A feasibility study of enhanced prompt gamma imaging for range verification in proton therapy using deep learning.

Background and objective. Range uncertainty is a major concern affecting the delivery precision in proton therapy. The Compton camera (CC)-based prompt-gamma (PG) imaging is a promising technique to provide 3Din vivorange verification. However, the conventional back-projected PG images suffer from severe distortions due to the limited view of the CC, significantly limiting its clinical utility. Deep learning has demonstrated effectiveness in enhancing medical images from limited-view measurements. But different from other medical images with abundant anatomical structures, the PGs emitted along the path of a proton pencil beam take up an extremely low portion of the 3D image space, presenting both the attention and the imbalance challenge for deep learning. To solve these issues, we proposed a two-tier deep learning-based method with a novel weighted axis-projection loss to generate precise 3D PG images to achieve accurate proton range verification.Materials and methods: the proposed method consists of two models: first, a localization model is trained to define a region-of-interest (ROI) in the distorted back-projected PG image that contains the proton pencil beam; second, an enhancement model is trained to restore the true PG emissions with additional attention on the ROI. In this study, we simulated 54 proton pencil beams (energy range: 75-125 MeV, dose level: 1 × 109protons/beam and 3 × 108protons/beam) delivered at clinical dose rates (20 kMU min-1and 180 kMU min-1) in a tissue-equivalent phantom using Monte-Carlo (MC). PG detection with a CC was simulated using the MC-Plus-Detector-Effects model. Images were reconstructed using the kernel-weighted-back-projection algorithm, and were then enhanced by the proposed method.Results. The method effectively restored the 3D shape of the PG images with the proton pencil beam range clearly visible in all testing cases. Range errors were within 2 pixels (4 mm) in all directions in most cases at a higher dose level. The proposed method is fully automatic, and the enhancement takes only ∼0.26 s.Significance. Overall, this preliminary study demonstrated the feasibility of the proposed method to generate accurate 3D PG images using a deep learning framework, providing a powerful tool for high-precisionin vivorange verification of proton therapy.

Proton dose perturbations caused by high-voltage leads from implanted cardioverter defibrillators.

An increasing number of patients undergoing proton radiotherapy have cardiac implantable electrical devices (CIEDs). We recently encountered a situation in which a high-voltage coil on a lead from an implanted cardiac defibrillator was located within the clinical treatment volume for a patient receiving proton radiotherapy for esophageal cancer. To study the effects of the lead on the dose delivery, we placed a high-Z CIED lead at both the center and the distal edge of a clinical spread-out Bragg peak (SOBP) in a water phantom, in both a stationary position and with the lead moving in a periodic pattern to simulate cardiorespiratory movement. We then calculated planned doses using a commercial proton treatment planning system (TPS), and compared them with the doses delivered in the phantom, measured using radiographic film. Dose profiles from TPS-calculated and measured dose distributions showed large pertubrations in the delivered proton dose in the vicinity of the CIED lead when it was not moving. The TPS predicted perturbations up to 20% and measurements revealed perturbations up to 35%. However, the perturbations were less than 3% when the lead was moving. Greater dose perturbations were seen when the lead was placed at the distal edge of the SOBP than when it was placed in the center of the SOBP. We conclude that although cardiorespiratory motion of the lead mitigates some of the perturbations, the effects of the leads should be considered and steps taken to reduce these effects during the treatment planning process.

The effects of Compton camera data acquisition and readout timing on PG imaging for proton range verification.

The purpose of this study was to determine how the characteristics of the data acquisition (DAQ) electronics of a Compton camera (CC) affect the quality of the recorded prompt gamma (PG) interaction data and the reconstructed images, during clinical proton beam delivery. We used the Monte-Carlo-plus-Detector-Effect (MCDE) model to simulate the delivery of a 150 MeV clinical proton pencil beam to a tissue-equivalent plastic phantom. With the MCDE model we analyzed how the recorded PG interaction data changed as two characteristics of the DAQ electronics of a CC were changed: (1) the number of data readout channels; and (2) the active charge collection, readout, and reset time. As the proton beam dose rate increased, the number of recorded PG single-, double-, and triple-scatter events decreased by a factor of 60× for the current DAQ configuration of the CC. However, as the DAQ readout channels were increased and the readout/reset timing decreased, the number of recorded events decreased by <5× at the highest clinical dose rate. The increased number of readout channels and reduced readout/reset timing also resulted in higher quality recorded data. That is, a higher percentage of the recorded double- and triple-scatters were "true" events (caused by a single incident gamma) and not "false" events (caused by multiple incident gammas). The increase in the number and the quality of recorded data allowed higher quality PG images to be reconstructed even at the highest clinical dose rates.

Applications of Machine Learning to Improve the Clinical Viability of Compton Camera Based in vivo Range Verification in Proton Radiotherapy.

We studied the application of a deep, fully connected Neural Network (NN) to process prompt gamma (PG) data measured by a Compton camera (CC) during the delivery of clinical proton radiotherapy beams. The network identifies 1) recorded "bad" PG events arising from background noise during the measurement, and 2) the correct ordering of PG interactions in the CC to help improve the fidelity of "good" data used for image reconstruction. PG emission from a tissue-equivalent target during irradiation with a 150 MeV proton beam delivered at clinical dose rates was measured with a prototype CC. Images were reconstructed from both the raw measured data and the measured data that was further processed with a neural network (NN) trained to identify "good" and "bad" PG events and predict the ordering of individual interactions within the good PG events. We determine if NN processing of the CC data could improve the reconstructed PG images to a level in which they could provide clinically useful information about the in vivo range and range shifts of the proton beams delivered at full clinical dose rates. Results showed that a deep, fully connected NN improved the achievable contrast to noise ratio (CNR) in our images by more than a factor of 8x. This allowed the path, range, and lateral width of the clinical proton beam within a tissue equivalent target to easily be identified from the PG images, even at the highest dose rates of a 150 MeV proton beam used for clinical treatments. On average, shifts in the beam range as small as 3 mm could be identified. However, when limited by the amount of PG data measured with our prototype CC during the delivery of a single proton pencil beam (~1 × 109 protons), the uncertainty in the reconstructed PG images limited the identification of range shift to ~5 mm. Substantial improvements in CC images were obtained during clinical beam delivery through NN pre-processing of the measured PG data. We believe this shows the potential of NNs to help improve and push CC-based PG imaging toward eventual clinical application for proton RT treatment delivery verification.

Pancreatic cancer derived 3D organoids as a clinical tool to evaluate the treatment response.

Background and purpose: Pancreatic cancer (PC) is the fourth leading cause of cancer death in both men and women. The standard of care for patients with locally advanced PC of chemotherapy, stereotactic radiotherapy (RT), or chemo-radiation-therapy has shown highly variable and limited success rates. However, three-dimensional (3D) Pancreatic tumor organoids (PTOs) have shown promise to study tumor response to drugs, and emerging treatments under in vitro conditions. We investigated the potential for using 3D organoids to evaluate the precise radiation and drug dose responses of in vivo PC tumors. Methods: PTOs were created from mouse pancreatic tumor tissues, and their microenvironment was compared to that of in vivo tumors using immunohistochemical and immunofluorescence staining. The organoids and in vivo PC tumors were treated with fractionated X-ray RT, 3-bromopyruvate (3BP) anti-tumor drug, and combination of 3BP + fractionated RT. Results: Pancreatic tumor organoids (PTOs) exhibited a similar fibrotic microenvironment and molecular response (as seen by apoptosis biomarker expression) as in vivo tumors. Untreated tumor organoids and in vivo tumor both exhibited proliferative growth of 6 folds the original size after 10 days, whereas no growth was seen for organoids and in vivo tumors treated with 8 (Gray) Gy of fractionated RT. Tumor organoids showed reduced growth rates of 3.2x and 1.8x when treated with 4 and 6 Gy fractionated RT, respectively. Interestingly, combination of 100 µM of 3BP + 4 Gy of RT showed pronounced growth inhibition as compared to 3-BP alone or 4 Gy of radiation alone. Further, positive identification of SOX2, SOX10 and TGFß indicated presence of cancer stem cells in tumor organoids which might have some role in resistance to therapies in pancreatic cancer. Conclusions: PTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments.

Initial Validation of Proton Dose Calculations on SPR Images from DECT in Treatment Planning System.

PURPOSE: To investigate and quantify the potential benefits associated with the use of stopping-power-ratio (SPR) images created from dual-energy computed tomography (DECT) images for proton dose calculation in a clinical proton treatment planning system (TPS). MATERIALS AND METHODS: The DECT and single-energy computed tomography (SECT) scans obtained for 26 plastic tissue surrogate plugs were placed individually in a tissue-equivalent plastic phantom. Relative-electron density (ρe) and effective atomic number (Z eff) images were reconstructed from the DECT scans and used to create an SPR image set for each plug. Next, the SPR for each plug was measured in a clinical proton beam for comparison of the calculated values in the SPR images. The SPR images and SECTs were then imported into a clinical TPS, and treatment plans were developed consisting of a single field delivering a 10 × 10 × 10-cm3 spread-out Bragg peak to a clinical target volume that contained the plugs. To verify the accuracy of the TPS dose calculated from the SPR images and SECTs, treatment plans were delivered to the phantom containing each plug, and comparisons of point-dose measurements and 2-dimensional γ-analysis were performed. RESULTS: For all 26 plugs considered in this study, SPR values for each plug from the SPR images were within 2% agreement with measurements. Additionally, treatment plans developed with the SPR images agreed with the measured point dose to within 2%, whereas a 3% agreement was observed for SECT-based plans. γ-Index pass rates were > 90% for all SECT plans and > 97% for all SPR image-based plans. CONCLUSION: Treatment plans created in a TPS with SPR images obtained from DECT scans are accurate to within guidelines set for validation of clinical treatment plans at our center. The calculated doses from the SPR image-based treatment plans showed better agreement to measured doses than identical plans created with standard SECT scans.

Determination of proton stopping power ratio with dual-energy CT in 3D-printed tissue/air cavity surrogates.

PURPOSE: To study the accuracy with which proton stopping power ratio (SPR) can be determined with dual-energy computed tomography (DECT) for small structures and bone-tissue-air interfaces like those found in the head or in the neck. METHODS: Hollow cylindrical polylactic acid (PLA) plugs (3 cm diameter, 5 cm height) were 3D printed containing either one or three septa with thicknesses tsepta  = 0.8, 1.6, 3.2, and 6.4 mm running along the length of the plug. The cylinders were inserted individually into a tissue-equivalent head phantom (16 cm diameter, 5 cm height). First, DECT scans were obtained using a Siemens SOMATOM Definition Edge CT scanner. Effective atomic number (Zeff ) and electron density (ρe ) images were reconstructed from the DECT to produce SPR-CT images of each plug. Second, independent elemental composition analysis of the PLA plastic was used to determine the Zeff and ρe for calculating the theoretical SPR (SPR-TH) using the Bethe-Bloch equation. Finally, for each plug, a direct measurement of SPR (SPR-DM) was obtained in a clinical proton beam. The values of SPR-CT, SPR-TH, and SPR-DM were compared. RESULTS: The SPR-CT for PLA agreed with SPR-DM for tsepta  ≥ 3 mm (for CT slice thicknesses of 0.5, 1.0, and 3.0 mm). The density of PLA was found to decrease with thickness when tsepta  < 3 mm. As tsepta (and density) decreased, the SPR-CT values also decreased, in good agreement with SPR-DM and SPR-TH. CONCLUSION: Overall, the DECT-based SPR-CT was within 3% of SPR-TH and SPR-DM in the high-density gradient regions of the 3D-printed plugs for septa greater than ~ 3mm in thickness.

Feasibility studies of a passive scatter proton therapy nozzle without a range modulator wheel.

The purpose of this work was to determine the feasibility of producing a spread out Bragg peak (SOBP) without a range modulation wheel (RMW) using the passive scattering beam delivery technique. For this study, a comprehensive Monte Carlo model of a passive scattering treatment nozzle was used. The RMW was removed from the model leaving only the initial fixed scatterer (RMW-free configuration). Range modulation was achieved by directly changing the energy of the proton beam entering the nozzle. To produce a uniform SOBP, the number of protons injected into the nozzle at each beam energy was "dose weighted." To do so, the effective number of protons was calculated for the individual initial energies using an analytical dose-weighting function, and the resulting weighted Bragg curves were summed together to produce an SOBP of the desired width. We found that SOBPs calculated using the RMW-free nozzle configuration were in very good agreement to those calculated with the standard nozzle configuration containing the RMW for the 250, 180, and 100 MeV maximum beam energies. The depth of the distal 90% dose and the 80%-20% distal dose falloff of SOBPs calculated with the two different nozzle configurations agreed to within a millimeter for the three beam energy options considered in this study. In addition, the 80%-20% lateral penumbra for the cross-field dose profiles calculated with the RMW-free delivery method agreed with results calculated using the standard RMW technique to less than one millimeter. For an equal number of protons injected into the nozzle, an increase of up to 10% in the delivered dose and a significant reduction in both the in-air secondary neutron fluence and dose equivalent (H/D) were observed at the isocenter by removing the RMW from the treatment nozzle and modulating the initial proton beam energy. However, increases in delivery time of up to 70% were also estimated with this method. Our results suggest that it is feasible to deliver a passively scattered dose distribution with an RMW-free nozzle configuration with clinical characteristics comparable to those using standard methods.

Characterizing the response of miniature scintillation detectors when irradiated with proton beams.

Designing a plastic scintillation detector for proton radiation therapy requires careful consideration. Most of the plastic scintillators should not perturb a proton beam if they are sufficiently small but may exhibit some energy dependence due to the quenching effect. In this work, we studied the factors that would affect the performance of such scintillation detectors. We performed Monte Carlo simulations of proton beams with energies between 50 and 250 MeV to study signal amplitude, water equivalence, spatial resolution and quenching of light output. Implementation of the quenching effect in the Monte Carlo simulations was then compared with prior experimental data for validation. The signal amplitude of a plastic scintillating fiber detector was on the order of 300 photons per MeV of energy deposited in the detector, corresponding to a power of about 30 pW at a proton dose rate of 100 cGy min(-1). The signal amplitude could be increased by up to a factor of 2 with reflective coating. We also found that Cerenkov light was not a significant source of noise. Dose deposited in the plastic scintillator was within 2% of the dose deposited in a similar volume of water throughout the whole depth-dose curve for protons with energies higher than 50 MeV. A scintillation detector with a radius of 0.5 mm offers a sufficient spatial resolution for use with a proton beam of 100 MeV or more. The main disadvantage of plastic scintillators when irradiated by protons was the quenching effect, which reduced the amount of scintillation and resulted in dose underestimation by close to 30% at the Bragg peak for beams of 150 MeV or more. However, the level of quenching was nearly constant throughout the proximal half of the depth-dose curve for all proton energies considered. We therefore conclude that it is possible to construct an effective detector to overcome the problems traditionally encountered in proton dosimetry. Scintillation detectors could be used for surface or shallow measurements with a single calibration for specific beam energy. For deeper measurements, Monte Carlo simulations can be used to generate depth-dependent correction factors.

In vivo range verification in particle therapy.

Exploitation of the full potential offered by ion beams in clinical practice is still hampered by several sources of treatment uncertainties, particularly related to the limitations of our ability to locate the position of the Bragg peak in the tumor. To this end, several efforts are ongoing to improve the characterization of patient position, anatomy, and tissue stopping power properties prior to treatment as well as to enable in vivo verification of the actual dose delivery, or at least beam range, during or shortly after treatment. This contribution critically reviews methods under development or clinical testing for verification of ion therapy, based on pretreatment range and tissue probing as well as the detection of secondary emissions or physiological changes during and after treatment, trying to disentangle approaches of general applicability from those more specific to certain anatomical locations. Moreover, it discusses future directions, which could benefit from an integration of multiple modalities or address novel exploitation of the measurable signals for biologically adapted therapy.

Initial beam size study for passive scatter proton therapy. II. Changes in delivered depth dose profiles.

In passively scattered proton radiotherapy, a clinically useful treatment beam is produced by spreading a small proton "pencil beam" extracted from the accelerator to create both a uniform dose profile laterally and a uniform spread-out Bragg peak (SOBP) in depth. Lateral spreading and range modulation of the beam are accomplished using specially designed components within the treatment delivery nozzle. The purpose of this study was to determine how changes in the size of the initial proton pencil beam affect the delivery of dose with a passive scatter treatment nozzle. Monte Carlo calculations were used to study changes of the beam's in-air energy distribution at the exit of the nozzle and the central axis depth dose profiles in water resulting from changes in the incident beam size. Our results indicate that the width of the delivered SOBP decreases as the size of the initial beam increases.

Initial beam size study for passive scatter proton therapy. I. Monte Carlo verification.

The purpose of this work was to provide an initial validation of a Monte Carlo (MC) model of the passive scattering treatment nozzle at the University of Texas M. D. Anderson Cancer Center Proton Therapy Center. The MC model included a detailed definition of each beam-modifying element in the nozzle, and calculations accounted for interactions of the beam with the rotating modulator wheel used to create the spread out Bragg peak. In this work we show comparisons of calculated dose and fluence profiles with measured data from the nozzle for the 250 and 180 MeV beam energies used for patient treatments. Agreement to within 1.5 mm of measured data was observed for all MC calculations. The high level of agreement between the measurements and the MC model for the two beam energies studied provides validation for use of the model in a study of the dosimetric effects of the proton beam size and shape at the nozzle entrance.

Anteriorly Oriented Beam Arrangements with Daily in Vivo Range Verification for Proton Therapy of Prostate Cancer: Rectal Toxicity Rates.

PURPOSE: To model whether in vivo range verification could reduce high-grade rectal toxicity for patients with prostate cancer treated with pencil beam scanning proton therapy by allowing novel proton beam arrangements compared to standard lateral opposed beams. MATERIALS AND METHODS: Proton plans were generated for 8 patients with prostate cancer previously treated with photons by volumetric-modulated arc therapy (VMAT). The VMAT plans were generated by using a uniform 6-mm planning target volume (PTV) expansion. For the proton plans an additional distal margin (3.5% of beam range) was added to the uniform 6-mm PTV to account for range uncertainty, using 3 beam arrangements: (1) lateral opposed beams (LAT), (2) left and right anterior oblique beams (LAO/RAO), and (3) a single anterior-posterior beam (AP). Assuming use of in vivo range verification, plans were generated by using a reduced distal PTV and distal range uncertainty expansion (2 mm each) with AP (AP-2 mm) and LAO/RAO (LAO/RAO-2 mm) beam arrangements. Estimates of normal tissue complication probability (NTCP) for ≥grade 2 rectal bleeding were generated by using the Lyman-Kutcher-Burman model. RESULTS: Each proton and photon plan was able to achieve all prespecified rectal and bladder constraints. For the VMAT, LAT, AP, and LAO/RAO plans, estimated NTCP values for ≥grade 2 rectal bleeding were 0.19, 0.21, 0.24, and 0.2, respectively. For the AP-2 mm and LAO/RAO-2 mm plans, NTCP values were reduced to 0.11 and 0.1 with respect to ≥grade 2 rectal bleeding. CONCLUSION: Presuming that in vivo range verification for pencil beam scanning proton therapy could localize the distal falloff of the Bragg peak to within 2 mm, novel beam arrangements (AP and LAO/RAO) may reduce the risk of serious rectal bleeding, compared to VMAT and LAT proton treatment techniques. These are achieved without an increase in modeled bladder complication rates.

Reply to Comment on 'Imaging of prompt gamma rays emitted during delivery of clinical proton beams with a Compton camera: feasibility studies for range verification'.

A reply is provided to the points raised in the comment by Dr Sitek (2016 Phys. Med. Biol. 61 8941) on Polf et al (2015 Phys. Med. Biol. 60 7085).

Benchmarking analytical calculations of proton doses in heterogeneous matter.

A proton dose computational algorithm, performing an analytical superposition of infinitely narrow proton beamlets (ASPB) is introduced. The algorithm uses the standard pencil beam technique of laterally distributing the central axis broad beam doses according to the Moliere scattering theory extended to slablike varying density media. The purpose of this study was to determine the accuracy of our computational tool by comparing it with experimental and Monte Carlo (MC) simulation data as benchmarks. In the tests, parallel wide beams of protons were scattered in water phantoms containing embedded air and bone materials with simple geometrical forms and spatial dimensions of a few centimeters. For homogeneous water and bone phantoms, the proton doses we calculated with the ASPB algorithm were found very comparable to experimental and MC data. For layered bone slab inhomogeneity in water, the comparison between our analytical calculation and the MC simulation showed reasonable agreement, even when the inhomogeneity was placed at the Bragg peak depth. There also was reasonable agreement for the parallelepiped bone block inhomogeneity placed at various depths, except for cases in which the bone was located in the region of the Bragg peak, when discrepancies were as large as more than 10%. When the inhomogeneity was in the form of abutting air-bone slabs, discrepancies of as much as 8% occurred in the lateral dose profiles on the air cavity side of the phantom. Additionally, the analytical depth-dose calculations disagreed with the MC calculations within 3% of the Bragg peak dose, at the entry and midway depths in the phantom. The distal depth-dose 20%-80% fall-off widths and ranges calculated with our algorithm and the MC simulation were generally within 0.1 cm of agreement. The analytical lateral-dose profile calculations showed smaller (by less than 0.1 cm) 20%-80% penumbra widths and shorter fall-off tails than did those calculated by the MC simulations. Overall, this work validates the usefulness of our ASPB algorithm as a reasonably fast and accurate tool for quality assurance in planning wide beam proton therapy treatment of clinical sites either composed of homogeneous materials or containing laterally extended inhomogeneities that are comparable in density and located away from the Bragg peak depths.

Calculations of neutron dose equivalent exposures from range-modulated proton therapy beams.

Passive beam spreading techniques have been used for most proton therapy treatments worldwide. This delivery method employs static scattering foils to spread the beam laterally and a range modulating wheel or ridge filter to spread the high dose region in depth to provide a uniform radiation dose to the treatment volume. Neutrons produced by interactions of the treatment beam with nozzle components, such as the range modulation wheel, can account for a large portion of the secondary dose delivered to healthy tissue outside the treatment volume. Despite this fact, little is known about the effects of range modulation on the secondary neutron exposures around passively scattered proton treatment nozzles. In this work, the neutron dose equivalent spectra per incident proton (H(E)/p) and total neutron dose equivalent per therapeutic absorbed dose (H/D) were studied using Monte Carlo techniques for various values of range modulation at 54 locations around a passive scattering proton therapy treatment nozzle. As the range modulator wheel step thickness increased from 1.0 to 11.5 cm, the peak values of H(E)/p decreased from approximately 1 x 10(-17) mSv Gy(-1) to approximately 2 x 10(-18) mSv Gy(-1) at 50 cm from isocentre along the beam's central axis. In general, H/D increased with increasing range modulation at all locations studied, and the maximum H/D exposures shifted away from isocentre.

Imaging of prompt gamma rays emitted during delivery of clinical proton beams with a Compton camera: feasibility studies for range verification.

The purpose of this paper is to evaluate the ability of a prototype Compton camera (CC) to measure prompt gamma rays (PG) emitted during delivery of clinical proton pencil beams for prompt gamma imaging (PGI) as a means of providing in vivo verification of the delivered proton radiotherapy beams. A water phantom was irradiated with clinical 114 MeV and 150 MeV proton pencil beams. Up to 500 cGy of dose was delivered per irradiation using clinical beam currents. The prototype CC was placed 15 cm from the beam central axis and PGs from 0.2 MeV up to 6.5 MeV were measured during irradiation. From the measured data (2D) images of the PG emission were reconstructed. (1D) profiles were extracted from the PG images and compared to measured depth dose curves of the delivered proton pencil beams. The CC was able to measure PG emission during delivery of both 114 MeV and 150 MeV proton beams at clinical beam currents. 2D images of the PG emission were reconstructed for single 150 MeV proton pencil beams as well as for a 5 × 5 cm mono-energetic layer of 114 MeV pencil beams. Shifts in the Bragg peak (BP) range were detectable on the 2D images. 1D profiles extracted from the PG images show that the distal falloff of the PG emission profile lined up well with the distal BP falloff. Shifts as small as 3 mm in the beam range could be detected from the 1D PG profiles with an accuracy of 1.5 mm or better. However, with the current CC prototype, a dose of 400 cGy was required to acquire adequate PG signal for 2D PG image reconstruction. It was possible to measure PG interactions with our prototype CC during delivery of proton pencil beams at clinical dose rates. Images of the PG emission could be reconstructed and shifts in the BP range were detectable. Therefore PGI with a CC for in vivo range verification during proton treatment delivery is feasible. However, improvements in the prototype CC detection efficiency and reconstruction algorithms are necessary to make it a clinically viable PGI system.

Detecting prompt gamma emission during proton therapy: the effects of detector size and distance from the patient.

Recent studies have suggested that the characteristics of prompt gammas (PGs) emitted from excited nuclei during proton therapy are advantageous for determining beam range during treatment delivery. Since PGs are only emitted while the beam is on, the feasibility of using PGs for online treatment verification depends greatly on the design of highly efficient detectors. The purpose of this work is to characterize how PG detection changes as a function of distance from the patient as a means of guiding the design and usage of clinical PG imaging detectors. Using a Monte Carlo model (GEANT4.9.4) we studied the detection rate (PGs per incident proton) of a high purity germanium detector for both the total PG emission and the characteristic 6.13 MeV PG emission from (16)O emitted during proton irradiation. The PG detection rate was calculated as a function of distance from the isocenter of the proton treatment nozzle for: (1) a water phantom irradiated with a proton pencil beam and (2) a prostate patient irradiated with a scanning beam proton therapy treatment field (lateral field size: ∼6 cm × 6 cm, beam range: 23.5 cm). An analytical expression of the PG detection rate as a function of distance from isocenter, detector size, and proton beam energy was then developed. The detection rates were found to be 1.3 × 10(-6) for oxygen and 3.9 × 10(-4) for the total PG emission, respectively, with the detector placed 11 cm from isocenter for a 40 MeV pencil beam irradiating a water phantom. The total PG detection rate increased by ∼85 ± 3% for beam energies greater than 150 MeV. The detection rate was found to be approximately 2.1 × 10(-6) and 1.7 × 10(-3) for oxygen and total PG emission, respectively, during delivery of a single pencil beam during a scanning beam treatment for prostate cancer. The PG detection rate as a function of distance from isocenter during irradiation of a water phantom with a single proton pencil beam was described well by the model of a point source irradiating a cylindrical detector of a known diameter over the range of beam energies commonly used for proton therapy. For the patient studies, it was necessary to divide the point source equation by an exponential factor in order to correctly predict the falloff of the PG detection rate as a function of distance from isocenter.

Tumor Spheroids as an in vitro model for determining the therapeutic response to proton beam radiotherapy and thermally sensitive nanocarriers.

Multicellular Tumor Spheroids (MCTS) strongly resemble tumor tissues, which makes them useful tools for radiation biology studies and screening of various chemotherapeutics. The goal of this pilot study was to use MCTS as an in vitro model to determine the response of cells to low temperature-sensitive liposomes (LTSLs) encapsulating doxorubicin (Dox) and proton beam radiotherapy (PBRT). Prior to treatment, MCTS were characterized for morphology and LTSLs were characterized for size, encapsulation efficiency, and ability to thermally release Dox (a model anticancer agent). Two groups of MCTS were treated with LTSL in combination with mild hyperthermia (40-42 °C) or PBRT alone in the presence of appropriate controls. Cytotoxic response was assessed after 48-72 h using an acid phosphatase assay. At 72 h, LTSL in combination with heat significantly reduced the viability of MCTS (15-30%) compared to the control (P < 0.05). A similar cytotoxic response was observed with PBRT treatment. The data suggest that like a monolayer cell culture, MCTS can be used to determine cytotoxic outcomes of thermal and proton therapy.

Measurement of characteristic prompt gamma rays emitted from oxygen and carbon in tissue-equivalent samples during proton beam irradiation.

The purpose of this work was to characterize how prompt gamma (PG) emission from tissue changes as a function of carbon and oxygen concentration, and to assess the feasibility of determining elemental concentration in tissues irradiated with proton beams. For this study, four tissue-equivalent water-sucrose samples with differing densities and concentrations of carbon, hydrogen, and oxygen were irradiated with a 48 MeV proton pencil beam. The PG spectrum emitted from each sample was measured using a high-purity germanium detector, and the absolute detection efficiency of the detector, average beam current, and delivered dose distribution were also measured. Changes to the total PG emission from (12)C (4.44 MeV) and (16)O (6.13 MeV) per incident proton and per Gray of absorbed dose were characterized as a function of carbon and oxygen concentration in the sample. The intensity of the 4.44 MeV PG emission per incident proton was found to be nearly constant for all samples regardless of their carbon concentration. However, we found that the 6.13 MeV PG emission increased linearly with the total amount (in grams) of oxygen irradiated in the sample. From the measured PG data, we determined that 1.64 × 10(7) oxygen PGs were emitted per gram of oxygen irradiated per Gray of absorbed dose delivered with a 48 MeV proton beam. These results indicate that the 6.13 MeV PG emission from (16)O is proportional to the concentration of oxygen in tissue irradiated with proton beams, showing that it is possible to determine the concentration of oxygen within tissues irradiated with proton beams by measuring (16)O PG emission.