Multi-institutional consensus on machine QA for isochronous cyclotron-based systems delivering ultra-high dose rate (FLASH) pencil beam scanning proton therapy in transmission mode.

BACKGROUND: The first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST-01, FAST-02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG-224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra-high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect. PURPOSE: The aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied. METHODS: A risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed. RESULTS: The risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG-224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus. CONCLUSIONS: Consensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron-based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedures.

Absolute dosimetry for FLASH proton pencil beam scanning radiotherapy.

A paradigm shift is occurring in clinical oncology exploiting the recent discovery that short pulses of ultra-high dose rate (UHDR) radiation-FLASH radiotherapy-can significantly spare healthy tissues whilst still being at least as effective in curing cancer as radiotherapy at conventional dose rates. These properties promise reduced post-treatment complications, whilst improving patient access to proton beam radiotherapy and reducing costs. However, accurate dosimetry at UHDR is extremely complicated. This work presents measurements performed with a primary-standard proton calorimeter and derivation of the required correction factors needed to determine absolute dose for FLASH proton beam radiotherapy with an uncertainty of 0.9% (1[Formula: see text]), in line with that of conventional treatments. The establishment of a primary standard for FLASH proton radiotherapy improves accuracy and consistency of the dose delivered and is crucial for the safe implementation of clinical trials, and beyond, for this new treatment modality.

Proton FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases: The FAST-01 Nonrandomized Trial.

Importance: To our knowledge, there have been no clinical trials of ultra-high-dose-rate radiotherapy delivered at more than 40 Gy/sec, known as FLASH therapy, nor first-in-human use of proton FLASH. Objectives: To assess the clinical workflow feasibility and treatment-related toxic effects of FLASH and pain relief at the treatment sites. Design, Setting, and Participants: In the FAST-01 nonrandomized trial, participants treated at Cincinnati Children's/UC Health Proton Therapy Center underwent palliative FLASH radiotherapy to extremity bone metastases. Patients 18 years and older with 1 to 3 painful extremity bone metastases and life expectancies of 2 months or more were eligible. Patients were excluded if they had foot, hand, and wrist metastases; metastases locally treated in the 2 weeks prior; metal implants in the treatment field; known enhanced tissue radiosensitivity; and implanted devices at risk of malfunction with radiotherapy. One of 11 patients who consented was excluded based on eligibility. The end points were evaluated at 3 months posttreatment, and patients were followed up through death or loss to follow-up for toxic effects and pain assessments. Of the 10 included patients, 2 died after the 2-month follow-up but before the 3-month follow-up; 8 participants completed the 3-month evaluation. Data were collected from November 3, 2020, to January 28, 2022, and analyzed from January 28, 2022, to September 1, 2022. Interventions: Bone metastases were treated on a FLASH-enabled (≥40 Gy/sec) proton radiotherapy system using a single-transmission proton beam. This is consistent with standard of care using the same prescription (8 Gy in a single fraction) but on a conventional-dose-rate (approximately 0.03 Gy/sec) photon radiotherapy system. Main Outcome and Measures: Main outcomes included patient time on the treatment couch, device-related treatment delays, adverse events related to FLASH, patient-reported pain scores, and analgesic use. Results: A total of 10 patients (age range, 27-81 years [median age, 63 years]; 5 [50%] male) underwent FLASH radiotherapy at 12 metastatic sites. There were no FLASH-related technical issues or delays. The average (range) time on the treatment couch was 18.9 (11-33) minutes per patient and 15.8 (11-22) minutes per treatment site. Median (range) follow-up was 4.8 (2.3-13.0) months. Adverse events were mild and consistent with conventional radiotherapy. Transient pain flares occurred in 4 of the 12 treated sites (33%). In 8 of the 12 sites (67%) patients reported pain relief, and in 6 of the 12 sites (50%) patients reported a complete response (no pain). Conclusions and Relevance: In this nonrandomized trial, clinical workflow metrics, treatment efficacy, and safety data demonstrated that ultra-high-dose-rate proton FLASH radiotherapy was clinically feasible. The treatment efficacy and the profile of adverse events were comparable with those of standard-of-care radiotherapy. These findings support the further exploration of FLASH radiotherapy in patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT04592887.

FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases (FAST-01): Protocol for the First Prospective Feasibility Study.

BACKGROUND: In preclinical studies, FLASH therapy, in which radiation delivered at ultrahigh dose rates of ≥40 Gy per second, has been shown to cause less injury to normal tissues than radiotherapy delivered at conventional dose rates. This paper describes the protocol for the first-in-human clinical investigation of proton FLASH therapy. OBJECTIVE: FAST-01 is a prospective, single-center trial designed to assess the workflow feasibility, toxicity, and efficacy of FLASH therapy for the treatment of painful bone metastases in the extremities. METHODS: Following informed consent, 10 subjects aged ≥18 years with up to 3 painful bone metastases in the extremities (excluding the feet, hands, and wrists) will be enrolled. A treatment field selected from a predefined library of plans with fixed field sizes (from 7.5 cm × 7.5 cm up to 7.5 cm × 20 cm) will be used for treatment. Subjects will receive 8 Gy of radiation in a single fraction-a well-established palliative regimen evaluated in prior investigations using conventional dose rate photon radiotherapy. A FLASH-enabled Varian ProBeam proton therapy unit will be used to deliver treatment to the target volume at a dose rate of ≥40 Gy per second, using the plateau (transmission) portion of the proton beam. After treatment, subjects will be assessed for pain response as well as any adverse effects of FLASH radiation. The primary end points include assessing the workflow feasibility and toxicity of FLASH treatment. The secondary end point is pain response at the treated site(s), as measured by patient-reported pain scores, the use of pain medication, and any flare in bone pain after treatment. The results will be compared to those reported historically for conventional dose rate photon radiotherapy, using the same radiation dose and fractionation. RESULTS: FAST-01 opened to enrollment on November 3, 2020. Initial results are expected to be published in 2022. CONCLUSIONS: The results of this investigation will contribute to further developing and optimizing the FLASH-enabled ProBeam proton therapy system workflow. The pain response and toxicity data acquired in our study will provide a greater understanding of FLASH treatment effects on tumor responses and normal tissue toxicities, and they will inform future FLASH trial designs. TRIAL REGISTRATION: : ClinicalTrials.gov NCT04592887; http://clinicaltrials.gov/ct2/show/NCT04592887. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41812.

Evaluation of a conventionally shielded proton treatment room for FLASH radiotherapy.

PURPOSE: FLASH radiotherapy (FLASH-RT) is the potential for a major breakthrough in cancer care, as preclinical results have shown significantly reduced toxicities to healthy tissues while maintaining excellent tumor control. However, FLASH conditions were not considered in the current proton facilities' shielding designs. The purpose of this study is to validate the adequacy of conventionally shielded proton rooms used for FLASH-RT. METHODS: Clinical FLASH irradiations typically take place in a few 100 ms, orders of magnitude shorter than the response time of the wide-energy neutron detector (WENDI-II). The nozzle beam current (representing the dose rate) dependence of the WENDI-II detector response was empirically determined to stabilize with a beam current of ≤10 nA at the measurement point with the highest dose rate. A large, predefined proton transmission FLASH plan (250 MeV, 7 × 20 cm2 , 8 Gy at isocenter) was commissioned as part of a FLASH clinical trial. For purpose of this study, that field was adjusted from 250 to 244 MeV, allowing a lower beam current of 10 nA to provide reliable detector response. Radiation surveys were performed for the proton beams with/without extra beam stopper (30 × 30 × 40-cm3 solid water slabs) at 0°, 90°, 180°, and 270° gantry angles. RESULTS: Ambient doses were recorded at seven different locations. A 170-nA beam current, commonly used for clinical FLASH plans, was chosen to normalize the average ambient dose rate to FLASH conditions. Assuming 200-Gy/h workload (25 FLASH beams, 8 Gy/beam), annual occupational dose at controlled areas was calculated. For all gantry angles, ≤0.4 mSv/year is expected at treatment room door. The highest ambient dose, 2.46 mSv/year, ∼5% of the maximum annual permissible occupational dose, was identified at the isocenter of the adjacent treatment room with 90° gantry. CONCLUSION: These survey results indicate that our conventionally shielded proton rotating gantry rooms result in acceptable occupational and public doses when the transmission FLASH beams delivered at four cardinal gantry angles based on 200-Gy/h workload assumption. These findings support that FLASH clinical trials in our conventionally shielded proton facilities can be safely implemented.

Ultrahigh dose rate pencil beam scanning proton dosimetry using ion chambers and a calorimeter in support of first in-human FLASH clinical trial.

PURPOSE: To provide ultrahigh dose rate (UHDR) pencil beam scanning (PBS) proton dosimetry comparison of clinically used plane-parallel ion chambers, PTW (Physikalisch-Technische Werkstaetten) Advanced Markus and IBA (Ion Beam Application) PPC05, with a proton graphite calorimeter in a support of first in-human proton FLASH clinical trial. METHODS: Absolute dose measurement intercomparison of the plane-parallel plate ion chambers and the proton graphite calorimeter was performed at 5-cm water-equivalent depth using rectangular 250-MeV single-layer treatment plans designed for the first in-human FLASH clinical trial. The dose rate for each field was designed to remain above 60 Gy/s. The ion recombination effects of the plane-parallel plate ion chambers at various bias voltages were also investigated in the range of dose rates between 5 and 60 Gy/s. Two independent model-based extrapolation methods were used to calculate the ion recombination correction factors ks to compare with the two-voltage technique from most widely used clinical protocols. RESULTS: The mean measured dose to water with the proton graphite calorimeter across all the predefined fields is 7.702 ± 0.037 Gy. The average ratio over the predefined fields of the PTW Advanced Markus chamber dose to the calorimeter reference dose is 1.002 ± 0.007, whereas the IBA PPC05 chamber shows ∼3% higher reading of 1.033 ± 0.007. The relative differences in the ks values determined from between the linear and quadratic extrapolation methods and the two-voltage technique for the PTW Advanced Markus chamber are not statistically significant, and the trends of dose rate dependence are similar. The IBA PPC05 shows a flat response in terms of ion recombination effects based on the ks values calculated using the two-voltage technique. Differences in ks values for the PPC05 between the two-voltage technique and other model-based extrapolation methods are not statistically significant at FLASH dose rates. Some of the ks values for the PPC05 that were extrapolated from the three-voltage linear method and the semiempirical model were reported less than unity possibly due to the charge multiplication effect, which was negligible compared to the volume recombination effect in FLASH dose rates. CONCLUSIONS: The absolute dose measurements of both PTW Advanced Markus and IBA PPC05 chambers are in a good agreement with the National Physical Laboratory graphite calorimeter reference dose considering overall uncertainties. Both ion chambers also demonstrate good reproducibility as well as stability as reference dosimeters in UHDR PBS proton radiotherapy. The dose rate dependency of the ion recombination effects of both ion chambers in cyclotron generated PBS proton beams is acceptable and therefore, both chambers are suitable to use in clinical practice for the range of dose rates between 5 and 60 Gy/s.

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.

Biological and dosimetric characterisation of spatially fractionated proton minibeams.

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30-109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02-1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

Functional lung avoidance and response-adaptive escalation (FLARE) RT: Multimodality plan dosimetry of a precision radiation oncology strategy.

PURPOSE: Nonsmall cell lung cancer (NSCLC) patient radiation therapy (RT) is planned without consideration of spatial heterogeneity in lung function or tumor response. We assessed the dosimetric and clinical feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [99m Tc]MAA-SPECT/CT perfused lung while redistributing an escalated boost dose within [18 F]FDG-PET/CT-defined biological target volumes (BTV). METHODS: Eight stage IIB-IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain < 20 Gy mean lung dose (MLD). Prescriptions included 60 Gy to the planning target volume (PTV) and concomitant boost of 74 Gy mean to biological target volumes (BTV = GTV + PET gradient segmentation) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial treatment planning systems via uptake threshold discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with volumetric modulated arc therapy (VMAT), proton pencil beam scanning (PBS) with 3%-3 mm robust optimization, and combination of PBS (avoidance) plus VMAT (escalation). The high boost dose region was evaluated within a standardized SUVpeak structure. FLARE RT plans were compared to reference VMAT plans. Linear regression between radiation dose to BTV and normalized FDG PET SUV at every voxel was conducted, from which Pearson linear correlation coefficients and regression slopes were extracted. Spearman rank correlation coefficients were estimated between radiation dose to lung and normalized SPECT uptake. Dosimetric differences between treatment modalities were evaluated by Friedman nonparametric paired test with multiple sampling correction. RESULTS: No unacceptable violations of PTV and normal tissue objectives were observed in 24 FLARE RT plans. Compared to reference VMAT plans, FLARE VMAT plans achieved a higher mean dose to BTV (73.7 Gy 98195. 61.3 Gy), higher mean dose to SUVpeak (89.7 Gy vs. 60.8 Gy), and lower mean dose to highly perfused lung (7.3 Gy vs. 14.9 Gy). These dosimetric gains came at the expense of higher mean heart dose (9.4 Gy vs. 5.8 Gy) and higher maximum cord dose (50.1 Gy vs. 44.6 Gy) relative to the reference VMAT plans. Between FLARE plans, FLARE VMAT achieved higher dose to the SUVpeak ROI than FLARE PBS (89.7 Gy vs. 79.2 Gy, P = 0.01), while FLARE PBS delivered lower dose to lung than FLARE VMAT (11.9 Gy vs. 15.6 Gy, P < 0.001). Voxelwise linear dose redistribution slope between BTV dose and FDG PET uptake was higher in magnitude for FLARE PBS + VMAT (0.36 Gy per %SUVmax ) compared to FLARE VMAT (0.27 Gy per %SUVmax ) or FLARE PBS alone (0.17 Gy per %SUVmax ). CONCLUSIONS: FLARE RT is clinically feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG PET dose escalation balanced target and normal tissue objective tradeoffs. These results provide a technical platform for testing of FLARE RT safety and efficacy within a precision radiation oncology trial.

Collimator design for spatially-fractionated proton beams for radiobiology research.

Preclinical and translational research is an imperative to improve the efficacy of proton radiotherapy. We present a feasible and practical method to produce spatially-modulated proton beams for cellular and small animal research for clinical and research facilities. The University of Washington (UW) 50.5 MeV proton research beamline hosting a brass collimation system was modeled using Monte Carlo simulations. This collimator consisted of an array of 2 cm long slits to cover an area of 2 × 2 cm(2). To evaluate the collimator design effects on dose rate, valley dose and the peak-to-valley dose ratios (PVDR) the following parameters were varied; slit width (0.1-1.0 mm), peak center-to-center distance (1-3 mm), collimator thickness (1-7 cm) and collimator location along the beam axis. Several combinations of slit widths and 1 mm spacing achieved uniform dose at the Bragg peak while maintaining spatial modulation on the beam entrance. A more detailed analysis was carried out for the case of a slit width of 0.3 mm, peak center-to-center distance of 1 mm, a collimator thickness of 5 cm and with the collimator flush against the water phantom. The dose rate at 5 mm depth dropped relative to an open field by a factor of 12 and produced a PVDR of 10.1. Technical realization of proton mini-beams for radiobiology small animal research is demonstrated to be feasible. It is possible to obtain uniform dose at depth while maintaining reasonable modulation at shallower depths near the beam entrance. While collimator design is important the collimator location has a strong influence on the entrance region PVDRs and on dose rate. These findings are being used to manufacture a collimator for installation on the UW cyclotron proton beam nozzle. This collimator will enable comparative studies on the radiobiological efficacy of x-rays and proton beams.

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.

Design Optimization of a TOF, Breast PET Scanner.

A dedicated breast positron emission tomography (PET) scanner with limited angle geometry can provide flexibility in detector placement around the patient as well as the ability to combine it with other imaging modalities. A primary challenge of a stationary limited angle scanner is the reduced image quality due to artifacts present in the reconstructed image leading to a loss in quantitative information. Previously it has been shown that using time-of-flight (TOF) information in image reconstruction can help reduce these image artifacts arising due to missing angular projections. Our goal in this work is to optimize the TOF, breast scanner design by performing studies for estimating image uniformity and lesion activity uptake as a function of system timing resolution, scanner angular coverage and shape. Our results show that (i) 1.5 × 1.5 × 15 mm3 lutetium oxy-orthosilicate (LSO) crystals provide a high spatial resolution and system sensitivity relative to clinical scanners, (ii) 2/3 angular coverage scanner design with TOF timing resolution less than 600 ps is appropriate for providing a tomographic image with fewer artifacts and good lesion uptake estimation relative to other partial ring designs studied in this work, (iii) a flat scanner design with 2/3 angular coverage is affected more by larger parallax error than a curved scanner geometry with the same angular coverage, but provides more uniform lesion contrast estimate over the imaging field-of-view (FOV), (iv) 2/3 angular coverage, flat, 300 ps TOF scanner design (for short, practical scan times of ≤ 5 mins per breast) provides similar precision of contrast recovery coefficient (CRC) values to a full curved, non-TOF scanner, and (v) employing depth-of-interaction (DOI) measuring detector and/or implementing resolution modeling (RM) in image reconstruction lead to improved and more uniform spatial resolution and lesion contrast over the whole FOV.