One-Year Efficacy and Safety of Proton-Beam Irradiation Combined with Intravitreal Conbercept for Refractory or Recurrent Polypoidal Choroidal Vasculopathy: A Pilot Study.

INTRODUCTION: To investigate the efficacy and safety of proton-beam irradiation (PBI) combined with intravitreal conbercept (IVC) injection for refractory or recurrent polypoidal choroidal vasculopathy (PCV). METHODS: A prospective interventional clinical trial included 12 patients with refractory PCV (defined as persistent exudation or fluid after six consecutive injections at monthly intervals and/or photodynamic therapy) or recurrent PCV (defined as new exudative signs after six monthly injections and/or photodynamic therapy) treated between January 2019 and September 2020. Every patient underwent single PBI (14 GyE) with concomitant IVC (0.5 mg) within 1 week and further doses of IVC were administered pro re nata. RESULTS: By the 12-month follow-up, the subretinal fluid was completely absorbed in 9 eyes (81.8%). The angiographic regression and closure rates of the polyps were 60% (12/20) and 90% (18/20), respectively. The mean number of IVC injections was 3.1 ± 1.37. The mean BCVA improved by 20 letters (P = 0.006). The mean central macular thickness (CMT) decreased from 476.50 ± 123.63 µm to 317.70 ± 89.34 µm (P = 0.004). The areas of branching vascular networks and polyps decreased by 37.2% and 72.3%, respectively. Radiation retinopathy was observed in five eyes, but no systemic adverse events were observed. CONCLUSION: PBI combined with IVC appears to promote polyp regression and closure, reduce CMT, and improve BCVA, with a favorable safety profile, after 12 months. Therefore, PBI may be a useful adjuvant therapy for patients with refractory or recurrent PCV. TRIAL REGISTRATION: Proton-Beam Irradiation Combined with Intravitreal Conbercept for Refractory or Recurrent Polypoidal Choroidal Vasculopathy: Prospective Phase II Clinical Study (ChiCTR2000038987).

Technical Note: A simple and fast daily quality assurance solution for modulated scanning proton and carbon ion beams.

PURPOSE: A typical ion beam treatment facility has multiple treatment rooms and may treat with more than one ion species, thus requiring a significant quality assurance (QA) effort. The goal of this work was to perform daily QA using a single irradiation per ion species to obtain the beam dosimetry parameters of dose per monitor unit (D/MU), range, and spot position. The X-ray alignment system should also be checked and the entire procedure performed by therapists. METHODS: This goal was achieved by designing a jig for the Sun Nuclear Daily QA™ 3 device and combining it with specific brass boluses, a standard QA plan, and a cuboid polyethylene phantom for positioning/repositioning tests. The design of the plan used for each ion species delivery ensured that there was no interference between the tests of the various characteristics. RESULTS: The 1-year monitoring results showed the proposed daily QA procedure was reliable and able to reflect each of the specified QA items of the proton and carbon ion beams. To simplify the daily analysis, the tolerances for the D/MU, beam range, and spot position (±1.5%, ±0.3 mm, ±1.5 mm, respectively) are checked using only the detector readings without the need for additional data processing. CONCLUSIONS: The proposed daily QA procedure was clinically implemented in our facility in April 2019 and has run smoothly for the first 2 years of operation. The total daily QA time for the four-room facility decreased from 1 to 1.5 h to 30 to 40 min and was achieved not by reducing QA tests but rather by implementing new technology and procedures permitting acquisition of multiple beam information.

Clinical commissioning of intensity-modulated proton therapy systems: Report of AAPM Task Group 185.

Proton therapy is an expanding radiotherapy modality in the United States and worldwide. With the number of proton therapy centers treating patients increasing, so does the need for consistent, high-quality clinical commissioning practices. Clinical commissioning encompasses the entire proton therapy system's multiple components, including the treatment delivery system, the patient positioning system, and the image-guided radiotherapy components. Also included in the commissioning process are the x-ray computed tomography scanner calibration for proton stopping power, the radiotherapy treatment planning system, and corresponding portions of the treatment management system. This commissioning report focuses exclusively on intensity-modulated scanning systems, presenting details of how to perform the commissioning of the proton therapy and ancillary systems, including the required proton beam measurements, treatment planning system dose modeling, and the equipment needed.

Scanned Proton Beam Performance and Calibration of the Shanghai Advanced Proton Therapy Facility.

The Shanghai Advanced Proton Therapy facility (SAPT) is a hospital-based facility that began construction in December of 2014 with commissioning of the first scanned proton beam line starting in October of 2017. Proton beams are extracted from a synchrotron accelerator with energies between 70 and 235 MeV. Beam delivery uses the modulated scanning and energy stacking techniques to produce a maximal scanning area of 40 × 30 cm2 at the iso-center. Prior to clinical use, the beam delivery system was characterized and calibrated following the guidelines of the IEC 62667 medical electronic equipment standard including the spot size in air, spot position, depth dose distributions, and lateral dose profiles, as well as the beam monitor calibrations following the IAEA TRS-398 recommendations with small differences. •The measured dosimetric results showed that the full width at half maximum (FWHM) for the beam spot size in air varied approximately from 6 mm to 13 mm. The dose fall-off (DDF) derived from the measured depth dose in water varied from 4.7 mm at 235 MeV to 0.7 mm at 70 MeV. The homogeneity of the scanned field was better than 2% for various energies as expected.•Furthermore, the beam reproducibility and proportionality delivery accuracy was also stable with the results better than 0.1% and 1% respectively. Finally, the dose monitor calibration factor, its reproducibility and stability were tested. Reproducibility tests exhibited a standard deviation (SD) result of less than 1% during the test period.•All the measured dosimetric parameters showed that the design specifications were well achieved and the results are suitable for being used as a part of the clinical commissioning and quality assurance program for treating patients.

Analysis of ion beam teletherapy patient-specific quality assurance.

The objective of this study was to evaluate the procedures for patient-specific quality assurance measurements using modulated scanned and energy stacked beams for proton and carbon ion teletherapy. Delivery records from 1734 portal measurements were analyzed using a 3-point pass criteria: more than 22 of 24 chambers in a water phantom (WP) had to have a measured dose difference from the planned portal doses less than or equal to 3%, or the distance from the measurement point location to a point location in the plan having the same dose had to be less than or equal to 3 mm (distance to agreement [DTA]), and the mean dose deviation of all chambers had to be less than 3%. Stratification of results showed some associations between measurement parameters and pass rates. For proton portals, pass rates were high at all measurement depths, but for carbon ion portals, pass rates decreased as a function of increasing measurement depth. Pass rates of both proton and carbon ion portals with 1 WP were slightly lower than those with a second WP. The total pass rates were 97.7% and 91.9% for proton and carbon ion patient portals, respectively. In general, the measured doses exhibited good agreement with the treatment planning system (TPS) calculated doses. When the chamber position was deeper than 150 mm in carbon ion beams, a lower pass rate was observed, which may have been caused by ion chamber array setup uncertainty (lateral and depth) in highly modulated portals or incorrect modeling of scatter by the TPS. These deviations need further investigation.

New horizons in particle therapy systems.

Particle therapy is rapidly expanding and claiming its position as the treatment modality of choice in teletherapy. However, the rate of expansion continues to be restricted by the size and cost of the associated particle therapy systems and their operation. Additional technical limitations such as dose delivery rate, treatment process efficiency, and achievement of superior dose conformity potentially hinder the complete fulfillment of the promise of particle therapy. These topics are explored in this review considering the current state of particle therapy systems and what improvements are required to overcome the current challenges. Beam production systems (accelerators), beam transport systems including gantries and beam delivery systems are addressed explicitly in these regards.

Technical Note: Spot characteristic stability for proton pencil beam scanning.

PURPOSE: The spot characteristics for proton pencil beam scanning (PBS) were measured and analyzed over a 16 month period, which included one major site configuration update and six cyclotron interventions. The results provide a reference to establish the quality assurance (QA) frequency and tolerance for proton pencil beam scanning. METHODS: A simple treatment plan was generated to produce an asymmetric 9-spot pattern distributed throughout a field of 16 × 18 cm for each of 18 proton energies (100.0-226.0 MeV). The delivered fluence distribution in air was measured using a phosphor screen based CCD camera at three planes perpendicular to the beam line axis (x-ray imaging isocenter and up/down stream 15.0 cm). The measured fluence distributions for each energy were analyzed using in-house programs which calculated the spot sizes and positional deviations of the Gaussian shaped spots. RESULTS: Compared to the spot characteristic data installed into the treatment planning system, the 16-month averaged deviations of the measured spot sizes at the isocenter plane were 2.30% and 1.38% in the IEC gantry x and y directions, respectively. The maximum deviation was 12.87% while the minimum deviation was 0.003%, both at the upstream plane. After the collinearity of the proton and x-ray imaging system isocenters was optimized, the positional deviations of the spots were all within 1.5 mm for all three planes. During the site configuration update, spot positions were found to deviate by 6 mm until the tuning parameters file was properly restored. CONCLUSIONS: For this beam delivery system, it is recommended to perform a spot size and position check at least monthly and any time after a database update or cyclotron intervention occurs. A spot size deviation tolerance of <15% can be easily met with this delivery system. Deviations of spot positions were <2 mm at any plane up/down stream 15 cm from the isocenter.

Use of proton beams with breast prostheses and tissue expanders.

Since the early 2000s, a small but rapidly increasing number of patients with breast cancer have been treated with proton beams. Some of these patients have had breast prostheses or tissue expanders in place during their courses of treatment. Procedures must be implemented to plan the treatments of these patients. The density, kilovoltage x-ray computed tomography numbers (kVXCTNs), and proton relative linear stopping powers (pRLSPs) were calculated and measured for several test sample devices. The calculated and measured kVXCTNs of saline were 1% and 2.4% higher than the values for distilled water while the calculated RLSP for saline was within 0.2% of the value for distilled water. The measured kVXCTN and pRLSP of the silicone filling material for the test samples were approximately 1120 and 0.935, respectively. The conversion of kVXCTNs to pRLSPs by the treatment planning system standard tissue conversion function is adequate for saline-filled devices but for silicone-filled devices manual reassignment of the pRLSPs is required.

Ion stopping powers and CT numbers.

One of the advantages of ion beam therapy is the steep dose gradient produced near the ion's range. Use of this advantage makes knowledge of the stopping powers for all materials through which the beam passes critical. Most treatment planning systems calculate dose distributions using depth dose data measured in water and an algorithm that converts the kilovoltage X-ray computed tomography (CT) number of a given material to its linear stopping power relative to water. Some materials present in kilovoltage scans of patients and simulation phantoms do not lie on the standard tissue conversion curve. The relative linear stopping powers (RLSPs) of 21 different tissue substitutes and positioning, registration, immobilization, and beamline materials were measured in beams of protons accelerated to energies of 155, 200, and 250 MeV; carbon ions accelerated to 290 MeV/n; and iron ions accelerated to 970 MeV/n. These same materials were scanned with both kilovoltage and megavoltage CT scanners to obtain their CT numbers. Measured RLSPs and CT numbers were compared with calculated and/or literature values. Relationships of RLSPs to physical densities, electronic densities, kilovoltage CT numbers, megavoltage CT numbers, and water equivalence values converted by a treatment planning system are given. Usage of CT numbers and substitution of measured values into treatment plans to provide accurate patient and phantom simulations are discussed.

Energy spectrum control for modulated proton beams.

In proton therapy delivered with range modulated beams, the energy spectrum of protons entering the delivery nozzle can affect the dose uniformity within the target region and the dose gradient around its periphery. For a cyclotron with a fixed extraction energy, a rangeshifter is used to change the energy but this produces increasing energy spreads for decreasing energies. This study investigated the magnitude of the effects of different energy spreads on dose uniformity and distal edge dose gradient and determined the limits for controlling the incident spectrum. A multilayer Faraday cup (MLFC) was calibrated against depth dose curves measured in water for nonmodulated beams with various incident spectra. Depth dose curves were measured in a water phantom and in a multilayer ionization chamber detector for modulated beams using different incident energy spreads. Some nozzle entrance energy spectra can produce unacceptable dose nonuniformities of up to +/-21% over the modulated region. For modulated beams and small beam ranges, the width of the distal penumbra can vary by a factor of 2.5. When the energy spread was controlled within the defined limits, the dose nonuniformity was less than +/-3%. To facilitate understanding of the results, the data were compared to the measured and Monte Carlo calculated data from a variable extraction energy synchrotron which has a narrow spectrum for all energies. Dose uniformity is only maintained within prescription limits when the energy spread is controlled. At low energies, a large spread can be beneficial for extending the energy range at which a single range modulator device can be used. An MLFC can be used as part of a feedback to provide specified energy spreads for different energies.

Range and modulation dependencies for proton beam dose per monitor unit calculations.

Calculations of dose per monitor unit (D/MU) are required in addition to measurements to increase patient safety in the clinical practice of proton radiotherapy. As in conventional photon and electron therapy, the D/MU depends on several factors. This study focused on obtaining range and modulation dependence factors used in D/MU calculations for the double scattered proton beam line at the Midwest Proton Radiotherapy Institute. Three dependencies on range and one dependency on modulation were found. A carefully selected set of measurements was performed to discern these individual dependencies. Dependencies on range were due to: (1) the stopping power of the protons passing through the monitor chamber; (2) the reduction of proton fluence due to nuclear interactions within the patient; and (3) the variation of proton fluence passing through the monitor chamber due to different source-to-axis distances (SADs) for different beam ranges. Different SADs are produced by reconfigurations of beamline elements to provide different field sizes and ranges. The SAD effect on the D/MU varies smoothly as the beam range is varied, except at the beam range for which the first scatterers are exchanged and relocated to accommodate low and high beam ranges. A geometry factor was devised to model the SAD variation effect on the D/MU. The measured D/MU variation as a function of range can be predicted within 1% using the three modeled dependencies on range. Investigation of modulated beams showed that an analytical formula can predict the D/MU dependency as a function of modulation to within 1.5%. Special attention must be applied when measuring the D/MU dependence on modulation to avoid interplay between range and SAD effects.

Isocenter characteristics of an external ring proton gantry.

PURPOSE: Determine the shape, size, geometric center, and virtual center of the isocenter for a proton gantry and compare to electron/X-ray accelerator gantries. METHODS AND MATERIALS: The majority of commercial electron/X-ray accelerator gantries consist of a rotating treatment head mounted to a stationary stand through a slewing ring bearing. The world's first proton gantry uses two rotating external rings, to which is mounted a fixed treatment nozzle with a movable snout that extends close to the center of rotation. The radial aspect of the isocenter for two similar proton gantries and two different electron/X-ray gantries were measured in the gantry frame of reference with a front pointer and a theodolite. These results were then transformed into room coordinates. The axial aspect of the isocenter was measured with a dial indicator. RESULTS: The radial aspect of the isocenter for slewing ring gantries has the shape of two concentric circles. The radial aspect of the isocenter for external ring gantries is shaped like a butterfly. The size of the mechanical isocenter is independent of the gantry style. CONCLUSIONS: The locations of the geometric and virtual centers can be determined to within 0.2 mm. Multiple gantry angle treatments can be delivered with a single setup allowing 2 mm for gantry and nozzle deflections. Precision treatments can be delivered allowing only 0.5 mm if the measured isocenter path is applied.

"Out-of-field" effects of head-localized proton irradiation on peripheral immune parameters.

The heads of Sprague-Dawley rats were irradiated with protons to total doses of 1.5, 3 and 4 Gy and euthanized 9-10 days later. Significant dose-dependent decreases were noted in thymus mass. Lymphocyte and platelet numbers were significantly reduced in blood. Flow cytometric analysis of blood and spleen showed that CD3+ T, CD3+/CD4+ TH, and CD3+/CD8+ TC cell numbers were low and proportions were significantly altered by radiation. CD4:CD8 ratios and CD45R+ B lymphocytes were unaffected. Spontaneous blastogenesis of blood and spleen leukocytes was significantly increased by radiation. Plasma TGF-beta 1 level in irradiated rats was consistently, but not significantly, higher than in non-irradiated animals. T and B cell proportions in lymph nodes from irradiated animals were similar to non-irradiated controls. Bone marrow from all irradiated groups had high CD90+/Gran+ cell numbers. The data show that head-localized proton irradiation at relatively modest doses can profoundly influence systemic distribution and composition of lymphocyte populations. The data also suggest that immune modulation induced by localized proton, as well as other forms of radiation, should be taken into consideration when evaluating adjunctive immunotherapies in patients receiving radiotherapy.