A Probability-Based Investigation on the Setup Robustness of Pencil-beam Proton Radiation Therapy for Skull-Base Meningioma.

INTRODUCTION: The intracranial skull-base meningioma is in proximity to multiple critical organs and heterogeneous tissues. Steep dose gradients often result from avoiding critical organs in proton treatment plans. Dose uncertainties arising from setup errors under image-guided radiation therapy are worthy of evaluation. PATIENTS AND METHODS: Fourteen patients with skull-base meningioma were retrospectively identified and planned with proton pencil beam scanning (PBS) single-field uniform dose (SFUD) and multifield optimization (MFO) techniques. The setup uncertainties were assigned a probability model on the basis of prior published data. The impact on the dose distribution from nominal 1-mm and large, less probable setup errors, as well as the cumulative effect, was analyzed. The robustness of SFUD and MFO planning techniques in these scenarios was discussed. RESULTS: The target coverage was reduced and the plan dose hot spot increased by all setup uncertainty scenarios regardless of the planning techniques. For 1 mm nominal shifts, the deviations in clinical target volume (CTV) coverage D99% was -11 ± 52 cGy and -45 ± 147 cGy for SFUD and MFO plans. The setup uncertainties affected the organ at risk (OAR) dose both positively and negatively. The statistical average of the setup uncertainties had <100 cGy impact on the plan qualities for all patients. The cumulative deviations in CTV D95% were 1 ± 34 cGy and -7 ± 18 cGy for SFUD and MFO plans. CONCLUSION: It is important to understand the impact of setup uncertainties on skull-base meningioma, as the tumor target has complex shape and is in proximity to multiple critical organs. Our work evaluated the setup uncertainty based on its probability distribution and evaluated the dosimetric consequences. In general, the SFUD plans demonstrated more robustness than the MFO plans in target coverages and brainstem dose. The probability-weighted overall effect on the dose distribution is small compared to the dosimetric shift during single fraction.

Radiotherapy fiber dosimeter probes based on silver-only coated hollow glass waveguides.

Manifestation of Cerenkov radiation as a contaminating signal is a significant issue in radiation therapy dose measurement by fiber-coupled scintillator dosimeters. To enhance the scintillation signal transmission while minimizing Cerenkov radiation contamination, we designed a fiber probe using a silver-only coated hollow waveguide (HWG). The HWG with scintillator inserted in its tip, embedded in tissue-mimicking phantoms, was irradiated with clinical electron and photon beams generated by a medical linear accelerator. Optical spectra of the irradiated tip were taken using a fiber spectrometer, and the signal was deconvolved with a linear fitting algorithm. The resultant decomposed spectra of the scintillator with and without Cerenkov correction were in agreement with measurements performed by a standard electron diode and ion chamber for electron and photon beam dosimetry, respectively, indicating the minimal effect of Cerenkov contamination in the HWG-based dosimeter. Furthermore, compared with a silver/dielectric-coated HWG fiber dosimeter design, we observed higher signal transmission in the design based on the use of silver-only HWG.

Acoustic-based proton range verification in heterogeneous tissue: simulation studies.

Acoustic-based proton range verification (protoacoustics) is a potential in vivo technique for determining the Bragg peak position. Previous measurements and simulations have been restricted to homogeneous water tanks. Here, a CT-based simulation method is proposed and applied to a liver and prostate case to model the effects of tissue heterogeneity on the protoacoustic amplitude and time-of-flight range verification accuracy. For the liver case, posterior irradiation with a single proton pencil beam was simulated for detectors placed on the skin. In the prostate case, a transrectal probe measured the protoacoustic pressure generated by irradiation with five separate anterior proton beams. After calculating the proton beam dose deposition, each CT voxel's material properties were mapped based on Hounsfield Unit values, and thermoacoustically-generated acoustic wave propagation was simulated with the k-Wave MATLAB toolbox. By comparing the simulation results for the original liver CT to homogenized variants, the effects of heterogeneity were assessed. For the liver case, 1.4 cGy of dose at the Bragg peak generated 50 mPa of pressure (13 cm distal), a 2× lower amplitude than simulated in a homogeneous water tank. Protoacoustic triangulation of the Bragg peak based on multiple detector measurements resulted in 0.4 mm accuracy for a δ-function proton pulse irradiation of the liver. For the prostate case, higher amplitudes are simulated (92-1004 mPa) for closer detectors (<8 cm). For four of the prostate beams, the protoacoustic range triangulation was accurate to ⩽1.6 mm (δ-function proton pulse). Based on the results, application of protoacoustic range verification to heterogeneous tissue will result in decreased signal amplitudes relative to homogeneous water tank measurements, but accurate range verification is still expected to be possible.

Proton range verification in homogeneous materials through acoustic measurements.

Clinical proton beam quality assurance (QA) requires a simple and accurate method to measure the proton beam Bragg peak (BP) depth. Protoacoustics, the measurement of the pressure waves emitted by thermal expansion resulting from proton dose deposition, may be used to obtain the depth of the BP in a phantom by measuring the time-of-flight of the pressure wave. Rectangular and cylindrical phantoms of different materials (aluminum, lead, and polyethylene) were used for protoacoustic studies. Four different methods for analyzing the protoacoustic signals are compared. Data analysis shows that, for Methods 1 and 2, plastic phantoms have better accuracy than metallic ones because of the lower speed of sound. Method 3 does not require characterizing the speed of sound in the material, but it results in the largest error. Method 4 exhibits minimal error, less than 3 mm (with an uncertainty ⩽1.5 mm) for all the materials and geometries. Psuedospectral wave-equation simulations (k-Wave MATLAB toolbox) are used to understand the origin of acoustic reflections within the phantom. The presented simulations and experiments show that protoacoustic measurements may provide a low cost and simple QA procedure for proton beam range verification as long as the proper phantoms and calculation methods are used.

Proton therapy dosimetry using the scintillation of the silica fibers.

We investigate the feasibility of proton therapy dose measurement by using scintillation of a bare silica glass fiber. The emission spectra of the optical fiber at various depths in tissue-mimicking phantoms, irradiated with proton beams of energies 100-225 MeV show two distinct peaks at 460 and 650 nm whose nature is connected with the silica point defects. Our experimental results and Monte Carlo simulation showed that the Cerenkov radiation cannot be responsible for such a phenomenon. We showed that the intensity of the peak at 650 nm correlates with the proton dose with a minimal effect of ionization quenching, while the intensity peak at 460 nm under-reports the radiation dose.

The visible signal responsible for proton therapy dosimetry using bare optical fibers is not Cerenkov radiation.

PURPOSE: Proton beam dosimetry using bare plastic optical fibers has emerged as a simple approach to proton beam dosimetry. The source of the signal in this method has been attributed to Cerenkov radiation. The aim of this work was a phenomenological study of the nature of the visible light responsible for the signal in bare fiber optic dosimetry of proton therapy beams. METHODS: Plastic fiber optic probes embedded in solid water phantoms were irradiated with proton beams of energies 100, 180, and 225 MeV produced by a proton therapy cyclotron. Luminescence spectroscopy was performed by a CCD-coupled spectrometer. The spectra were acquired at various depths in phantom to measure the percentage depth dose (PDD) for each beam energy. For comparison, the PDD curves were acquired using a standard multilayer ion chamber device. In order to further analyze the contribution of the Cerenkov radiation in the spectra, Monte Carlo simulation was performed using fluka Monte Carlo code to stochastically simulate radiation transport, ionizing radiation dose deposition, and optical emission of Cerenkov radiation. RESULTS: The measured depth doses using the bare fiber are in agreement with measurements performed by the multilayer ion chamber device, indicating the feasibility of using bare fiber probes for proton beam dosimetry. The spectroscopic study of proton-irradiated fibers showed a continuous spectrum with a shape different from that of Cerenkov radiation. The Monte Carlo simulations confirmed that the amount of the generated Cerenkov light does not follow the radiation absorbed dose in a medium. CONCLUSIONS: The source of the optical signal responsible for the proton dose measurement using bare optical fibers is not Cerenkov radiation. It is fluorescence of the plastic material of the fiber.

A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT).

With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as well as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients' average CT. All the plans delivered 50.4Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V18Gy), stomach (mean and V20Gy), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V18Gy), liver (mean dose), total bowel (V20Gy and mean dose), and small bowel (V15Gy absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose escalation and combining with radiosensitizing chemotherapy.

Abdominal and pancreatic motion correlation using 4D CT, 4D transponders, and a gating belt.

The correlation between the pancreatic and external abdominal motion due to respiration was investigated on two patients. These studies utilized four dimensional computer tomography (4D CT), a four dimensional (4D) electromagnetic transponder system, and a gating belt system. One 4D CT study was performed during simulation to quantify the pancreatic motion using computer tomography images at eight breathing phases. The motion under free breathing and breath-hold were analyzed for the 4D electromagnetic transponder system and the gating belt system during treatment. A linear curve was fitted for all data sets and correlation factors were evaluated between the 4D electromagnetic transponder system and the gating belt system data. The 4D CT study demonstrated a modest correlation between the external marker and the pancreatic motion with R-square values larger than 0.8 for the inferior-superior (inf-sup). Then, the relative pressure from the belt gating system correlated well with the 4D electromagnetic transponder system's motion in the anterior-posterior (ant-post) and the inf-post directions. These directions have a correlation value of -0.93 and 0.76, while the lateral only had a 0.03 correlation coefficient. Based on our limited study, external surrogates can be used as predictors of the pancreatic motion in the inf-sup and the ant-post directions. Although there is a low correlation on the lateral direction, its motion is significantly shorter. In conclusion, an appropriate treatment delivery can be used for pancreatic cancer when an internal tracking system, such as the 4D electromagnetic transponder system, is unavailable.

Effects on the photon beam from an electromagnetic array used for patient localization and tumor tracking.

One of the main components in a Calypso 4D localization and tracking system is an electromagnetic array placed above patients that is used for target monitoring during radiation treatment. The beam attenuation and beam spoiling properties of the Calypso electromagnetic array at various beam angles were investigated. Measurements were performed on a Varian Clinac iX linear accelerator with 6 MV and 15 MV photon beams. The narrow beam attenuation properties were measured under a field size of 1 cm × 1 cm, with a photon diode placed in a cylindrical graphite buildup cap. The broad beam attenuation properties were measured under a field size of 10 cm × 10 cm, with a 0.6 cc cylindrical Farmer chamber placed in a polystyrene buildup cap. Beam spoiling properties of the array were studied by measuring depth-dose change from the array under a field size of 10 cm × 10 cm in a water-equivalent plastic phantom with an embedded Markus parallel plate chamber. Change in depth doses were measured with the array placed at distances of 2, 5, and 10 cm from the phantom surface. Narrow beam attenuation and broad beam attenuation from the array were found to be less than 2%-3% for both 6 MV and 15 MV beams at angles less than 40°, and were more pronounced at more oblique angles. Spoiling effects are appreciable at beam buildup region, but are insignificant at depths beyond dmax. Dose measurements in a QA phantom using patient IMRT and VMAT treatment plans were shown to have less than 2.5% dose difference with the Calypso array. The results indicate that the dose difference due to the placement of Calypso array is clinically insignificant.

Feasibility of electromagnetic transponder use to monitor inter- and intrafractional motion in locally advanced pancreatic cancer patients.

PURPOSE: The primary objective of this study was to determine the feasibility of electromagnetic transponder implantation in patients with locally advanced unresectable pancreatic cancer. Secondarily, the use of transponders to monitor inter- and intrafractional motion, and the efficacy of breath holding for limiting target motion, were examined. METHODS AND MATERIALS: During routine screening laparoscopy, 5 patients without metastatic disease were implanted with transponders peri-tumorally. The Calypso System's localization and tracking modes were used to monitor inter- and intrafractional motion, respectively. Intrafractional motion, with and without breath holding, was also examined using Calypso tracking mode. RESULTS: Transponder implantation was well tolerated in all patients, with minimal migration, aside from 1 patient who expulsed a single transponder. Interfractional motion based on mean shifts from setup using tattoos/orthogonal imaging to transponder based localization from 164 treatments was significant in all dimensions. Mean shift (in millimeters), followed by the standard deviation and p value, were as follows: X-axis: 4.5 mm (1.0, p = 0.01); Y axis: 6.4 mm (1.9, p = 0.03); and Z-axis 3.9 mm (0.6, p = 0.002). Mean intrafractional motion was also found to be significant in all directions: superior, 7.2 mm (0.9, p = 0.01); inferior, 11.9 mm (0.9, p < 0.01); anterior: 4.9 mm (0.5, p = 0.01); posterior, 2.9 mm (0.5, p = 0.02); left, 2.2 mm (0.4, p = 0.02); and right, 3.1 mm (0.6, p = 0.04). Breath holding during treatment significantly decreased tumor motion in all directions. CONCLUSIONS: Electromagnetic transponder implantation appears to be safe and effective for monitoring inter- and intrafractional motion. Based on these results a larger clinical trial is underway.

Daily isocenter correction with electromagnetic-based localization improves target coverage and rectal sparing during prostate radiotherapy.

PURPOSE: To evaluate dosimetric consequences of daily isocenter correction during prostate cancer radiation therapy using the Calypso 4D localization system. METHODS AND MATERIALS: Data were analyzed from 28 patients with electromagnetic transponders implanted in their prostates for daily target localization and tracking. Treatment planning isocenters were recorded based on the values of the vertical, longitudinal, and lateral axes. Isocenter location obtained via alignment with skin tattoos was compared with that obtained via the electromagnetic localization system. Daily isocenter shifts, based on the isocenter location differences between the two alignment methods in each spatial axis, were calculated for each patient over their entire course. The mean isocenter shifts were used to determine dosimetric consequences of treatment based on skin tattoo alignments alone. RESULTS: The mean SD of the percentages of treatment days with shifts beyond 0.5 cm for vertical, longitudinal and lateral shifts were 62% 28%, 35% 26%, and 38% 21%, respectively. If daily electromagnetic localization was not used, the excess in prescribed dose delivered to 70% of the rectum was 10 Gy and the deficit in prescribed dose delivered to 95% of the planning target volume was 10 Gy. The mean isocenter shift was not associated with the volumes of the prostate, rectum, or bladder, or with patient body mass index. CONCLUSIONS: Daily isocenter localization can reduce the treatment dose to the rectum. Correcting for this variability could lead to improved dose delivery, reduced side effects, and potentially improved treatment outcomes.

Analysis of interfraction and intrafraction variation during tangential breast irradiation with an electronic portal imaging device.

PURPOSE: To evaluate the daily setup variation and the anatomic movement of the heart and lungs during breast irradiation with tangential photon beams, as measured with an electronic portal imaging device. METHODS AND MATERIALS: Analysis of 1,709 portal images determined changes in the radiation field during a treatment course in 8 patients. Values obtained for every image included central lung distance (CLD) and area of lung and heart within the irradiated field. The data from these measurements were used to evaluate variation from setup between treatment days and motion due to respiration and/or patient movement during treatment delivery. RESULTS: The effect of respiratory motion and movement during treatment was minimal: the maximum range in CLD for any patient on any day was 0.25 cm. The variation caused by day-to-day setup variation was greater, with CLD values for patients ranging from 0.59 cm to 2.94 cm. Similar findings were found for heart and lung areas. CONCLUSIONS: There is very little change in CLD and corresponding lung and heart area during individual radiation treatment fractions in breast tangential fields, compared with a relatively greater amount of variation that occurs between days.

Comparison of manual vs. automated multimodality (CT-MRI) image registration for brain tumors.

Computed tomgoraphy-magnetic resonance imaging (CT-MRI) registrations are routinely used for target-volume delineation of brain tumors. We clinically use 2 software packages based on manual operation and 1 automated package with 2 different algorithms: chamfer matching using bony structures, and mutual information using intensity patterns. In all registration algorithms, a minimum of 3 pairs of identical anatomical and preferably noncoplanar landmarks is used on each of the 2 image sets. In manual registration, the program registers these points and links the image sets using a 3-dimensional (3D) transformation. In automated registration, the 3 landmarks are used as an initial starting point and further processing is done to complete the registration. Using our registration packages, registration of CT and MRI was performed on 10 patients. We scored the results of each registration set based on the amount of time spent, the accuracy reported by the software, and a final evaluation. We evaluated each software program by measuring the residual error between "matched" points on the right and left globes and the posterior fossa for fused image slices. In general, manual registration showed higher misalignment between corresponding points compared to automated registration using intensity matching. This error had no directional dependence and was, most of the time, larger for a larger structure in both registration techniques. Automated algorithm based on intensity matching also gave the best results in terms of registration accuracy, irrespective of whether or not the initial landmarks were chosen carefully, when compared to that done using bone matching algorithm. Intensity-matching algorithm required the least amount of user-time and provided better accuracy.

Transmission and dose perturbations with high-Z materials in clinical electron beams.

High density and atomic number (Z) materials used in various prostheses, eye shielding, and beam modifiers produce dose enhancements on the backscatter side in electron beams and is well documented. However, on the transmission side the dose perturbation is given very little clinical importance, which is investigated in this study. A simple and accurate method for dose perturbation at metallic interfaces with soft tissues and transmission through these materials is required for all clinical electron beams. Measurements were taken with thin-window parallel plate ion chambers for various high-Z materials (Al, Ti, Cu, and Pb) on a Varian and a Siemens accelerator in the energy range of 5-20 MeV. The dose enhancement on both sides of the metallic sheet is due to increased electron fluence that is dependent on the beam energy and Z. On the transmission side, the magnitude of dose enhancement depends on the thickness of the high-Z material. With increasing thickness, dose perturbation reduces to the electron transmission. The thickness of material to reduce 100% (range of dose perturbation), 50% and 10% transmission is linear with the beam energy. The slope (mm/MeV) of the transmission curve varies exponentially with Z. A nonlinear regression expression (t=E[alpha+beta exp(-0.1Z)]) is derived to calculate the thickness at a given transmission, namely 100%, 50%, and 10% for electron energy, E, which is simple, accurate and well suited for a quick estimation in clinical use. Caution should be given to clinicians for the selection of thickness of high-Z materials when used to shield critical structures as small thickness increases dose significantly at interfaces.

Homeostatic proliferation is a barrier to transplantation tolerance.

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.

Modification of Gill-Thomas-Cosman frame for extracranial head-and-neck stereotactic radiotherapy.

PURPOSE: A modification of a commercially available, noninvasive, relocatable, stereotactic Gill-Thomas-Cosman (GTC) head frame is presented for treatment of extracranial lesions of the head and neck, base of the skull, and inferior nasopharyngeal region. METHODS AND MATERIALS: Skull-based and nasopharyngeal lesions cannot be treated with the GTC frame because it obstructs the beam path. To treat those lesions, the GTC frame was modified without compromising the integrity, flexibility, or use of the treatment software. The modification uses a set of aluminum extension rods of variable lengths and bevels to support a modified dental plate. The extension rods allow the dental tray and attached GTC frame to be lowered so that the more inferior regions may be treated. Ten patients underwent CT with the modified frame and CT localizer. For some patients, MRI was acquired without the frame. Image fusion of MRI and CT scans was used to delineate the target volume, and planning was done with the existing software for proper treatment. RESULTS: The modification of the GTC frame has been successful in imaging, planning, and extending the treatment domain for the base of the skull, nasopharyngeal regions, and other superior lesions of the head and neck. The reproducibility of the modified frame and the patient localization helmet technique was identical to that of the unmodified frame. CONCLUSION: The modification of the GTC frame is simple and accurate. It provides flexibility in treating an extended range of the base of the skull, nasopharyngeal region, and other superior lesions of the head and neck that otherwise could not be treated with the GTC frame.