Per-fraction positional and dosimetric performance of prone breast tangential radiotherapy on Halcyon™ linear accelerator assessed with daily rapid kilo-voltage cone beam computed tomography: a single-institution pilot study.

BACKGROUND: This study investigates daily breast geometry and delivered dose to prone-positioned patients undergoing tangential whole breast radiation therapy (WBRT) on an O-ring linear accelerator with 6X flattening filter free mode (6X-FFF), planned with electronic compensation (ECOMP) method. Most practices rely on skin marks or daily planar image matching for prone breast WBRT. This system provides low dose daily CBCT, which was used to study daily robustness of delivered dose parameters for prone-positioned WBRT. METHODS: Eight patients treated with 16-fraction prone-breast WBRT were retrospectively studied. Planning CTs were deformed to daily CBCT to generate daily synthetic CTs, on which delivered dose distributions were calculated. A total of 8 × 16 = 128 synthetic CTs were generated. Consensus ASTRO definition was used to contour Breast PTV Eval for each daily deformed CT. Breast PTV Eval coverage (V90%) and hotspot (V105% and Dmax) were monitored daily to compare prescription dose with daily delivered dose. Various predictors including patient weight, breast width diameter (BWD), and Dice similarity coefficient (DSC) were fit into an analysis of covariance model predicting V90% and V105% deviation from prescribed (ΔV90%, ΔV105%). Statistical significance is indicated with asterisks (* for p < 0.05; ** for p < 0.001). RESULTS: Daily delivered Breast PTV Eval V90% was moderately smaller than prescribed (median ΔV90% = - 0.1%*), while V105% was much larger (median ΔV105% = + 10.1%** or + 92.4 cc**). Patient's weight loss correlated with significantly increased ΔV105% (+ 4.6%/ - 1% weight, R2 = 0.4**) and moderately decreased ΔV90% (- 0.071%/ - 1% wt., R2 = 0.2**). Comprehensive ANCOVA models indicated three factors affect ΔV90% and ΔV105% the most: (1) BWD decrease (- 0.09%* and + 10%**/ - 1 cm respectively), (2) PTV Eval volume decrease (- 0.4%** and + 9%**/ - 100 cc), and for ΔV105% only, (3) the extent of breast deformation (+ 10%**/ - 0.01 DSC). Breast PTV Eval volume also decreased with time (- 2.21*cc/fx), possibly indicating seroma resolution and increase in V105% over time. CONCLUSIONS: Daily CBCT revealed key delivered dose parameters vary significantly for patients undergoing tangential prone breast WBRT planned with ECOMP using 6X-FFF. Patient weight, BWD, and breast shape deformation could be used to predict dosimetric variations from prescribed. Preliminary findings suggest an adaptive plan based on daily CBCT could reduce excessive dose to the breast.

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%.

Evaluation of UVA emission from x-ray megavoltage-irradiated tissues and phantoms.

RECA (Radiotherapy enhanced with Cherenkov photo-activation) is a proposed treatment where the anti-cancer drug psoralen is photo-activated in situ by UVA (Ultraviolet A, 320-400 nm) Cherenkov light (CL) produced directly by the treatment beam itself. In this study, we develop a UVA-imaging technique to quantify relative UVA CL produced by bulk tissues and other phantoms upon clinical x-ray megavoltage irradiation. UVA CL emission (320-400 nm) was quantified in tissue samples of porcine and poultry and in two kinds of solid waters (SW): brown (Virtual Waters, Standard Imaging, WI) and white (Diagnostic Therapy, CIRS, VA), and in 1% agarose gels variously doped with absorbing dye. Quantification was achieved through cumulative imaging of the samples placed in a dark, light-blocking chamber during irradiation on a Varian 21 EX accelerator. UVA imaging required a specialized high-sensitivity cooled camera equipped with UVA lenses and a filter. At 15 MV, white SW emitted [Formula: see text], [Formula: see text] and [Formula: see text] less UVA than chicken breast, pork loin and pork belly, respectively. Similar under-response was observed at 6 MV. Brown SW had [Formula: see text] less UVA emission than white SW at 15 MV, and negligible emission at 6 MV. Agarose samples (1% by weight) doped with 250 ppm India ink exhibited equivalent UVA CL emission to chicken breast (within 8%). The results confirm that for the same absorbed dose, SW emits less UVA light than the tissue samples, indicating that prior in vitro studies utilizing SW as the CL-generating source may have underestimated the RECA therapeutic effect. Agarose doped with 250 ppm India ink is a convenient tissue-equivalent phantom for further work.

Technical Note: On maximizing Cherenkov emissions from medical linear accelerators.

PURPOSE: Cherenkov light during MV radiotherapy has recently found imaging and therapeutic applications but is challenged by relatively low fluence. Our purpose is to investigate the feasibility of increasing Cherenkov light production during MV radiotherapy by increasing photon energy and applying specialized beam-hardening filtration. METHODS: GAMOS 5.0.0, a GEANT4-based framework for Monte Carlo simulations, was used to model standard clinical linear accelerator primary photon beams. The photon source was incident upon a 17.8 cm3 cubic water phantom with a 94 cm source to surface distance. Dose and Cherenkov production was determined at depths of 3-9 cm. Filtration was simulated 15 cm below the photon beam source. Filter materials included aluminum, iron, and copper with thicknesses of 2-20 cm. Histories used depended on the level of attenuation from the filter, ranging from 100 million to 2 billion. Comparing average dose per history also allowed for evaluation of dose-rate reduction for different filters. RESULTS: Overall, increasing photon beam energy is more effective at improving Cherenkov production per unit dose than is filtration, with a standard 18 MV beam yielding 3.3-4.0× more photons than 6 MV. Introducing an aluminum filter into an unfiltered 2400 cGy/min 10 MV beam increases the Cherenkov production by 1.6-1.7×, while maintaining a clinical dose rate of 300 cGy/min, compared to increases of ~1.5× for iron and copper. Aluminum was also more effective than the standard flattening filter, with the increase over the unfiltered beam being 1.4-1.5× (maintaining 600 cGy/min dose rate) vs 1.3-1.4× for the standard flattening filter. Applying a 10 cm aluminum filter to a standard 18 MV, photon beam increased the Cherenkov production per unit dose to 3.9-4.3× beyond that of 6 MV (vs 3.3-4.0× for 18 MV with no aluminum filter). CONCLUSIONS: Through a combination of increasing photon energy and applying specialized beam-hardening filtration, the amount of Cherenkov photons per unit radiotherapy dose can be increased substantially.

Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy.

PURPOSE: This work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions. METHODS AND MATERIALS: In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation. RESULTS: Luminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P << .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present. CONCLUSION: This work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam.

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.

Measuring diffusion limitation with a perfusion-limited gas--hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis.

Although xenon is classically taught to be a "perfusion-limited" gas, (129)Xe in its hyperpolarized (HP) form, when detected by magnetic resonance (MR), can probe diffusion limitation. Inhaled HP (129)Xe diffuses across the pulmonary blood-gas barrier, and, depending on its tissue environment, shifts its resonant frequency relative to the gas-phase reference (0 ppm) by 198 ppm in tissue/plasma barrier and 217 ppm in red blood cells (RBCs). In this work, we hypothesized that in patients with idiopathic pulmonary fibrosis (IPF), the ratio of (129)Xe spectroscopic signal in the RBCs vs. barrier would diminish as diffusion-limitation delayed replenishment of (129)Xe magnetization in RBCs. To test this hypothesis, (129)Xe spectra were acquired in 6 IPF subjects as well as 11 healthy volunteers to establish a normal range. The RBC:barrier ratio was 0.55 ± 0.13 in healthy volunteers but was 3.3-fold lower in IPF subjects (0.16 ± 0.03, P = 0.0002). This was caused by a 52% reduction in the RBC signal (P = 0.02) and a 58% increase in the barrier signal (P = 0.01). Furthermore, the RBC:barrier ratio strongly correlated with lung diffusing capacity for carbon monoxide (DLCO) (r = 0.89, P < 0.0001). It exhibited a moderate interscan variability (8.25%), and in healthy volunteers it decreased with greater lung inflation (r = -0.78, P = 0.005). This spectroscopic technique provides a noninvasive, global probe of diffusion limitation and gas-transfer impairment and forms the basis for developing 3D MR imaging of gas exchange.