Relative thoracic changes from supine to upright patient position: A proton collaborative group study.

This study presents position changes of a few radiotherapy-relevant thoracic organs between upright and typical supine patient orientations. Using tools in a commercial treatment planning system (TPS), key anatomical distances were measured for four-dimensional CT data sets and analyzed for the two patient orientations. The uncertainty was calculated as the 95% confidence interval (CI) on the relative difference for each of the four analyzed changes for upright relative to supine, as follows: the distance of the bottom of the heart to the top of the sternum, it changed +2.6% or +4 mm (95% CI [+0.30%,+4.9%]); the distance of the center of the C3 vertebra to the backrest, it changed +29% (95% CI [+22%,+36%]); the contoured left and right lungs increased their volumes respectively: +17% (95% CI [+12%,+21%]) for the left, and +9.9% (95% CI [+4.1%,+16%]); and lastly, the distance from the top of the sternum to the top of the liver, but its uncertainty far exceeded the average change by a factor of two. This last result is therefore inconclusive, the others show that with 95% confidence that a change in internal positions is observed for lung volumes and heart position that could be important for upright treatments.

Comparative accuracy and resolution assessment of two prototype proton computed tomography scanners.

BACKGROUND: Improving the accuracy of relative stopping power (RSP) in proton therapy may allow reducing range margins. Proton computed tomography (pCT) has been shown to provide state-of-the-art RSP accuracy estimation, and various scanner prototypes have recently been built. The different approaches used in scanner design are expected to impact spatial resolution and RSP accuracy. PURPOSE: The goal of this study was to perform the first direct comparison, in terms of spatial resolution and RSP accuracy, of two pCT prototype scanners installed at the same facility and by using the same image reconstruction algorithm. METHODS: A phantom containing cylindrical inserts of known RSP was scanned at the phase-II pCT prototype of the U.S. pCT collaboration and at the commercially oriented ProtonVDA scanner. Following distance-driven binning filtered backprojection reconstruction, the radial edge spread function of high-density inserts was used to estimate the spatial resolution. RSP accuracy was evaluated by the mean absolute percent error (MAPE) over the inserts. No direct imaging dose estimation was possible, which prevented a comparison of the two scanners in terms of RSP noise. RESULTS: In terms of RSP accuracy, both scanners achieved the same MAPE of 0.72% when excluding the porous sinus insert from the evaluation. The ProtonVDA scanner reached a better overall MAPE when all inserts and the body of the phantom were accounted for (0.81%), compared to the phase-II scanner (1.14%). The spatial resolution with the phase-II scanner was found to be 0.61 lp/mm, while for the ProtonVDA scanner somewhat lower at 0.46 lp/mm. CONCLUSIONS: The comparison between two prototype pCT scanners operated in the same clinical facility showed that they both fulfill the requirement of an RSP accuracy of about 1%. Their spatial resolution performance reflects the different design choices of either a scanner with full tracking capabilities (phase-II) or of a more compact tracker system, which only provides the positions of protons but not their directions (ProtonVDA).

Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial.

PURPOSE: Hypofractionated radiation therapy has been safely implemented in the treatment of early-stage non-small cell lung cancer (NSCLC) but not locally advanced NSCLC owing to prohibitive toxicities with photon therapy. Proton therapy, however, may allow for safe delivery of hypofractionated radiation therapy. We sought to determine whether hypofractionated proton therapy with concurrent chemotherapy improves overall survival. METHODS AND MATERIALS: The Proton Collaborative Group conducted a phase 1/2 single-arm nonrandomized prospective multicenter trial from 2013 through 2018. We received consent from 32 patients, of whom 28 were eligible for on-study treatment. Patients had stage II or III unresectable NSCLC (based on the 7th edition of the American Joint Committee on Cancer's staging manual) and received hypofractionated proton therapy at 2.5 to 4 Gy per fraction to a total 60 Gy with concurrent platin-based doublet chemotherapy. The primary outcome was 1-year overall survival comparable to the 62% reported for the Radiation Therapy Oncology Group (RTOG) 9410 trial. RESULTS: The trial closed early owing to slow accrual, in part, from a competing trial, RTOG 1308. Median patient age was 70 years (range, 50-86 years). Patients were predominantly male (n = 20), White (n = 23), and prior smokers (n = 27). Most had stage III NSCLC (n = 22), 50% of whom had adenocarcinoma. After a median follow-up of 31 months, the 1- and 3-year overall survival rates were 89% and 49%, respectively, and progression-free survival rates were 58% and 32%, respectively. No acute grade ≥3 esophagitis occurred. Only 14% developed a grade ≥3 radiation-related pulmonary toxic effect. CONCLUSIONS: Hypofractionated proton therapy delivered at 2.5 to 3.53 Gy per fraction to a total 60 Gy with concurrent chemotherapy provides promising survival, and additional examination through larger studies may be warranted.

A comparison of proton stopping power measured with proton CT and x-ray CT in fresh postmortem porcine structures.

PURPOSE: Currently, calculations of proton range in proton therapy patients are based on a conversion of CT Hounsfield units of patient tissues into proton relative stopping power. Uncertainties in this conversion necessitate larger proximal and distal planned target volume margins. Proton CT can potentially reduce these uncertainties by directly measuring proton stopping power. We aim to demonstrate proton CT imaging with complex porcine samples, to analyze in detail three-dimensional regions of interest, and to compare proton stopping powers directly measured by proton CT to those determined from x-ray CT scans. METHODS: We have used a prototype proton imaging system with single proton tracking to acquire proton radiography and proton CT images of a sample of porcine pectoral girdle and ribs, and a pig's head. We also acquired close in time x-ray CT scans of the same samples and compared proton stopping power measurements from the two modalities. In the case of the pig's head, we obtained x-ray CT scans from two different scanners and compared results from high-dose and low-dose settings. RESULTS: Comparing our reconstructed proton CT images with images derived from x-ray CT scans, we find agreement within 1% to 2% for soft tissues and discrepancies of up to 6% for compact bone. We also observed large discrepancies, up to 40%, for cavitated regions with mixed content of air, soft tissue, and bone, such as sinus cavities or tympanic bullae. CONCLUSIONS: Our images and findings from a clinically realistic proton CT scanner demonstrate the potential for proton CT to be used for low-dose treatment planning with reduced margins.

Proton Therapy for Breast Cancer: A Consensus Statement From the Particle Therapy Cooperative Group Breast Cancer Subcommittee.

Radiation therapy plays an important role in the multidisciplinary management of breast cancer. Recent years have seen improvements in breast cancer survival and a greater appreciation of potential long-term morbidity associated with the dose and volume of irradiated organs. Proton therapy reduces the dose to nontarget structures while optimizing target coverage. However, there remain additional financial costs associated with proton therapy, despite reductions over time, and studies have yet to demonstrate that protons improve upon the treatment outcomes achieved with photon radiation therapy. There remains considerable heterogeneity in proton patient selection and techniques, and the rapid technological advances in the field have the potential to affect evidence evaluation, given the long latency period for breast cancer radiation therapy recurrence and late effects. In this consensus statement, we assess the data available to the radiation oncology community of proton therapy for breast cancer, provide expert consensus recommendations on indications and technique, and highlight ongoing trials' cost-effectiveness analyses and key areas for future research.

Selection of Mediastinal Lymphoma Patients for Proton Therapy Within the Proton Collaborative Group Registry: Concordance With the ILROG Guidelines.

PURPOSE: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). METHODS: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). RESULTS: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. CONCLUSIONS: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

Individualized quality of life benefit and cost-effectiveness estimates of proton therapy for patients with oropharyngeal cancer.

BACKGROUND: Proton therapy is a promising advancement in radiation oncology especially in terms of reducing normal tissue toxicity, although it is currently expensive and of limited availability. Here we estimated the individual quality of life benefit and cost-effectiveness of proton therapy in patients with oropharyngeal cancer treated with definitive radiation therapy (RT), as a decision-making tool for treatment individualization. METHODS AND MATERIALS: Normal tissue complication probability models were used to estimate the risk of dysphagia, esophagitis, hypothyroidism, xerostomia and oral mucositis for 33 patients, comparing delivered photon intensity-modulated RT (IMRT) plans to intensity-modulated proton therapy (IMPT) plans. Quality-adjusted life years (QALYs) lost were calculated for each complication while accounting for patient-specific conditional survival probability and assigning quality-adjustment factors based on complication severity. Cost-effectiveness was modeled based on upfront costs of IMPT and IMRT, and the cost of acute and/or long-term management of treatment complications. Uncertainties in all model parameters and sensitivity analyses were included through Monte Carlo sampling. RESULTS: The incremental cost-effectiveness ratios (ICERs) showed considerable variability in the cost of QALYs spared between patients, with median $361,405/QALY for all patients, varying from $54,477/QALY to $1,508,845/QALY between individual patients. Proton therapy was more likely to be cost-effective for patients with p16-positive tumors ($234,201/QALY), compared to p16-negative tumors ($516,297/QALY). For patients with p16-positive tumors treated with comprehensive nodal irradiation, proton therapy is estimated to be cost-effective in ≥ 50% of sampled cases for 8/9 patients at $500,000/QALY, compared to 6/24 patients who either have p16-negative tumors or receive unilateral neck irradiation. CONCLUSIONS: Proton therapy cost-effectiveness varies greatly among oropharyngeal cancer patients, and highlights the importance of individualized decision-making. Although the upfront cost, societal willingness to pay and healthcare administration can vary greatly among different countries, identifying patients for whom proton therapy will have the greatest benefit can optimize resource allocation and inform prospective clinical trial design.

Technical Note: A fast and monolithic prototype clinical proton radiography system optimized for pencil beam scanning.

PURPOSE: To demonstrate a proton-imaging system based on well-established fast scintillator technology to achieve high performance with low cost and complexity, with the potential of a straightforward translation into clinical use. METHODS: The system tracks individual protons through one (X, Y) scintillating fiber tracker plane upstream and downstream of the object and into a 13-cm -thick scintillating block residual energy detector. The fibers in the tracker planes are multiplexed into silicon photomultipliers (SiPMs) to reduce the number of electronics channels. The light signal from the residual energy detector is collected by 16 photomultiplier tubes (PMTs). Only four signals from the PMTs are output from each event, which allows for fast signal readout. A robust calibration method of the PMT signal to residual energy has been developed to obtain accurate proton images. The development of patient-specific scan patterns using multiple input energies allows for an image to be produced with minimal excess dose delivered to the patient. RESULTS: The calibration of signals in the energy detector produces accurate residual range measurements limited by intrinsic range straggling. We measured the water-equivalent thickness (WET) of a block of solid water (physical thickness of 6.10 mm) with a proton radiograph. The mean WET from all pixels in the block was 6.13 cm (SD 0.02 cm). The use of patient-specific scan patterns using multiple input energies enables imaging with a compact range detector. CONCLUSIONS: We have developed a prototype clinical proton radiography system for pretreatment imaging in proton radiation therapy. We have optimized the system for use with pencil beam scanning systems and have achieved a reduction of size and complexity compared to previous designs.

Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation.

PURPOSE: Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Müllerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after in vivo mouse pelvic GRT versus PRT. METHODS AND MATERIALS: One hundred twenty-four female prepubertal mice received sham, GRT, or PRT with ovaries positioned at various depth with respect to the proton SOBP, with single doses of 1.8 or 0.2 Gy. AMH was measured at baseline, 1, 3, and 8 weeks after treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiation therapy modality and dose on AMH and primordial follicle survival. RESULTS: For ovaries beyond the SOBP, ovarian function (P = .5) and ovarian primordial follicle (OPF; P = 1.0) were spared relative to sham controls. For ovaries in the SOBP plateau, ovarian function and primordial follicle reserve 8 weeks after treatment were reduced for all groups: 1.8 Gy GRT (ßAMH = -4.9 ng/mL; ßOPF = -728.2/animal), 1.8 Gy (relative biological effectiveness [RBE] = 1.1) PRT (ßAMH = -5.1 ng/mL; ßOPF = -728.2/animal), 0.2 Gy GRT (ßAMH = -2.5 ng/mL; ßOPF = -595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (ßAMH = -3.0 ng/mL; ßOPF = -555.4/animal) relative to sham controls (all differences P < .001). CONCLUSIONS: This study uses an animal model to demonstrate the safety of proton therapy in sparing fertility. Ovaries positioned beyond the SOBP during PRT maintain ovarian reserve, suggesting that a proton beam has no energy and exit dose beyond SOBP. This study proposes that proton therapy is much safer than photon radiation therapy to protect ovarian follicles with the same dose, and it supports further testing of proton therapy for abdominopelvic tumors in young women.

Experimental and Monte Carlo characterization of a dynamic collimation system prototype for pencil beam scanning proton therapy.

PURPOSE: There has been a growing interest in the development of energy-specific collimators for low-energy pencil beam scanning (PBS) to reduce the lateral penumbra. One particular device that has been the focus of several recent published works is the dynamic collimation system (DCS), which provides energy-specific collimation by intercepting the scanned proton beam as it nears to target edge with a set of orthogonal trimmer blades. While several computational studies have shown that this dynamic collimator can provide additional healthy tissue sparing, there has not been any rigorous experimental work to benchmark the theoretical models used in these initial studies. Therefore, it was the purpose of this work to demonstrate an experimental method that could integrate an experimental prototype with a clinical PBS system and benchmark the Monte Carlo methods that have been used to model the DCS. METHODS: An experimental DCS prototype was designed and built in house to actively collimate individual proton beamlets during PBS within a well-characterized experimental setup. Monte Carlo methods were initially used to assess construction tolerances and later benchmarked against measurements, including integral depth dose and lateral asymmetric beamlet profiles. The experimental apparatus and measurement geometry were modeled using MCNP6 benchmarked from measurements performed at the Northwestern Chicago Proton Center. RESULTS: Gamma analysis tests were used to evaluate the agreement between the measured and simulated profiles with a strict 1 mm/1% criteria and 5% dose threshold. Excellent agreement was observed between the simulated and measured profiles, which included 1 mm/1% gamma analysis pass rates of at least 100% and 95% for the integral depth dose (IDD) profiles and lateral profiles, respectively. Differences in the relative profile shape were observed experimentally between beamlets collimated on- and off-axis, which was attributed to the partial transmission of the beam through an unfocused collimator. Exposure rates resulting from the activation of the device were monitored with survey meter measurements and were found to agree with Monte Carlo estimates of the exposure rate to within 20%. CONCLUSION: A DCS prototype was constructed and integrated into a clinical dose delivery system. While the results of this work are not exhaustive, they demonstrate the effects of beam source divergence, device activation, and beamlet deflection during scanning, which were found to be successfully modeled using Monte Carlo methods and experimentally benchmarked. Excellent agreement was achieved between the simulated and measured lateral spot profiles of collimated beamlets delivered on- and off-axis in PBS. The Monte Carlo models adequately predicted the measured elevated plateau region in the integral depth-dose profiles from the low-energy scatter off the collimators.

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

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

Experimental comparison of proton CT and dual energy x-ray CT for relative stopping power estimation in proton therapy.

Proton computed tomography (pCT) has been proposed as an alternative to x-ray computed tomography (CT) for acquiring relative to water stopping power (RSP) maps used for proton treatment planning dose calculations. In parallel, it has been shown that dual energy x-ray CT (DECT) improves RSP accuracy when compared to conventional single energy x-ray CT. This study aimed at directly comparing the RSP accuracy of both modalities using phantoms scanned at an advanced prototype pCT scanner and a state-of-the-art DECT scanner. Two phantoms containing 13 tissue-mimicking inserts of known RSP were scanned at the pCT phase II prototype and a latest generation dual-source DECT scanner (Siemens SOMATOM Definition FORCE). RSP accuracy was compared by mean absolute percent error (MAPE) over all inserts. A highly realistic Monte Carlo (MC) simulation was used to gain insight on pCT image artifacts which degraded MAPE. MAPE was 0.55% for pCT and 0.67% for DECT. The realistic MC simulation agreed well with pCT measurements ([Formula: see text]). Both simulation and experimental results showed ring artifacts in pCT images which degraded the MAPE compared to an ideal pCT simulation ([Formula: see text]). Using the realistic simulation, we could identify sources of artifacts, which are attributed to the interfaces in the five-stage plastic scintillator energy detector and calibration curve interpolation regions. Secondary artifacts stemming from the proton tracker geometry were also identified. The pCT prototype scanner outperformed a state-of-the-art DECT scanner in terms of RSP accuracy (MAPE) for plastic tissue mimicking inserts. Since artifacts tended to concentrate in the inserts, their mitigation may lead to further improvements in the reported pCT accuracy.

AAPM task group 224: Comprehensive proton therapy machine quality assurance.

PURPOSE:  Task Group (TG) 224 was established by the American Association of Physicists in Medicine's Science Council under the Radiation Therapy Committee and Work Group on Particle Beams. The group was charged with developing comprehensive quality assurance (QA) guidelines and recommendations for the three commonly employed proton therapy techniques for beam delivery: scattering, uniform scanning, and pencil beam scanning. This report supplements established QA guidelines for therapy machine performance for other widely used modalities, such as photons and electrons (TG 142, TG 40, TG 24, TG 22, TG 179, and Medical Physics Practice Guideline 2a) and shares their aims of ensuring the safe, accurate, and consistent delivery of radiation therapy dose distributions to patients. METHODS:  To provide a basis from which machine-specific QA procedures can be developed, the report first describes the different delivery techniques and highlights the salient components of the related machine hardware. Depending on the particular machine hardware, certain procedures may be more or less important, and each institution should investigate its own situation. RESULTS:  In lieu of such investigations, this report identifies common beam parameters that are typically checked, along with the typical frequencies of those checks (daily, weekly, monthly, or annually). The rationale for choosing these checks and their frequencies is briefly described. Short descriptions of suggested tools and procedures for completing some of the periodic QA checks are also presented. CONCLUSION:  Recommended tolerance limits for each of the recommended QA checks are tabulated, and are based on the literature and on consensus data from the clinical proton experience of the task group members. We hope that this and other reports will serve as a reference for clinical physicists wishing either to establish a proton therapy QA program or to evaluate an existing one.

Reconstructed and Real Proton Radiographs for Image-Guidance in Proton Beam Therapy.

One of the major challenges to proton beam therapy at this time is the uncertainty of the true range of a clinical treatment proton beam as it traverses the various tissues and organs in a human body. This uncertainty necessitates the addition of greater "margins" to the planning target volume along the direction of the beam to ensure safety and tumor target coverage. Proton radiography holds promise as both an image-guidance method for proton beam therapy and as a means of estimating particle beam range in the clinic. In this brief report, we present some of the first real and reconstructed proton radiographs using our particular system. Our qualitative review of these images indicates that this method has excellent potential as a proton radiography-based image guidance system. Based on the encouraging results of our preliminary work, more rigorous and quantitative analyses will be performed shortly and we shall continue to explore the potential of this approach for addressing the particle beam range uncertainty issue.

Fast In Situ Image Reconstruction for Proton Radiography.

OBJECTIVE: Proton beam therapy is an emerging modality for cancer treatment that, compared to X-ray radiation therapy, promises to provide better dose delivery to clinical targets with lower doses to normal tissues. Crucial to accurate treatment planning and dose delivery is knowledge of the water equivalent path length (WEPL) of each ray, or pencil beam, from the skin to every point in the target. For protons, this length is estimated from relative stopping power based on X-ray Hounsfield units. Unfortunately, such estimates lead to 3 to 4% uncertainties in the proton range prediction. Therefore, protons in the Bragg peak may overshoot (or undershoot) the desired stopping depth in the target causing tissue damage beyond the target volume. Recent studies indicate that tomographic imaging using protons has the potential to provide directly more accurate measurement of RSPs with significantly lower radiation dose than X-rays. We are currently working on a proton radiography system that promises to provide accurate two-dimensional (2D) images of WEPL values for protons that pass through the body. These will be suitable for positioning and range verification in daily treatments. In this study, we demonstrate that this system is capable of rapidly achieving such accurate images in clinically meaningful times. METHODS: We have developed a software platform to characterize the potential performance of the prototype proton radiography system. We use Geant4 to simulate raw data detected by the device. An especially-written software - pRad - was written to process these data as they are received and uses iterative methods to generate radiographs. The software has been designed to generate a radiograph from a few million protons in under a minute after receiving the first proton from the device. We used a head phantom with known chemical compositions that could be modelled quite accurately in Geant4 simulations of proton radiographs. The radiographs are displayed as pixelated WEPL values displayed on a 2D gray scale image of WEPL values. RESULTS: Rapid radiograph reconstruction of 3D phantoms using simulated proton pencil beams have been achieved with our software platform. On a modest desktop computer with a single central processing unit (CPU) and a single graphics processing unit (GPU), it takes about 11 seconds to reconstruct images using iterative linear algorithms to reconstruct a radiograph from 7.6 million protons. For the radiographic reconstructions of the head phantom described here, the mean WEPL errors, in the proton radiograph using a large majority of the pixels in the complete image were less than 1 mm when compared to images obtained without proton scattering and without detector resolution included. CONCLUSION: We have demonstrated, through computer simulations of proton irradiation of a pediatric head phantom using the newly built pRad detector and image reconstruction software, that high quality proton radiographs can be generated for patient alignment and verification of water equivalent thickness of the patient before each treatment.

A Quantitative Clinical Decision-Support Strategy Identifying Which Patients With Oropharyngeal Head and Neck Cancer May Benefit the Most From Proton Radiation Therapy.

PURPOSE: Developing a quantitative decision-support strategy estimating the impact of normal tissue complications from definitive radiation therapy (RT) for head and neck cancer (HNC). We developed this strategy to identify patients with oropharyngeal HNC who may benefit most from receiving proton RT. METHODS AND MATERIALS: Recent normal tissue complication probability (NTCP) models for dysphagia, esophagitis, hypothyroidism, xerostomia, and oral mucositis were used to estimate NTCP for 33 patients with oropharyngeal HNC previously treated with photon intensity modulated radiation therapy (IMRT). Comparative proton therapy plans were generated using clinical protocols for HNC RT at a collaborating proton center. Organ-at-risk (OAR) doses from photon and proton RT plans were used to calculate NTCPs; Monte Carlo sampling 10,000 times was used for each patient to account for model parameter uncertainty. The latency and duration of each complication were modeled from calculated NTCP, accounting for age-, sex-, smoking- and p16-specific conditional survival probability. Complications were then assigned quality-adjustment factors based on severity to calculate quality-adjusted life years (QALYs) lost from each complication. RESULTS: Based on our institutional-delivered photon IMRT doses and the achievable proton therapy doses, the average QALY reduction from all HNC RT complications for photon and proton therapy was 1.52 QALYs versus 1.15 QALYs, with proton therapy sparing 0.37 QALYs on average (composite 95% confidence interval, 0.27-2.53 QALYs). Long-term complications (dysphagia and xerostomia) contributed most to the QALY reduction. The QALYs spared with proton RT varied considerably among patients, ranging from 0.06 to 0.84 QALYs. Younger patients with p16-positive tumors who smoked ≤10 pack-years may benefit most from proton therapy, although this finding should be validated using larger patient series. A sensitivity analysis reducing photon IMRT doses to all OARs by 20% resulted in no overall estimated benefit with proton therapy with -0.02 QALYs spared, although some patients still had an estimated benefit in this scenario, ranging from -0.50 to 0.43 QALYs spared. CONCLUSIONS: This quantitative decision-support strategy allowed us to identify patients with oropharyngeal cancer who might benefit the most from proton RT, although the estimated benefit of proton therapy ultimately depends on the OAR doses achievable with modern photon IMRT solutions. These results can help radiation oncologists and proton therapy centers optimize resource allocation and improve quality of life for patients with HNC.

Initial toxicity, quality-of-life outcomes, and dosimetric impact in a randomized phase 3 trial of hypofractionated versus standard fractionated proton therapy for low-risk prostate cancer.

PURPOSE: Randomized evidence for extreme hypofractionation in prostate cancer is lacking. We aimed to identify differences in toxicity and quality-of-life outcomes between standard fractionation and extreme hypofractionated radiation in a phase 3 randomized trial. METHODS AND MATERIALS: We analyzed the results of the first 75 patients in our phase 3 trial, comparing 38 Gy relative biologic effectiveness (RBE) in 5 fractions (n = 46) versus 79.2 Gy RBE in 44 fractions (n = 29). Patients received proton radiation using fiducials and daily image guidance. We evaluated American Urological Association Symptom Index (AUASI), adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains. The primary endpoint of this interim analysis was the cumulative incidence of grade 2 (G2) or higher AEs. The randomized patient allocation scheme was a 2:1 ratio favoring the 38 Gy RBE arm. RESULTS: The median follow-up was 36 months; 30% of patients reached 48-month follow-up. AUASI scores differed <5 points (4.4 vs 8.6; P = .002) at 1 year, favoring the 79.2 Gy arm. Differences in AUASI were not significant at ≥18 months. EPIC urinary symptoms favored the 79.2 Gy arm at 1 year (92.3 vs 84.5; P = .009) and 18 months (92.3 vs 85.3; P = .03); bother scores were not significant at other time points. Cumulative ≥G2 genitourinary toxicity was similar between the 79.2 Gy and 38 Gy arms (34.5% vs 30.4%; P = .80). We found no differences in the EPIC domains of bowel symptoms, sexual symptoms, or bowel ≥G2 toxicities. Bladder V80 (79.2 Gy arm; P = .04) and V39 (38 Gy arm; P = .05) were predictive for cumulative G2 genitourinary AEs. CONCLUSIONS: Low AE rates were seen in both study arms. Early temporary differences in genitourinary scores disappeared over time. Bladder constraints were associated with genitourinary AEs.

Experimental fluence-modulated proton computed tomography by pencil beam scanning.

PURPOSE: This experimental study is aimed at demonstrating, using a simple cylindrical water phantom, the feasibility of fluence-modulated proton computed tomography (FMpCT) by pencil beam scanning (PBS) proton computed tomography (pCT). METHODS: The phase II pCT prototype of the Loma Linda U. and U. C. Santa Cruz was operated using the PBS beam line of the Northwestern Medicine Chicago Proton Center. A 20 × 10 grid of 1.37 cm full width half maximum pencil beams (PB) equally spaced by 1 cm was used to acquire 45 projections in step and shoot mode. The PB pattern's fluence was modified to allow FMpCT scans with fluence modulation factors (FMF) of 50% and 20%. A central FMpCT region of interest (FMpCT-ROI) was used to define a high image quality region. Reconstructed images were evaluated in terms of relative stopping power (RSP) accuracy and noise using annular ROIs. The FMpCT dose savings were estimated by Monte Carlo (MC) simulation of the pCT acquisitions using beam phase space distributions. PBS pCT results with homogeneous fluence were additionally compared to broad beam results in terms of RSP accuracy and noise. RESULTS: PBS pCT scans with acceptable pileup were possible, and images were comparable to previously acquired broad beam pCT images in terms of both noise and accuracy. In the FMpCT-ROI, the noise and accuracy from full fluence (FF) scans were preserved. Dose savings of up to 60% were achieved at the object's edge when using FMF of 20%. CONCLUSION: In this study, we have demonstrated that PBS pCT scans can achieve equivalent accuracy as those obtained from broad beams. The feasibility of FMpCT scans was demonstrated; image accuracy and noise were successfully preserved in the central FMpCT-ROI chosen for this study, and dose reduction of up to 60% at the object's edge was realized.