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.

An empirical artifact correction for proton computed tomography.

PURPOSE: To reduce image artifacts of proton computed tomography (pCT) from a preclinical scanner, for imaging of the relative stopping power (RSP) needed for particle therapy treatment planning using a simple empirical artifact correction method. METHODS: We adapted and employed a correction method previously used for beam-hardening correction in x-ray CT which makes use of a single scan of a custom-built homogeneous phantom with known RSP. Exploiting the linearity of the filtered backprojection operation, a function was found which corrects water-equivalent path lengths (RSP line integrals) in experimental scans using a prototype pCT scanner. The correction function was applied to projection values of subsequent scans of a homogeneous water phantom, a sensitometric phantom with various inserts and an anthropomorphic head phantom. Data were acquired at two different incident proton energies to test the robustness of the method. RESULTS: Inaccuracies in the detection process caused an offset and known ring artifacts in the water phantom which were considerably reduced using the proposed method. The mean absolute percentage error (MAPE) of mean RSP values of all inserts of the sensitometric phantom and the water phantom was reduced from 0.87% to 0.44% and from 0.86% to 0.48% for the two incident energies respectively. In the head phantom a clear reduction of artifacts was observed. CONCLUSIONS: Image artifacts of experimental pCT scans with a prototype scanner could substantially be reduced both in homogeneous, heterogeneous and anthropomorphic phantoms. RSP accuracy was also improved.

Particle-Tracking Proton Computed Tomography-Data Acquisition, Preprocessing, and Preconditioning.

Proton CT (pCT) is a promising new imaging technique that can reconstruct relative stopping power (RSP) more accurately than x-ray CT in each cubic millimeter voxel of the patient. This, in turn, will result in better proton range accuracy and, therefore, smaller planned tumor volumes (PTV). The hardware description and some reconstructed images have previously been reported. In a series of two contributions, we focus on presenting the software algorithms that convert pCT detector data to the final reconstructed pCT images for application in proton treatment planning. There were several options on how to accomplish this, and we will describe our solutions at each stage of the data processing chain. In the first paper of this series, we present the data acquisition with the pCT tracking and energy-range detectors and how the data are preprocessed, including the conversion to the well-formatted track information from tracking data and water-equivalent path length from the data of a calibrated multi-stage energy-range detector. These preprocessed data are then used for the initial image formation with an FDK cone-beam CT algorithm. The output of data acquisition, preprocessing, and FDK reconstruction is presented along with illustrative imaging results for two phantoms, including a pediatric head phantom. The second paper in this series will demonstrate the use of iterative solvers in conjunction with the superiorization methodology to further improve the images resulting from the upfront FDK image reconstruction and the implementation of these algorithms on a hybrid CPU/GPU computer cluster.

Analysis of characteristics of images acquired with a prototype clinical proton radiography system.

PURPOSE: Verification of patient-specific proton stopping powers obtained in the patient's treatment position can be used to reduce the distal and proximal margins needed in particle beam planning. Proton radiography can be used as a pretreatment instrument to verify integrated stopping power consistency with the treatment planning CT. Although a proton radiograph is a pixel by pixel representation of integrated stopping powers, the image may also be of high enough quality and contrast to be used for patient alignment. This investigation quantifies the accuracy and image quality of a prototype proton radiography system on a clinical proton delivery system. METHODS: We have developed a clinical prototype proton radiography system designed for integration into efficient clinical workflows. We tested the images obtained by this system for water-equivalent thickness (WET) accuracy, image noise, and spatial resolution. We evaluated the WET accuracy by comparing the average WET and rms error in several regions of interest (ROI) on a proton radiograph of a custom peg phantom. We measured the spatial resolution on a CATPHAN Line Pair phantom and a custom edge phantom by measuring the 10% value of the modulation transfer function (MTF). In addition, we tested the ability to detect proton range errors due to anatomical changes in a patient with a customized CIRS pediatric head phantom and inserts of varying WET placed in the posterior fossae of the brain. We took proton radiographs of the phantom with each insert in place and created difference maps between the resulting images. Integrated proton range was measured from an ROI in the difference maps. RESULTS: We measured the WET accuracy of the proton radiographic images to be ±0.2 mm (0.33%) from known values. The spatial resolution of the images was 0.6 lp/mm on the line pair phantom and 1.13 lp/mm on the edge phantom. We were able to detect anatomical changes producing changes in WET as low as 0.6 mm. CONCLUSION: The proton radiography system produces images with image quality sufficient for pretreatment range consistency verification.

Proof of concept image artifact reduction by energy-modulated proton computed tomography (EMpCT).

PURPOSE: To reduce imaging artifacts and improve image quality of a specific proton computed tomography (pCT) prototype scanner by combining pCT data acquired at two different incident proton energies to avoid protons stopping in sub-optimal detector sections. METHODS: Image artifacts of a prototype pCT scanner are linked to protons stopping close to internal structures of the scanner's multi-stage energy detector. We aimed at avoiding such protons by acquiring pCT data at two different incident energies and combining the data in post-processing from which artifact-reduced images of the relative stopping power (RSP) were calculated. Energy-modulated pCT (EMpCT) images were assessed visually and quantitatively and compared to the original mono-energetic images in terms of RSP accuracy and noise. Data were acquired for a homogeneous water phantom. RESULTS: RSP images reconstructed from the mono-energetic datasets displayed local image artifacts which were ring-shaped due to the homogeneity of the phantom. The merged EMpCT dataset achieved a superior visual image quality with reduced artifacts and only minor remaining rings. The inter-quartile range (25/75) of RSP values was reduced from 0.7% with the current standard acquisition to 0.2% with EMpCT due to the reduction of ring artifacts. In this study, dose was doubled compared to a standard scan, but we discuss strategies to reduce excess dose. CONCLUSIONS: EMpCT allows to effectively avoid regions of the energy detector that cause image artifacts. Thereby, image quality is improved.

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.

Accuracy of low-dose proton CT image registration for pretreatment alignment verification in reference to planning proton CT.

PURPOSE: Proton CT (pCT) has the ability to reduce inherent uncertainties in proton treatment by directly measuring the relative proton stopping power with respect to water, thereby avoiding the uncertain conversion of X-ray CT Hounsfield unit to relative stopping power and the deleterious effect of X- ray CT artifacts. The purpose of this work was to further evaluate the potential of pCT for pretreatment positioning using experimental pCT data of a head phantom. METHODS: The performance of a 3D image registration algorithm was tested with pCT reconstructions of a pediatric head phantom. A planning pCT simulation scan of the phantom was obtained with 200 MeV protons and reconstructed with a 3D filtered back projection (FBP) algorithm followed by iterative reconstruction and a representative pretreatment pCT scan was reconstructed with FBP only to save reconstruction time. The pretreatment pCT scan was rigidly transformed by prescribing random errors with six degrees of freedom or deformed by the deformation field derived from a head and neck cancer patient to the pretreatment pCT reconstruction, respectively. After applying the rigid or deformable image registration algorithm to retrieve the original pCT image before transformation, the accuracy of the registration was assessed. To simulate very low-dose imaging for patient setup, the proton CT images were reconstructed with 100%, 50%, 25%, and 12.5% of the total number of histories of the original planning pCT simulation scan, respectively. RESULTS: The residual errors in image registration were lower than 1 mm and 1° of magnitude regardless of the anatomic directions and imaging dose. The mean residual errors ranges found for rigid image registration were from -0.29 ± 0.09 to 0.51 ± 0.50 mm for translations and from -0.05 ± 0.13 to 0.08 ± 0.08 degrees for rotations. The percentages of sub-millimetric errors found, for deformable image registration, were between 63.5% and 100%. CONCLUSION: This experimental head phantom study demonstrated the potential of low-dose pCT imaging for 3D image registration. Further work is needed to confirm the value pCT for pretreatment image-guided proton therapy.

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.

Microdosimetric comparison of scanned and conventional proton beams used in radiation therapy.

Multiple groups have hypothesised that the use of scanning beams in proton therapy will reduce the neutron component of secondary radiation in comparison with conventional methods with a corresponding reduction in risks of radiation-induced cancers. Loma Linda University Medical Center (LLUMC) has had FDA marketing clearance for scanning beams since 1988 and an experimental scanning beam has been available at the LLUMC proton facility since 2001. The facility has a dedicated research room with a scanning beam and fast switching that allows its use during patient treatments. Dosimetric measurements and microdosimetric distributions for a scanned beam are presented and compared with beams produced with the conventional methods presently used in proton therapy.

Response of extracellular matrix regulators in mouse lung after exposure to photons, protons and simulated solar particle event protons.

This study compared the effects of photons (gamma rays), protons and simulated solar particle event protons (sSPE) on the expression of profibrotic factors/extracellular matrix (ECM) regulators in lung tissue after whole-body irradiation. TGF-beta1, matrix metalloproteinase 2 and 9 (MMP-2, -9), and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1, -2) were assessed on days 4 and 21 in lungs from C57BL/6 mice exposed to 0 Gy or 2 Gy photons (0.7 Gy/min), protons (0.9 Gy/min) and sSPE (0.056 Gy/h). RT-PCR, histological and immunohistochemical techniques were used. The most striking changes included (1) up-regulation of TGF-beta1 by photons and sSPE, but not protons, at both times, (2) MMP-2 enhancement by photons and sSPEs, (3) TIMP-1 up-regulation by photons at both times, and (4) more collagen accumulation after exposure to either photons or sSPE than after exposure to protons. The findings demonstrate that expression of important ECM regulators was highly dependent upon the radiation regimen as well as the time after exposure. The data further suggest that irradiation during an SPE may increase an astronaut's risk for pulmonary complications. The greater perturbations after photon exposure compared to proton exposure have clinical implications and warrant further investigation.

Low-dose, low-dose-rate proton radiation modulates CD4(+) T cell gene expression.

PURPOSE: To evaluate cluster of differentiation 4(+) (CD4(+)) T cell gene expression and related parameters after whole-body exposure to proton radiation as it occurs in the spaceflight environment. MATERIALS AND METHODS: C57BL/6 mice were irradiated to total doses of 0, 0.01, 0.05, and 0.1 gray (Gy) at 0.1 cGy/h. On day 0 spleens were harvested from a subset in the 0, 0.01 and 0.1 Gy groups; (CD4(+)) T cells were isolated; and expression of 84 genes relevant to T helper (Th) cell function was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). Remaining mice were euthanized on days 0, 4, and 21 for additional analyses. RESULTS: Genes with >2-fold difference and p < 0.05 compared to 0 Gy were noted. After 0.01 Gy, five genes were up-regulated (Ccr5, Cd40, Cebpb, Igsf6, Tnfsf4) and three were down-regulated (Il4ra, Mapk8, Nfkb1). After 0.1 Gy there were nine up-regulated genes (Ccr4, Cd40, Cebpb, Cxcr3, Socs5, Stat4, Tbx21, Tnfrsf4, Tnfsf4); none were down-regulated. On day 0 after 0.01 Gy, CD4(+) T cell counts and CD4:CD8 ratio were low in the spleen (p < 0.05). Spontaneous DNA synthesis in both spleen and blood was lowest in the 0.01 Gy group on day 0; on days 4 and 21 all p values were >0.1. CONCLUSION: The data show that the pattern of gene expression in CD4(+) T cells after protracted low-dose proton irradiation was significantly modified and highly dependent upon total dose. The findings also suggest that low-dose radiation, especially 0.01 Gy, may enhance CD4(+) T cell responsiveness.

Variable hematopoietic responses to acute photons, protons and simulated solar particle event protons.

UNLABELLED: The goal of this study was to evaluate, for the first time, the response of bone marrow-derived cell populations to protons mimicking a space radiation environment. MATERIALS AND METHODS: C57BL/6 mice were exposed to 2 Gray (Gy) simulated solar particle event protons (sSPE) over 36 h; energies ranged from 15 to 215 MeV/n and were administered in 10 MeV increments. Acute 2 Gy irradiation with photons (gamma-rays) and protons were administered to different groups at 0.7 Gy/min and 0.9 Gy/min, respectively, for comparison with sSPE. The animals were euthanized on days 4 and 21 post-exposure for analyses. RESULTS: Exposure to radiation, regardless of regimen, resulted in immune depression and other abnormalities in cell populations residing in the blood and spleen; the extent of the radiation damage was somewhat dependent upon body compartment and time postexposure. However, variations were also noted among the three radiation regimens in a number of measurements: relative spleen mass, basal DNA synthesis by leukocytes, white blood cell counts and three-part differentials (lymphocytes, granulocytes, monocytes-macrophages), lymphocyte subpopulations (CD4+ T, CD8+ T, B and NK cells) and erythrocyte and thrombocyte characteristics. CONCLUSION: The data demonstrate that exposure to proton radiation mimicking a solar explosion induces abnormalities in leukocytes, erythrocytes and platelets that may have adverse health consequences. However, the damaging effects of sSPE on leukocytes and platelets were generally less pronounced compared to the other radiation regimens. Results obtained with photons (gamma-rays, X-rays) and monoenergetic protons at space-relevant total doses may not necessarily predict biological responses after exposure to a solar particle event.

Low-dose photons modify liver response to simulated solar particle event protons.

The health consequences of exposure to low-dose radiation combined with a solar particle event during space travel remain unresolved. The goal of this study was to determine whether protracted radiation exposure alters gene expression and oxidative burst capacity in the liver, an organ vital in many biological processes. C57BL/6 mice were whole-body irradiated with 2 Gy simulated solar particle event (SPE) protons over 36 h, both with and without pre-exposure to low-dose/low-dose-rate photons ((57)Co, 0.049 Gy total at 0.024 cGy/h). Livers were excised immediately after irradiation (day 0) or on day 21 thereafter for analysis of 84 oxidative stress-related genes using RT-PCR; genes up or down-regulated by more than twofold were noted. On day 0, genes with increased expression were: photons, none; simulated SPE, Id1; photons + simulated SPE, Bax, Id1, Snrp70. Down-regulated genes at this same time were: photons, Igfbp1; simulated SPE, Arnt2, Igfbp1, Il6, Lct, Mybl2, Ptx3. By day 21, a much greater effect was noted than on day 0. Exposure to photons + simulated SPE up-regulated completely different genes than those up-regulated after either photons or the simulated SPE alone (photons, Cstb; simulated SPE, Dctn2, Khsrp, Man2b1, Snrp70; photons + simulated SPE, Casp1, Col1a1, Hspcb, Il6st, Rpl28, Spnb2). There were many down-regulated genes in all irradiated groups on day 21 (photons, 13; simulated SPE, 16; photons + simulated SPE, 16), with very little overlap among groups. Oxygen radical production by liver phagocytes was significantly enhanced by photons on day 21. The results demonstrate that whole-body irradiation with low-dose-rate photons, as well as time after exposure, had a great impact on liver response to a simulated solar particle event.

Accelerators for heavy-charged-particle radiation therapy.

This paper focuses on current and future designs of medical hadron accelerators for treating cancers and other diseases. Presently, five vendors and several national laboratories have produced heavy-particle medical accelerators for accelerating nuclei from hydrogen (protons) up through carbon and oxygen. Particle energies are varied to control the beam penetration depth in the patient. As of the end of 2006, four hospitals and one clinic in the United States offer proton treatments; there are five more such facilities in Japan. In most cases, these facilities use accelerators designed explicitly for cancer treatments. The accelerator types are a combination of synchrotrons, cyclotrons, and linear accelerators; some carry advanced features such as respiration gating, intensity modulation, and rapid energy changes, which contribute to better dose conformity on the tumor when using heavy charged particles. Recent interest in carbon nuclei for cancer treatment has led some vendors to offer carbon-ion and proton capability in their accelerator systems, so that either ion can be used. These features are now being incorporated for medical accelerators in new facilities.