the intensity only, and the intensity-weighted RMS were tested and compared in terms of the quality of obtained radiograph images and the accuracy of WEPL values. A Gammex CT calibration phantom containing inserts made of various tissue substitute materials with independently measured relative stopping powers (RSP) was used to assess the imaging performances. Improved image quality with enhanced interfaces was achieved while preserving the accuracy by using intensity information in the calibration. Other objects, including an anthropomorphic head phantom, a proton therapy range compensator, a frozen lamb's head and an 'image quality phantom' were also imaged. Both the RMS only and the intensity-weighted RMS methods derived RSPs within ± 1% for most of the Gammex phantom inserts, with a mean absolute percentage error of 0.66% for all inserts. In the case of the insert with a titanium rod, the method based on RMS completely failed, whereas that based on the intensity-weighted RMS was qualitatively valid. The use of intensity greatly enhanced the interfaces between different materials in the obtained WEPL images, suggesting the potential for image guidance in areas such as patient positioning and tumor tracking by proton radiography.

Investigation of real tissue water equivalent path lengths using an efficient dose extinction method.

For proton therapy, an accurate conversion of CT HU to relative stopping power (RSP) is essential. Validation of the conversion based on real tissue samples is more direct than the current practice solely based on tissue substitutes and can potentially address variations over the population. Based on a novel dose extinction method, we measured water equivalent path lengths (WEPL) on animal tissue samples to evaluate the accuracy of CT HU to RSP conversion and potential variations over a population. A broad proton beam delivered a spread out Bragg peak to the samples sandwiched between a water tank and a 2D ion-chamber detector. WEPLs of the samples were determined from the transmission dose profiles measured as a function of the water level in the tank. Tissue substitute inserts and Lucite blocks with known WEPLs were used to validate the accuracy. A large number of real tissue samples were measured. Variations of WEPL over different batches of tissue samples were also investigated. The measured WEPLs were compared with those computed from CT scans with the Stoichiometric calibration method. WEPLs were determined within ±0.5% percentage deviation (% std/mean) and ±0.5% error for most of the tissue surrogate inserts and the calibration blocks. For biological tissue samples, percentage deviations were within ±0.3%. No considerable difference (<1%) in WEPL was observed for the same type of tissue from different sources. The differences between measured WEPLs and those calculated from CT were within 1%, except for some bony tissues. Depending on the sample size, each dose extinction measurement took around 5 min to produce ~1000 WEPL values to be compared with calculations. This dose extinction system measures WEPL efficiently and accurately, which allows the validation of CT HU to RSP conversions based on the WEPL measured for a large number of samples and real tissues.

Irradiation of anatomically defined pelvic subsites and acute hematologic toxicity in anal cancer patients undergoing chemoradiation.

PURPOSE: Chemoradiation for the treatment of anal cancer is known to cause significant hematologic toxicity (HT). We sought to investigate if radiation dose to specific pelvic subsites is associated with increased HT risk. METHODS AND MATERIALS: Forty-five patients with nonmetastatic anal cancer who received definitive chemoradiation with intensity modulated radiation therapy and concurrent mitomycin-C and 5-fluorouracil were studied. Total pelvic bone marrow (TBM) was divided into 3 subsites: lumbosacral bone marrow (LSBM), including the entire sacrum and L5 vertebral body; iliac bone marrow (IBM) extending from the iliac crests to the superior border of the femoral head; and lower pelvic bone marrow, including the pubic bones, ischia, acetabula, and proximal femurs. The primary endpoint was absolute neutrophil count (ANC) nadir during or within 2 weeks of treatment completion. Generalized linear modeling was used to analyze the correlation between the equivalent uniform dose (with an "a" value of 0.5) to the individual pelvic subsites and the various hematologic endpoints. Age, body mass index, sex, baseline blood counts, and immunosuppression were analyzed as potential covariates. RESULTS: Mean ± standard deviation ANC nadir was 0.77 × 109/L (±0.66 × 109/L). Grades 3+ and 4+ neutropenia occurred in 71.1% and 44.4% of patients, respectively. In addition to radiation dose to pelvic bone marrow, baseline ANC was the only significant predictor of hematologic toxicity on multivariable analysis and was included in all models. The equivalent uniform doses of TBM, LSBM, and IBM were each significantly associated with neutropenia. The model performance of TBM (adjusted R2 = 0.226) was similar to both LSBM (adjusted R2 = 0.206) and IBM (adjusted R2 = 0.249). CONCLUSIONS: Radiation doses to TBM, LSBM, and IBM were individually associated with HT, suggesting that sparing just a portion of pelvic bone marrow is insufficient to decrease rates of clinically significant bone marrow suppression.

Impacts of gantry angle dependent scanning beam properties on proton PBS treatment.

While proton beam models in treatment planning systems are generally assumed invariant with respect to the beam deliveries at different gantry angles. Physical properties of scanning pencil beams can change. The gantry angle dependent properties include the delivered charge to the monitor unit chamber, the spot position and the spot shape. The aim of this study is to investigate the extent of the changes and their dosimetric impacts using historical pencil beam scanning (PBS) treatment data. Online beam delivery records at the time of the patient-specific qualify assurance were retrospectively collected for a total of 34 PBS fields from 28 patients treated at our institution. For each field, proton beam properties at two different gantry angles (the planned and zero gantry angles) were extracted by a newly-developed machine log analysis method and used to reconstruct the delivered dose distributions in the cubic water phantom geometry. The reconstructed doses at the two different angles and a planar dose measurement by a 2D ion-chamber array were compared and the dosimetric impacts of the gantry angle dependency were accessed by a 3D γ-index analysis. In addition, the pencil beam spot size was independently characterized as a function of the gantry angle and the beam energy. The dosimetric effects of the perturbed beam shape were also investigated. Comparisons of spot-by-spot beam positions between both gantry angles show a mean deviation of 0.4 and 0.7 mm and a standard deviation of 0.3 and 0.6 mm for x and y directions, respectively. The delivered giga-protons per spot show a percent mean difference and a standard deviation of 0.01% and 0.3%, respectively, from each planned spot weight. These small deviations lead to an excellent agreement in dose comparisons with an average γ passing rate of 99.1%. When each calculation for both planned and zero gantry angles was compared to the measurement, a high correlation in γ values was also observed, also indicating the dosimetric differences are small when a field is delivered at different gantry angles. Utilizing the online beam delivery records, the gantry angle dependencies of the PBS beam delivery were assessed and quantified. The study confirms the variations of the physical properties to be sufficiently small within the clinical tolerances without taking into account the gantry angle variation.