Feasibility of Synchrotron-Based Ultra-High Dose Rate (UHDR) Proton Irradiation with Pencil Beam Scanning for FLASH Research.

BACKGROUND: This study aims to present the feasibility of developing a synchrotron-based proton ultra-high dose rate (UHDR) pencil beam scanning (PBS) system. METHODS: The RF extraction power in the synchrotron system was increased to generate 142.4 MeV pulsed proton beams for UHDR irradiation at ~100 nA beam current. The charge per spill was measured using a Faraday cup. The spill length and microscopic time structure of each spill was measured with a 2D strip transmission ion chamber. The measured UHDR beam fluence was used to derive the spot dwell time for pencil beam scanning. Absolute dose distributions at various depths and spot spacings were measured using Gafchromic films in a solid-water phantom. RESULTS: For proton UHDR beams at 142.4 MeV, the maximum charge per spill is 4.96 ± 0.10 nC with a maximum spill length of 50 ms. This translates to an average beam current of approximately 100 nA during each spill. Using a 2 × 2 spot delivery pattern, the delivered dose per spill at 5 cm and 13.5 cm depth is 36.3 Gy (726.3 Gy/s) and 56.2 Gy (1124.0 Gy/s), respectively. CONCLUSIONS: The synchrotron-based proton therapy system has the capability to deliver pulsed proton UHDR PBS beams. The maximum deliverable dose and field size per pulse are limited by the spill length and extraction charge.

Dosimetric characterization of a rotating anode x-ray tube for FLASH radiotherapy research.

PURPOSE: Most current research toward ultra-high dose rate (FLASH) radiation is conducted with advanced proton and electron accelerators, which are of limited accessibility to basic laboratory research. An economical alternative to charged particle accelerators is to employ high-capacity rotating anode x-ray tubes to produce kilovoltage x-rays at FLASH dose rates at short source-to-surface distances (SSD). This work describes a comprehensive dosimetric evaluation of a rotating anode x-ray tube for potential application in laboratory FLASH study. METHODS AND MATERIALS: A commercially available high-capacity fluoroscopy x-ray tube with 75 kW input power was implemented as a potential FLASH irradiator. Radiochromic EBT3 film and thermoluminescent dosimeters (TLDs) were used to investigate the effects of SSD and field size on dose rates and depth-dose characteristics in kV-compatible solid water phantoms. Custom 3D printed accessories were developed to enable reproducible phantom setup at very short SSD. Open and collimated radiation fields were assessed. RESULTS: Despite the lower x-ray energy and short SSD used, FLASH dose rates above 40 Gy/s were achieved for targets up to 10-mm depth in solid water. Maximum surface dose rates of 96 Gy/s were measured in the open field at 47 mm SSD. A non-uniform high-to-low dose gradient was observed in the planar dose distribution, characteristic of anode heel effects. With added collimation, beams up to 10-mm diameter with reasonable uniformity can be produced. Typical 80%-20% penumbra in the collimated x-ray FLASH beams were less than 1 mm at 5-mm depth in phantom. Ramp-up times at the maximum input current were less than 1 ms. CONCLUSION: Our dosimetric characterization demonstrates that rotating anode x-ray tube technology is capable of producing radiation beams in support of preclinical FLASH radiobiology research.

Inter-Breath-Hold Geometric and Dosimetric Variations in Organs at Risk during Pancreatic Stereotactic Body Radiotherapy: Implications for Adaptive Radiation Therapy.

Pancreatic cancer is the fourth leading cause of cancer-related death, with nearly 60,000 cases each year and less than a 10% 5-year overall survival rate. Radiation therapy (RT) is highly beneficial as a local-regional anticancer treatment. As anatomical variation is of great concern, motion management techniques, such as DIBH, are commonly used to minimize OARs toxicities; however, the variability between DIBHs has not been well studied. Here, we present an unprecedented systematic analysis of patients' anatomical reproducibility over multiple DIBH motion-management technique uses for pancreatic cancer RT. We used data from 20 patients; four DIBH scans were available for each patient to design 80 SBRT plans. Our results demonstrated that (i) there is considerable variation in OAR geometry and dose between same-subject DIBH scans; (ii) the RT plan designed for one scan may not be directly applicable to another scan; (iii) the RT treatment designed using a DIBH simulation CT results in different dosimetry in the DIBH treatment delivery; and (iv) this confirms the importance of adaptive radiation therapy (ART), such as MR-Linacs, for pancreatic RT delivery. The ART treatment delivery technique can account for anatomical variation between referenced and scheduled plans, and thus avoid toxicities of OARs because of anatomical variations between DIBH patient setups.

FLASH Effects Induced by Orthovoltage X-Rays.

PURPOSE: This work describes the first implementation and in vivo study of ultrahigh-dose-rate radiation (>37 Gy/s; FLASH) effects induced by kilovoltage (kV) x-ray from a rotating-anode x-ray source. METHODS AND MATERIALS: A high-capacity rotating-anode x-ray tube with an 80-kW generator was implemented for preclinical FLASH radiation research. A custom 3-dimensionally printed immobilization and positioning tool was developed for reproducible irradiation of a mouse hind limb. Calibrated Gafchromic (EBT3) film and thermoluminescent dosimeters (LiF:Mg,Ti) were used for in-phantom and in vivo dosimetry. Healthy FVB/N and FVBN/C57BL/6 outbred mice were irradiated on 1 hind leg to doses up to 43 Gy at FLASH (87 Gy/s) and conventional (CONV; <0.05 Gy/s) dose rates. The radiation doses were delivered using a single pulse with the widths up to 500 ms and 15 minutes at FLASH and CONV dose rates. Histologic assessment of radiation-induced skin damage was performed at 8 weeks posttreatment. Tumor growth suppression was assessed using a B16F10 flank tumor model in C57BL6J mice irradiated to 35 Gy at both FLASH and CONV dose rates. RESULTS: FLASH-irradiated mice experienced milder radiation-induced skin injuries than CONV-irradiated mice, visible by 4 weeks posttreatment. At 8 weeks posttreatment, normal tissue injury was significantly reduced in FLASH-irradiated animals compared with CONV-irradiated animals for histologic endpoints including inflammation, ulceration, hyperplasia, and fibrosis. No difference in tumor growth response was observed between FLASH and CONV irradiations at 35 Gy. The normal tissue sparing effects of FLASH irradiations were observed only for high-severity endpoint of ulceration at 43 Gy, which suggests the dependency of biologic endpoints to FLASH radiation dose. CONCLUSIONS: Rotating-anode x-ray sources can achieve FLASH dose rates in a single pulse with dosimetric properties suitable for small-animal experiments. We observed FLASH normal tissue sparing of radiation toxicities in mouse skin irradiated at 35 Gy with no sacrifice to tumor growth suppression. This study highlights an accessible new modality for laboratory study of the FLASH effect.

A method for generating intensity-modulated radiation therapy fields for small animal irradiators utilizing 3D-printed compensator molds.

PURPOSE: The purpose of this study was to investigate the feasibility of using fused deposition modeling (FDM) three-dimensional (3D) printer to generate radiation compensators for high-resolution (~1 mm) intensity-modulated radiation therapy (IMRT) for small animal radiation treatment. We propose a novel method incorporating 3D-printed compensator molds filled with NaI powder. METHODS: The inverse planning module of the computational environment for radiotherapy research (CERR) software was adapted to simulate the XRAD-225Cx irradiator, both geometry and kV beam quality (the latter using a phase space file provided for XRAD-225Cx). A nine-field IMRT treatment was created for a scaled-down version of the imaging and radiation oncology core (IROC) Head and Neck IMRT credentialing test, recreated on a 2.2-cm-diameter cylindrical phantom. Optimized fluence maps comprising nine fields and a total of 2564 beamlets were calculated at resolution of 1.25 × 1.25 mm2 . A hollow compensator mold was created (using in-house software and algorithm) for each field using 3D printing with polylactic acid (PLA) filaments. The molds were then packed with sodium iodide powder (NaI, measured density ρNaI  = 2.062 g/cm3 ). The mounted compensator mold thickness was limited to 13.8 mm due to clearance issues with couch collision. At treatment delivery, each compensator was manually mounted to a customized block tray attached to the reference 40 × 40 mm2 collimator. Compensator reproducibility among three repeated 3D-printed molds was measured with Radiochromic EBT2 film. The two-dimensional (2D) dose distributions of the nine fields were compared to calculated 2D doses from CERR using gamma comparisons with distance-to-agreement criteria of 0.5-0.25 mm and dose difference criteria of 3-5%. RESULTS: Good reproducibility of 3D-printed compensator manufacture was observed with mean error of ±0.024 Gy and relative dose error of ±4.2% within the modulated part of the beam. Within the limit of 13.8 mm compensator height, a maximum radiation blocking efficiency of 91.5% was achieved. Per field, about 45.5 g of NaI powder was used. Gamma analysis on each of the nine delivered IMRT fields using radiochromic films resulted in eight of nine treatment fields with >90% pass rate with 5%/0.5 mm tolerances. However, low gamma passing rate of 49-66% (3%/0.25 mm to 5%/0.5 mm) was noted in one field, attributed to fabrication errors resulting in over-filling the mold. The nine-field treatment plan was delivered in under 30 min with no mechanical or collisional issues. CONCLUSIONS: We show the feasibility of high spatial resolution IMRT treatment on a small animal irradiator utilizing 3D-printed compensator shells packed with NaI powder. Using the PLA mold with NaI powder was attractive due to the ease of 3D printing a PLA mold at high geometric resolution and the well-balanced attenuation properties of NaI powders that prevented the mold from becoming too bulky. IMRT fields with 1.25-mm resolution are capable with significant fluence modulation with relative dose accuracy of ±4.2%.

Development and Preliminary Evaluation of a Murine Model of Chronic Radiation-Induced Proctitis.

PURPOSE: Radiotherapy (RT) is commonly used to treat most pelvic malignancies. While treatment is often effective, curative radiation doses to the rectum can result in chronic radiation-induced proctitis, which is characterized by diarrhea, tenesmus, and/or rectal bleeding, recently termed pelvic radiation disease. An animal model of chronic radiation-induced proctitis would be useful to test both preventative and therapeutic strategies to limit this morbidity but has been elusive because of the high rodent mortality associated with acute bowel RT injury. The objective of this research was to develop a novel mouse model of chronic radiation-induced proctitis using advanced technology. METHODS AND MATERIALS: Using an X-RAD 225-Cx (Precision X-Ray) small animal irradiator, multiple plan configurations were evaluated for planning treatment volume and organ-at-risk avoidance to deliver a 15 Gy 3D conformal treatment plan. The final plan was verified by high resolution 3D dosimetry (PRESAGE/optical-CT), and delivered using a single arc. Mice were monitored for mortality for 250 days, followed by histopathological correlates including mucicarmine, Masson's trichrome, and fecal pellet length. RESULTS: Six beam arrangements were considered: single and parallel-opposed fields with whole-pelvis coverage, and collimated fields in parallel-opposed, 3-field, 4-field, and arc geometries. A collimated arc plan offered superior planning treatment volume coverage and organ-at-risk avoidance compared to whole-pelvis irradiation. Treatment verification with PRESAGE 3D dosimetry (Heuris Inc) showed >99% of voxels passing gamma analysis with 2%/2 mm criteria. Our treatment resulted in no acute mortality and 40% mortality at 250 days. Histopathological analysis showed increased mucous production and fibrosis of the irradiated colon, but no change in fecal pellet length. CONCLUSIONS: Our model was able to target successfully lower colon and rectum with lower mortality than other published models. This permitted measurement of late effects that recapitulate some features of rectal damage in humans.

A precision 3D conformal treatment technique in rats: Application to whole-brain radiotherapy with hippocampal avoidance.

PURPOSE: To develop and validate three-dimensional (3D) conformal hippocampal sparing whole-brain radiation therapy (HA-WBRT) for Wistar rats utilizing precision 3D-printed immobilization and micro-blocks. This technique paves the way for future preclinical studies investigating brain treatments that reduce neurotoxicity. METHODS AND MATERIALS: A novel preclinical treatment planning and delivery process was developed to enable precision 3D conformal treatment and hippocampal avoidance capability for the Xrad 225cx small animal irradiator. A range of conformal avoidance plans were evaluated consisting of equiangularly spaced coplanar axial beams, with plans containing 2, 4, 7, and 8 fields. The hippocampal sparing and coverage of these plans were investigated through Monte Carlo dose calculation (SmART-Plan Xrad 225cx planning system). Treatment delivery was implemented through a novel process where hippocampal block shapes were computer generated from an MRI rat atlas which was registered to on-board cone beam CT of the rat in treatment position. The blocks were 3D printed with a tungsten-doped filament at lateral resolution of 80 µm. Precision immobilization was achieved utilizing a 3D-printed support system which enabled angled positioning of the rat head in supine position and bite block to improve coverage of the central diencephalon. Treatment delivery was verified on rodent-morphic Presage® 3D dosimeters optically scanned at 0.2-mm isotropic resolution. Biological verification of hippocampal avoidance was performed with immunohistologic staining. RESULTS: All simulated plans spared the hippocampus while delivering high dose to the brain (22.5-26.2 Gy mean dose to brain at mean hippocampal dose of 7 Gy). No significant improvement in hippocampal sparing was observed by adding beams beyond four fields. Dosimetric sparing of hippocampal region of the four-field plan was verified with the Presage® dosimeter (mean dose = 9.6 Gy, D100% = 7.1 Gy). Simulation and dosimeter match at distance-to-agreement of 2 mm and dose difference of ±3% at 91.7% gamma passing rate (passing criteria of γ < 1). Agreement is less at 1 mm and ±5% at 69.0% gamma passing rate. The four-field plan was further validated with immunohistochemistry and showed a significant reduction in DNA double-strand breaks within the spared region compared with whole-brain irradiated groups (P = 0.021). However, coverage of the whole brain was low at 48.5-57.8% of the volume receiving 30Gy at 7Gy mean hippocampal dose in simulation and 46.7-52.5% in dosimetric measurements. This can be attributed to the shape of the rat hippocampus and the inability of treatment platform to employ non-coplanar beams. CONCLUSION: A novel approach for conformal microradiation therapy using 3D-printing technology was developed, implemented, and validated. A workflow was developed to generate accurate 3D-printed blocks from registered high-resolution rat MRI atlas structures. Although hippocampus was spared with this technique, whole-brain target coverage was suboptimal, indicating that non-coplanar beams and IMRT capability may be required to meet stringent dose criteria associated with current human RTOG trials.

Three-Dimensional Dosimetric Validation of a Magnetic Resonance Guided Intensity Modulated Radiation Therapy System.

PURPOSE: To validate the dosimetric accuracy of a commercially available magnetic resonance guided intensity modulated radiation therapy (MRgIMRT) system using a hybrid approach: 3-dimensional (3D) measurements and Monte Carlo calculations. METHODS AND MATERIALS: We used PRESAGE radiochromic plastic dosimeters with remote optical computed tomography readout to perform 3D high-resolution measurements, following a novel remote dosimetry protocol. We followed the intensity modulated radiation therapy commissioning recommendations of American Association of Physicists in Medicine Task Group 119, adapted to incorporate 3D data. Preliminary tests ("AP" and "3D-Bands") were delivered to 9.5-cm usable diameter cylindrical PRESAGE dosimeters to validate the treatment planning system (TPS) for nonmodulated deliveries; assess the sensitivity, uniformity, and rotational symmetry of the PRESAGE dosimeters; and test the robustness of the remote dosimetry protocol. Following this, 4 clinical MRgIMRT plans ("MultiTarget," "Prostate," "Head/Neck," and "C-Shape") were measured using 13-cm usable diameter PRESAGE dosimeters. For all plans, 3D-γ (3% or 3 mm global, 10% threshold) passing rates were calculated and 3D-γ maps were examined. Point doses were measured with an IBA-CC01 ionization chamber for validation of absolute dose. Finally, by use of an in-house-developed, GPU-accelerated Monte Carlo algorithm (gPENELOPE), we independently calculated dose for all 6 Task Group 119 plans and compared against the TPS. RESULTS: For PRESAGE measurements, 3D-γ analysis yielded passing rates of 98.7%, 99.2%, 98.5%, 98.0%, 99.2%, and 90.7% for AP, 3D-Bands, MultiTarget, Prostate, Head/Neck, and C-Shape, respectively. Ion chamber measurements were within an average of 0.5% (±1.1%) from the TPS dose. Monte Carlo calculations demonstrated good agreement with the TPS, with a mean 3D-γ passing rate of 98.5% ± 1.9% using a stricter 2%/2-mm criterion. CONCLUSIONS: We have validated the dosimetric accuracy of a commercial MRgIMRT system using high-resolution 3D techniques. We have demonstrated for the first time that hybrid 3D remote dosimetry is a comprehensive and feasible approach to commissioning MRgIMRT. This may provide better sensitivity in error detection compared with standard 2-dimensional measurements and could be used when implementing complex new magnetic resonance guided radiation therapy technologies.

Investigations into the feasibility of optical-CT 3D dosimetry with minimal use of refractively matched fluids.

PURPOSE: In optical-CT, the use of a refractively matched polyurethane solid-tank in place of a fluid bath has the potential to greatly increase practical convenience, reduce cost, and possibly improve the efficacy of flood corrections. This work investigates the feasibility of solid-tank optical-CT imaging for 3D dosimetry through computer simulation. METHODS: A matlab ray-tracing simulation platform, ScanSim, was used to model a parallel-source telecentric optical-CT imaging system through a polyurethane solid-tank containing a central cylindrical hollow into which PRESAGE radiochromic dosimeters can be placed. A small amount of fluid fills the 1-5 mm gap between the dosimeter and the walls of the tank. The use of the solid-tank reduces the required amount of fluid by approximately 97%. To characterize the efficacy of solid-tank, optical-CT scanning simulations investigated sensitivity to refractive index (RI) mismatches between dosimeter, solid-tank, and fluid, for a variety of dosimeter (RI = 1.5-1.47) and fluid (RI = 1.55-1.0) combinations. Efficacy was evaluated through the usable radius (ru) metric, defined as the fraction of the radius of the dosimeter where measured dose is predicted to be within 2% of the ground truth entered into the simulation. Additional simulations examined the effect of increasing gap size (1-5 mm) between the dosimeter and solid-tank well. The effects of changing the lens tolerance (0.5°-5.0°) were also investigated. RESULTS: As the RI mismatch between the dosimeter and solid-tank increased from 0 to 0.02, the usable radius decreased from 97.6% to 50.2%. The optimal fluid RI decreased nonlinearly from 1.5 to 1.34 as the mismatch increased and was up to 9% lower than the tank. Media mismatches between the dosimeter and solid-tank also exacerbate the effects of changing the gap size, with no easily quantifiable relationship with usable radius. Generally, the optimal fluid RI value increases as gap size increases and is closely matched to the dosimeter at large gap sizes (> 3 mm). Increasing the telecentric lens tolerance increases the usable radius for all refractive media combinations and improves the maximum usable radius of mismatched media to that of perfectly matched media for tolerances > 5.0°. The maximum usable radius can be improved up to a factor of 2 when lens tolerances are small (< 1.0°). CONCLUSIONS: Dry solid-tank optical-CT imaging in a telecentric system is feasible if the dosimeter RI is a close match with the solid-tank (< 0.01 difference), providing accurate dose measurements within ± 2% of true dose to over 80% of the dosimeter volume. In order to achieve accurate measurements over 96% of the dosimeter volume (representing out to 2 mm from the dosimeter edge), the dosimeter-tank RI mismatch must be less than 0.005. Optimal results occur when the RI of the dosimeter and tank is the same, in which case the fluid will have the same RI. If mismatches between the tank and dosimeter RI occur, the RI of the matching fluid needs to be fine tuned to achieve the highest usable radius.