Sectored single-energy volumetric-modulated proton arc therapy (VPAT): A preliminary multi-disease-site concept study.

PURPOSE: To explore the feasibility of a novel intensity-modulated proton arc technique that uses a single-energy beam from the cyclotron. The beam energy is externally modulated at each gantry angle by a tertiary energy modulator (EM). We hypothesize that irradiating in an arc without requiring an energy change from the cyclotron will achieve a faster delivery (main advantage of our technique) while keeping clinically desirable dosimetric results. METHODS: In a retrospective cohort of four patients with female pelvis, prostate, lung, and brain cancers, we investigated our volumetric-modulated proton arc therapy (VPAT) technique. Arcs were simulated by sectors of 1°-spaced static beams. Keeping the energy requested from the cyclotron the same for each entire arc was supported by a predesigned EM placed in front of the nozzle. As a feasibility measure, EM thicknesses were calculated. Delivery times and doses to targets and organs at risk (OARs) were compared to those of the clinical plans. RESULTS: VPAT plans were comparable to their clinical counterparts in achieving target dose conformity, being robust to uncertainties, and meeting clinical dose-volume constraints. Cyclotron energies for the four cases were within 159-220 MeV, and energy modulation range was 69-100 MeV, equivalent to 13-19 cm of water-equivalent thickness (WET). Plan delivery times were reduced from > 5 min in our clinical practice to < 3.5 min in VPAT. CONCLUSION: For the evaluated plans, the novel VPAT approach achieved shorter delivery times without sacrificing robustness, OAR sparing or target coverage. VPAT's EMs had WETs implementable in a clinical setup.

Correlation between local instantaneous dose rate and oxygen pressure reduction during proton pencil beam scanning irradiation.

Background and purpose: Oxygen dynamics may be important for the tissue-sparing effect observed at ultra-high dose rates (FLASH sparing effect). This study investigated the correlation between local instantaneous dose rate and radiation-induced oxygen pressure reduction during proton pencil beam scanning (PBS) irradiations of a sample and quantified the oxygen consumption g-value. Materials and methods: A 0.2 ml phosphorescent sample (1 µM PtG4 Oxyphor probe in saline) was irradiated with a 244 MeV proton PBS beam. Four irradiations were performed with variations of a PBS spot pattern with 5 × 7 spots. During irradiation, the partial oxygen pressure (pO2) was measured with 4.5 Hz temporal resolution with a phosphorometer (Oxyled) that optically excited the probe and recorded the subsequently emitted light. A calibration was performed to calculate the pO2 level from the measured phosphorescence lifetime. A fiber-coupled scintillator simultaneously measured the instantaneous dose rate in the sample with 50 kHz sampling rate. The oxygen consumption g-value was determined on a spot-by-spot level and using the total pO2 change for full spot pattern irradiation. Results: A high correlation was found between the local instantaneous dose rate and pO2 reduction rate, with a correlation coefficient of 0.96-0.99. The g-vales were 0.18 ± 0.01 mmHg/Gy on a spot-by-spot level and 0.17 ± 0.01 mmHg/Gy for full spot pattern irradiation. Conclusions: The pO2 reduction rate was directly related to the local instantaneous dose rate per delivered spot in PBS deliveries. The methodology presented here can be applied to irradiation at ultra-high dose rates with modifications in the experimental setup.

Optimal minimum MU for intensity-modulated proton therapy with pencil-beam scanning proton beams.

PURPOSE: A higher minimum monitor unit (minMU) for pencil-beam scanning proton beams in intensity-modulated proton therapy is preferred for more efficient delivery. However, plan quality may be compromised when the minMU is too large. This study aimed to identify the optimal minMU (OminMU) to improve plan delivery efficiency while maintaining high plan quality. METHODS: We utilized clinical plans including six anatomic sites (brain, head and neck, breast, lung, abdomen, and prostate) from 23 patients previously treated with the Varian ProBeam system. The minMU of each plan was increased from the current clinical minMU of 1.1 to 3-24 MU depending on the daily prescribed dose (DPD). The dosimetric parameters of the plans were evaluated for consistency against a 1.1-minMU plan for target coverage as well as organs-at-risk dose sparing. DPD/minMU was defined as the ratio of DPD to minMU (cGy/MU) to find the OminMU by ensuring that dosimetric parameters did not differ by >1% compared to those of the 1.1-minMU plan. RESULTS: All plans up to 5 minMU showed no significant dose differences compared to the 1.1-minMU plan. Plan qualities remained acceptable when DPD/minMU ≥35 cGy/MU. This suggests that the 35 cGy/MU criterion can be used as the OminMU, which implies that 5 MU is the OminMU for a conventional fraction dose of 180 cGy. Treatment times were decreased by an average of 32% (max 56%, min 7%) and by an average of 1.6 min when the minMU was increased from 1.1 to OminMU. CONCLUSION: A clinical guideline for OminMU has been established. The minMU can be increased by 1 MU for every 35 cGy of DPD without compromising plan quality for most cases analyzed in this study. Significant treatment time reduction of up to 56% was observed when the suggested OminMU is used.

Pencil Beam Scanning Proton Bragg Peak Conformal FLASH in Prostate Cancer Stereotactic Body Radiotherapy.

Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.

Advances in treatment planning and management for the safety and accuracy of lung stereotactic body radiation therapy using proton pencil beam scanning: Simulation, planning, quality assurance, and delivery recommendations.

This study presents the clinical experiences of the New York Proton Center in employing proton pencil beam scanning (PBS) for the treatment of lung stereotactic body radiation therapy. It encompasses a comprehensive examination of multiple facets, including patient simulation, delineation of target volumes and organs at risk, treatment planning, plan evaluation, quality assurance, and motion management strategies. By sharing the approaches of the New York Proton Center and providing recommendations across simulation, treatment planning, and treatment delivery, it is anticipated that the valuable experience will be provided to a broader proton therapy community, serving as a useful reference for future clinical practice and research endeavors in the field of stereotactic body proton therapy for lung tumors.

Pencil Beam Scanning Bragg Peak FLASH Technique for Ultra-High Dose Rate Intensity-Modulated Proton Therapy in Early-Stage Breast Cancer Treatment.

Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications.

Small field proton irradiation for in vivo studies: Potential and limitations when adapting clinical infrastructure.

PURPOSE: To evaluate the dosimetric accuracy for small field proton irradiation relevant for pre-clinical in vivo studies using clinical infrastructure and technology. In this context additional beam collimation and range reduction was implemented. METHODS AND MATERIALS: The clinical proton beam line employing pencil beam scanning (PBS) was adapted for the irradiation of small fields at shallow depths. Cylindrical collimators with apertures of 15, 12, 7 and 5mm as well as two different range shifter types, placed at different distances relative to the target, were tested: a bolus range shifter (BRS) attached to the collimator and a clinical nozzle mounted range shifter (CRS) placed at a distance of 72cm from the collimator. The Monte Carlo (MC) based dose calculation engine implemented in the clinical treatment planning system (TPS) was commissioned for these two additional hardware components. The study was conducted with a phantom and cylindrical target sizes between 2 and 25mm in diameter following a dosimetric end-to-end test concept. RESULTS: The setup with the CRS provided a uniform dose distribution across the target. An agreement of better than5% between the planned dose and the measurements was obtained for a target with 3mm diameter (collimator 5mm). A 2mm difference between the collimator and the target diameter (target being 2 mm smaller than the collimator) sufficed to cover the whole target with the planned dose in the setup with CRS. Using the BRS setup (target 8mm, collimator 12mm) resulted in non-homogeneous dose distributions, with a dose discrepancy of up to 10% between the planned and measured doses. CONCLUSION: The clinical proton infrastructure with adequate beam line adaptations and a state-of-the-art TPS based on MC dose calculations enables small animal irradiations with a high dosimetric precision and accuracy for target sizes down to 3mm.

Investigation of the impact of machine operating parameters on beam delivery time and its correlation with treatment plan characteristics for synchrotron-based proton pencil beam spot scanning system.

Purpose: To investigate the beam delivery time (BDT) reduction due to the improvement of machine parameters for Hitachi synchrotron-based proton PBS system. Methods: BDTs for representative treatment plans were calculated to quantitatively estimate the BDT improvement from our 2015 system at Mayo Clinic in Arizona to our system to be implemented in 2025 at Mayo Clinic in Florida, and to a hypothetical future system. To specifically assess how each incremental improvement in the operating parameters reduced the total BDT, for each plan, we simulated the BDT 10,368 times with various settings of the nine different operating parameters. The effect of each operating parameter on BDT reduction and its correlation with treatment plan characteristics were analyzed. The optimal number of multiple energy extraction (MEE) layers per spill for different systems was also investigated. Results: The median (range) decrease in BDT was 60% (56%-70%) from the 2015 to the 2025 system. The following incremental improvement in parameters of the 2015 system for the 2025 system played an important role in this decreased BDT: beam intensity (8 to 20 MU/s), recapture efficiency (50% to 80%), number of MEE layers per spill (4 to 8), scanning magnet preparation and verification time (1.9 to 0.95 msec), and MEE layer switch time (200 to 100 msec). Reducing the total spill change time and scanning magnet preparation and verification time from those of the 2025 system further reduced BDT in the hypothetical future system. 8 MEE layers per spill is optimal for a system with 50% recapture efficiency; 16 MEE layers per spill is optimal for a system with 80% recapture efficiency; and more than 16 MEE layers per spill is beneficial only for a system close to 100% recapture efficiency. Conclusions: We systematically studied the effect of each machine operating parameter on the reduction in total BDT and its correlation with treatment plan characteristics. Our findings will aid new and existing synchrotron-based proton beam therapy centers to make balanced decisions on BDT benefits vs. costs when considering machine upgrade or new system selection.

Advanced pencil beam scanning Bragg peak FLASH-RT delivery technique can enhance lung cancer planning treatment outcomes compared to conventional multiple-energy proton PBS techniques.

PURPOSE: To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application. METHODS: Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensity-modulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34 Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V40Gy/s) were calculated as a metric of the FLASH-sparing effect. RESULTS: For higher dose thresholds, the Bragg peak plans achieved greater V40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were > 5 Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D2%(%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p < 0.01) and that of Bragg peak 1200 MU plans of 115.95% (p < 0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p > 0.05). CONCLUSION: Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques.

Use of single-energy proton pencil beam scanning Bragg peak for intensity-modulated proton therapy FLASH treatment planning in liver-hypofractionated radiation therapy.

PURPOSE: The transmission proton FLASH technique delivers high doses to the normal tissue distal to the target, which is less conformal compared to the Bragg peak technique. To investigate FLASH radiotherapy (RT) planning using single-energy Bragg peak beams with a similar beam arrangement as clinical intensity-modulated proton therapy (IMPT) in a liver stereotactic body radiation therapy (SBRT) and to characterize the plan quality, dose sparing of organs-at-risk (OARs), and FLASH dose rate percentage. MATERIALS AND METHODS: An in-house platform was developed to enable inverse IMPT-FLASH planning using single-energy Bragg peaks. A universal range shifter and range compensators were utilized to effectively align the Bragg peak to the distal edge of the target. Two different minimum MU settings of 400 and 800 MU/spot (Bragg-400 MU and Bragg-800 MU) plans were investigated on 10 consecutive hepatocellular carcinoma patients previously treated by IMPT-SBRT to evaluate the FLASH dose and dose rate coverage for OARs. The IMPT-FLASH using single-energy Bragg peaks delivered 50 Gy in five fractions with similar or identical beam arrangement to the clinical IMPT-SBRT plans. NRG GI003 dose constraint metrics were used. Three dose rate calculation methods, including average dose rate (ADR), dose threshold dose rate (DTDR), and dose-ADR (DADR), were all studied. RESULTS: The novel spot map optimization can fulfill the inverse planning using single-energy Bragg peaks. All the Bragg peak FLASH plans achieved similar results for the liver-gross tumor volume (GTV) Dmean and heart D 0.5 c m 3 ${D_{0.5\,{\rm{c}}{{\rm{m}}^3}}}$ , compared to SBRT-IMPT. The Bragg-800 MU plans resulted in 18.3% higher clinical target volume (CTV) D 2 c m 3 ${D_{2\,{\rm{c}}{{\rm{m}}^{\rm{3}}}}}$ compared with SBRT (p < 0.05), and no significant difference was found between Bragg-400 MU and SBRT plans. For the CTV Dmax , SBRT plans resulted in 10.3% (p < 0.01) less than Bragg-400 MU plans and 16.6% (p < 0.01) less than Bragg-800 MU plans. The Bragg-800 MU plans generally achieved higher ADR, DADR, and DTDR dose rates than Bragg-400 MU plans, and DADR mostly led to the highest V40 Gy/s compared to other dose rate calculation methods, whereas ADR led to the lowest. The lower dose rate portions in certain OARs are related to the lower dose deposited due to the farther distances from targets, especially in the penumbra of the beams. CONCLUSION: Single-energy Bragg peak IMPT-FLASH plans eliminate the exit dose in normal tissues, maintaining comparable dose metrics to the conventional IMPT-SBRT plans, while achieving a sufficient FLASH dose rate for liver cancers. This study demonstrates the feasibility of and sufficiently high dose rate when applying the Bragg peak FLASH treatment for a liver cancer hypofractionated FLASH therapy. The advancement of this novel method has the potential to optimize treatment for liver cancer patients.

Dosimetric Comparison of Various Spot Placement Techniques in Proton Pencil Beam Scanning.

Purpose: To present quantitative dosimetric evaluations of five proton pencil beam spot placement techniques. Materials and Methods: The spot placement techniques that were investigated include two grid-based (rectilinear grid and hexagonal grid, both commonly available in commercial planning systems) and three boundary-contoured (concentric contours, hybrid, and optimized) techniques. Treatment plans were created for two different target volumes, one spherical and one conical. An optimal set of planning parameters was defined for all treatment plans and the impact of spot placement techniques on the plan quality was evaluated in terms of lateral/distal dose falloff, normal tissue sparing, conformity and homogeneity of dose distributions, as well as total number of spots used. Results: The results of this work highlight that for grid-based spot placement techniques, the dose conformity is dependent on target cross-sectional shape perpendicular to beam direction, which changes for each energy layer. This variable conformity problem is mitigated by using boundary contoured spot placement techniques. However, in the case of concentric contours, the conformity is improved but at the cost of decreased homogeneity inside the target. Hybrid and optimized spot placement techniques, which use contoured spots at the boundary and gridlike interior spot patterns, provide more uniform dose distributions inside the target volume while maintaining the improved dose conformity. The optimized spot placement technique improved target coverage, homogeneity of dose, and minimal number of spots. The dependence of these results on spot size is also presented for both target shapes. Conclusion: This work illustrates that boundary-contoured spot placement techniques offer marked improvement in dosimetry metrics when compared to commercially available grid-based techniques for a range of proton scanned beam spot sizes.

Technical Note: Long-term monitoring of diode sensitivity degradation induced by proton irradiation.

PURPOSE: To measure diode sensitivity degradation (DSD) induced by cumulative proton dose delivered to a commercial daily quality assurance (QA) device. METHODS: At our institution, six Daily QA 3 (DQA3, Sun Nuclear Corporation, Melbourne, FL, USA) devices have been used for daily proton pencil beam scanning QA in four proton gantry rooms over a span of 4 years. DQA3 diode counts were cross-calibrated using a homogenous field with a known dose of 1 Gy. The DSD rate (ΔR%/100 Gy) was calculated using linear regression on time-series plots of diode counts and an estimate of cumulative dose per year based on the cross-calibration. The effect of DSD on daily QA spot position measurements was quantified by converting DSD to baseline spot position shift. RESULTS: The average dose delivered to the four inner DQA3 diodes was 104 ± 5 Gy/year, and the rate of DSD was -5.1% ± 1.0/100 Gy with the exception of one DQA3 device that had a significantly higher rate of DSD (-12%/100 Gy). The R2 s of the linear fit to time-series plots were between 0.92 and 0.98. The DSD rates were not constant but decreases with accumulated doses. The four center diodes, which received 40% of the cumulative dose received by inner diodes, had a DSD rate of -7.2% ± 0.9/100 Gy. For our daily QA program, 1 year of DSD was equivalent to a 0.2 mm shift in spot position. CONCLUSIONS: The DSD rate of DQA3 diodes determined by long-term proton daily QA data was about -5%/100 Gy, which is more than 10 times greater than the reported DSD rate from photon irradiation. DQA3 diodes may be used for daily proton QA programs, provided that they are recalibrated at an appropriate frequency that should be determined specifically for different daily QA programs.

Development of a storage phosphor imaging system for proton pencil beam spot profile determination.

PURPOSE: Accurate two-dimensional (2D) profile measurements at submillimeter precision are necessary for proton beam commissioning and periodic quality assurance (QA) purposes and are currently performed at our institution with a commercial scintillation detector (Lynx PT) with limited means for independent checks. The purpose of this work was to create an independent dosimetry system consisting of an in-house optical scanner and a BaFBrI:Eu2+ storage phosphor dosimeter by: (a) determining the optimal settings for the optical scanner, (b) measuring 2D proton spot profiles with the storage phosphors, and (c) comparing them to similar measurements using a commercial scintillation detector. METHODS: An in-house 2D laboratory optical scanner was constructed and spatially calibrated for accurate 2D photostimulated luminescence (PSL) dosimetry. Square 5 × 5 cm2 BaFBrI:Eu2+ dosimeter samples were uniformly irradiated with line scans performed to determine the physical and electronic scanner settings resulting in the highest signal-to-noise ratios (SNR) at a sub-millimeter spatial resolution. The resultant spatial resolution of the scanner was then quantitatively assessed by measuring (a) line pairs on a standard X-ray lead bar phantom and (b) modulation transfer functions. Following this, 2D proton spot profiles from a Mevion S250i Hyperscan proton unit were obtained at 1, 10, 20, 30, 40, and 50 monitor unit (MU) settings at maximum energy (E0  = 227.1 MeV) and compared to baseline profiles from a commercial scintillation detector, where 1 MU is calibrated to deliver 1 Gy absolute proton dose-to-water under reference conditions, that is, 41 × 41 proton spots uniformly spaced by 0.25 cm within a 10 × 10 cm2 square field size at maximum energy (227.1 MeV) in water at depth of 5 cm at isocenter. The dosimetric system's sensitivities to (a) ±1 mm positional shifts and (b) ±0.3 mm beam lateral spread changes were quantitatively evaluated through a Gaussian fitting of the crossline and inline plots of the respective artificially shifted beam profiles. RESULTS: The physical scanner settings of (a) Δτ = 27 ms time interval between data samples, (b) vx  = 1.235 cm/s scanning speed, (c) 1% laser transmission (0.02 mW power) and (d) (Δx, Δy) = (0.33, 0.50 mm) pixel sizes with electronic settings of (a) 300 microseconds time constant, (b) normal dynamic reserve, (c) 24 dB/oct low pass filter slope, and (d) 160 Hz chopping frequency resulted in the highest SNR while maintaining sub-millimeter spatial resolution. The BaFBr0.85 I0.15 :Eu2+ storage phosphor dosimeters were linear from 1 to 50 MU and their profiles did not saturate up to 150 MU. The scanner was able to detect lateral displacements of ±1 mm in both the crossline and inline directions and ±0.3 mm beam spread changes that were artificially introduced by varying the incident proton energy. Specific to our proton unit, proton energy changes of ±1 MeV can also be detected indirectly via beam spread measurements. CONCLUSION: Our combined dosimetric system including an in-house laboratory optical scanner and reusable BaFBr0.85 I0.15 :Eu2+ storage phosphors demonstrated a sufficient spatial resolution and dosimetric accuracy to support its use as an independent proton spot measurement dosimeter system. Its wide dynamic range allows for other versatile applications such as proton halo measurements.

Combined Effect of Neutron and Proton Radiations on the Growth of Solid Ehrlich Ascites Carcinoma and Remote Effects in Mice.

The combined effect of the irradiation with a proton pencil scanning beam (PBS) at a total dose of 80 Gy and neutron radiation at a dose of 5 Gy on the growth of solid Ehrlich ascites carcinoma (EAC) and the remote effects in tumor-bearing mice was studied. Combined irradiation of mice with neutrons before and after irradiation with PBS, as well as irradiation only with PBS, effectively suppressed the growth of solid EAC within 1 month. In terms of the frequency and severity of radiation-induced skin reactions of mice observed 15-40 days after therapy, neutron irradiation after the irradiation with PBS showed better values of these parameters as compared to only PBS; however, exposure to neutrons before PBS was more damaging as compared to the other two options. It was also shown that the tumor relapse rate in the groups of animals with combined irradiation was higher, and the total lifespan was lower than the group of mice irradiated with PBS alone.

FLASH Radiotherapy Using Single-Energy Proton PBS Transmission Beams for Hypofractionation Liver Cancer: Dose and Dose Rate Quantification.

PURPOSE: This work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode. METHODS AND MATERIALS: An in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s). RESULTS: All plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans. CONCLUSION: This is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage.

Evaluation of GATE-RTion (GATE/Geant4) Monte Carlo simulation settings for proton pencil beam scanning quality assurance.

PURPOSE: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. METHODS: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. RESULTS: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). CONCLUSIONS: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.

Measurement-based study on characterizing symmetric and asymmetric respiratory motion interplay effect on target dose distribution in the proton pencil beam scanning.

Pencil beam scanning proton therapy makes possible intensity modulation, resulting in improved target dose conformity and organ-at-risk (OAR) dose sparing. This benefit, however, results in increased sensitivity to certain clinical and beam delivery parameters, such as respiratory motion. These effects can cause plan degeneration, which could lead to decreased tumor dose or increased OAR dose. This study evaluated the measurements of proton pencil beam scanning delivery made with a 2D ion chamber array in solid water on a 1D motion platform, where respiratory motion was simulated using sine and cosine4 waves representing sinusoidal symmetric and realistic asymmetric breathing motions, respectively. Motion amplitudes were 0.5 cm and 1 cm corresponding to 1 cm and 2 cm of maximum respiratory excursions, respectively, with 5 sec fixed breathing cycle. The treatment plans were created to mimic spherical targets of 3 cm or 10 cm diameter located at 5 cm or 1 cm depth in solid water phantom. A reference RBE dose of 200 cGy per fraction was delivered in 1, 5, 10, and 15 fractions for each dataset. We evaluated dose conformity and uniformity at the center plane of targets by using the Conformation Number and the Homogeneity Index, respectively. Results indicated that dose conformity as well as homogeneity was more affected by motion for smaller targets. Dose conformity was better achieved for symmetric breathing patterns than asymmetric breathing patterns regardless of the number of fractions. The presence of a range shifter with shallow targets reduced the motion effect by improving dose homogeneity. While motion effects are known to be averaged out over the course of multifractional treatments, this might not be true for proton pencil beam scanning under asymmetrical breathing pattern.

Technical Note: Comprehensive evaluation and implementation of two independent methods for beam monitor calibration for proton scanning beam.

PURPOSE: To clinically implement and comprehensively evaluate two independent methods for beam monitor calibration of scanning proton beam. METHODS: Seven proton energies that represent the lowest to highest energy proton beams were selected. Single energy layer circular fields of diameter 15 cm with 2.5 mm spot spacing and 10 times of repainting (FS15cm ) were designed for all energies. The effective measurement points of Bragg peak chamber (BPC), advanced Markus chamber (AMC) and farmer chamber (FC) were all aligned to 2 cm depth in water using SSD setup. The BPC and AMC were cross-calibrated with farmer chamber (FC) using the field FS15cm . In order to evaluate BPC's lateral response uniformity, a collimated narrow proton beam (5.8 mm diameter) was delivered to the active area and edge of the BPC. The dose area product (DAP) was measured using two methods by two BPCs, one AMC and one FC. For method 1, a single spot proton beam was delivered to the geometric center of the BPC. For method 2, the fields FS15cm were delivered to FC and AMC, respectively. Accumulated charges by these chambers were converted to DAPs, and the quantitative difference of DAPs between both methods was calculated. The causes of the uncertainties were discussed, and the advantages of the two methods were compared. RESULTS: The two BPCs showed different lateral response uniformity. BPC1 has a uniform response from the center up to a radius of 3.5 cm. BPC2 has a uniform response only to 2 cm and the response dropped 1% to 2% at 3.5 cm from center. BPC2 also has significant over-response compared to BPC1. A 2.2% systematic error would be transferred to DAP if the over-response from BPC2 was not considered. The DAPs measured by method 1 with two BPCs and by method 2 with FC and AMC were consistent to 0.5%. The major uncertainty component of method 1 is from the cross-calibration of the BPC. CONCLUSIONS: The two independent methods for DAP were shown to give consistent results, given the sources of uncertainties were carefully addressed in the measurements. Direct measurement of DAP with BPC is very efficient, but it may be subject to more than 2% systematic error if the BPC lateral response is not carefully evaluated.

Ion recombination and polarity correction factors for a plane-parallel ionization chamber in a proton scanning beam.

PURPOSE: To evaluate the effect on charge collection in the ionization chamber (IC) in proton pencil beam scanning (PBS), where the local dose rate may exceed the dose rates encountered in conventional MV therapy by up to three orders of magnitude. METHODS: We measured values of the ion recombination (ks ) and polarity (kpol ) correction factors in water, for a plane-parallel Markus TM23343 IC, using the cyclotron-based Proteus-235 therapy system with an active proton PBS of energies 30-230 MeV. Values of ks were determined from extrapolation of the saturation curve and the Two-Voltage Method (TVM), for planar fields. We compared our experimental results with those obtained from theoretical calculations. The PBS dose rates were estimated by combining direct IC measurements with results of simulations performed using the FLUKA MC code. Values of ks were also determined by the TVM for uniformly irradiated volumes over different ranges and modulation depths of the proton PBS, with or without range shifter. RESULTS: By measuring charge collection efficiency versus applied IC voltage, we confirmed that, with respect to ion recombination, our proton PBS represents a continuous beam. For a given chamber parameter, e.g., nominal voltage, the value of ks depends on the energy and the dose rate of the proton PBS, reaching c. 0.5% for the TVM, at the dose rate of 13.4 Gy/s. For uniformly irradiated regular volumes, the ks value was significantly smaller, within 0.2% or 0.3% for irradiations with or without range shifter, respectively. Within measurement uncertainty, the average value of kpol , for the Markus TM23343 IC, was close to unity over the whole investigated range of clinical proton beam energies. CONCLUSION: While no polarity effect was observed for the Markus TM23343 IC in our pencil scanning proton beam system, the effect of volume recombination cannot be ignored.

Field-Specific Intensity-modulated Proton Therapy Optimization Technique for Breast Cancer Patients with Tissue Expanders Containing Metal Ports.

This report aims to propose and present an evaluation of a robust pencil beam scanning proton multi-field optimized treatment planning technique for postmastectomy radiation of breast cancer patients with implanted tissue expanders containing an internal metal port. Field-specific split targets were created for optimization to prevent spots from traveling through the metal port, while providing uniform coverage of the target with the use of a multi-field intensity modulated optimization approach. Two beam angles were strategically selected to provide complementary target coverage and plan robustness. The plan was compared with an independently developed photon plan and evaluated for robustness with respect to isocenter shifts, range shifts, and variation of the water-equivalent thickness of the port. The proton plan resulted in clinically acceptable target coverage and dosage to neighboring normal tissues. The D95% coverage was 95.3% in the nominal proton plan, with a worst-case coverage of 90.1% (when considering 0.3 cm isocenter shifts combined with 3.5% range uncertainty), and the coverage varied less than 1% under a hypothetically extreme variation of the port density. The proton plan had improved dose homogeneity compared with the photon plan, and reduced ipsilateral lung and mean heart doses. We demonstrated that a practical, field-specific intensity-modulated proton therapy (IMPT) optimization technique can be used to deal with the challenge of metal port in breast cancer patients with tissue expanders. The resulting proton plan has superior dosimetric characteristics over the best-case scenario photon plan, and is also robust to setup and proton range uncertainties.