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Title: TU-H-CAMPUS-TeP2-02: FLASH Irradiation Improves the Therapeutic Index Following GI Tract Irradiation

Abstract

Purpose: To investigate and characterize the radiobiological effectiveness of very high dose rate radiotherapy (FLASH) compared to conventional irradiation in an in vivo model. Methods: The gastrointestinal (GI) tract of C57BL/6 mice were irradiated with doses ranging between 10 and 18 Gy using a custom stereotactic jig. A Varian Clinac 21EX was modified to allow dose rates ranging from 0.05 to 240 Gy/s at the position of the mirror. With the gantry at 180 degrees, the jig holding the individual animals was placed above the mirror to take advantage of the reduced source to target distance. Mice were irradiated with 20MeV electrons. Following irradiation, the mice were monitored twice daily for morbidity and daily for weight changes. Results: Mice irradiated with FLASH irradiation had lower weight loss compared to the mice receiving conventional irradiation. Following FLASH irradiation, a maximum weight loss of ∼20% was observed at day 6 with subsequent recovery, while following conventional irradiation, higher weight losses was observed with fewer instances of recovery. Concerning survival, all mice in the conventionally irradiated groups had a 100% mortality in the range of 15.5–18 Gy, while the mice irradiated with FLASH irradiation had a 100% survival in the same range. Conclusion:more » These results have demonstrated proof of principle that FLASH irradiations have a dramatic impact on the overall survival of mice following GI tract irradiations. If the increase in the therapeutic window can be validated and understood, this would revolutionize the field of radiation oncology and lead to increased cure rates with reduced side effects following treatment, resulting in increased quality of life for cancer survivors. Funding: DoD, Award#:W81XWH-14-1-0014, Weston Havens Foundation, Bio-X (Stanford University), the Office of the Dean of the Medical School, the Office of the Provost (Stanford University), and the Swedish Childhood Cancer Foundation; BL and PM are founders of TibaRay,Inc.; BL and PM have received research grants from Varian and RaySearch Laboratory.« less

Authors:
; ; ; ; ; ;  [1]
  1. Stanford University School of Medicine, Palo Alto, California (United States)
Publication Date:
OSTI Identifier:
22654066
Resource Type:
Journal Article
Resource Relation:
Journal Name: Medical Physics; Journal Volume: 43; Journal Issue: 6; Other Information: (c) 2016 American Association of Physicists in Medicine; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 61 RADIATION PROTECTION AND DOSIMETRY; DISEASE INCIDENCE; DOSE RATES; EDUCATIONAL FACILITIES; IRRADIATION; MICE; RADIOTHERAPY; RATS; SIDE EFFECTS

Citation Formats

Schueler, E, Trovati, S, King, G, Lartey, F, Rafat, M, Loo, B, and Maxim, P. TU-H-CAMPUS-TeP2-02: FLASH Irradiation Improves the Therapeutic Index Following GI Tract Irradiation. United States: N. p., 2016. Web. doi:10.1118/1.4957690.
Schueler, E, Trovati, S, King, G, Lartey, F, Rafat, M, Loo, B, & Maxim, P. TU-H-CAMPUS-TeP2-02: FLASH Irradiation Improves the Therapeutic Index Following GI Tract Irradiation. United States. doi:10.1118/1.4957690.
Schueler, E, Trovati, S, King, G, Lartey, F, Rafat, M, Loo, B, and Maxim, P. Wed . "TU-H-CAMPUS-TeP2-02: FLASH Irradiation Improves the Therapeutic Index Following GI Tract Irradiation". United States. doi:10.1118/1.4957690.
@article{osti_22654066,
title = {TU-H-CAMPUS-TeP2-02: FLASH Irradiation Improves the Therapeutic Index Following GI Tract Irradiation},
author = {Schueler, E and Trovati, S and King, G and Lartey, F and Rafat, M and Loo, B and Maxim, P},
abstractNote = {Purpose: To investigate and characterize the radiobiological effectiveness of very high dose rate radiotherapy (FLASH) compared to conventional irradiation in an in vivo model. Methods: The gastrointestinal (GI) tract of C57BL/6 mice were irradiated with doses ranging between 10 and 18 Gy using a custom stereotactic jig. A Varian Clinac 21EX was modified to allow dose rates ranging from 0.05 to 240 Gy/s at the position of the mirror. With the gantry at 180 degrees, the jig holding the individual animals was placed above the mirror to take advantage of the reduced source to target distance. Mice were irradiated with 20MeV electrons. Following irradiation, the mice were monitored twice daily for morbidity and daily for weight changes. Results: Mice irradiated with FLASH irradiation had lower weight loss compared to the mice receiving conventional irradiation. Following FLASH irradiation, a maximum weight loss of ∼20% was observed at day 6 with subsequent recovery, while following conventional irradiation, higher weight losses was observed with fewer instances of recovery. Concerning survival, all mice in the conventionally irradiated groups had a 100% mortality in the range of 15.5–18 Gy, while the mice irradiated with FLASH irradiation had a 100% survival in the same range. Conclusion: These results have demonstrated proof of principle that FLASH irradiations have a dramatic impact on the overall survival of mice following GI tract irradiations. If the increase in the therapeutic window can be validated and understood, this would revolutionize the field of radiation oncology and lead to increased cure rates with reduced side effects following treatment, resulting in increased quality of life for cancer survivors. Funding: DoD, Award#:W81XWH-14-1-0014, Weston Havens Foundation, Bio-X (Stanford University), the Office of the Dean of the Medical School, the Office of the Provost (Stanford University), and the Swedish Childhood Cancer Foundation; BL and PM are founders of TibaRay,Inc.; BL and PM have received research grants from Varian and RaySearch Laboratory.},
doi = {10.1118/1.4957690},
journal = {Medical Physics},
number = 6,
volume = 43,
place = {United States},
year = {Wed Jun 15 00:00:00 EDT 2016},
month = {Wed Jun 15 00:00:00 EDT 2016}
}
  • Purpose: To evaluate the use of post-irradiation changes in respiratory rate and CBCT-based morphology as predictors of survival in mice. Methods: C57L/J mice underwent whole-thorax irradiation with a Co-60 beam to four different doses [0Gy (n=3), 9Gy (n=5), 11Gy (n=7), and 13Gy (n=5)] in order to induce varying levels of pneumonitis. Respiratory rate measurements, breath-hold CBCTs, and free-breathing CBCTs were acquired pre-irradiation and at six time points between two and seven months post-irradiation. For respiratory rate measurements, we developed a novel computer-vision-based technique. We recorded mice sleeping in standard laboratory cages with a 30 fps, 1080p webcam (Logitech C920). Wemore » calculated respiratory rate using corner detection and optical flow to track cyclical motion in the fur in the recorded video. Breath-hold and free-breathing CBCTs were acquired on the X-RAD225Cx system. For breathhold imaging, the mice were intubated and their breath was held at full-inhale for 20 seconds. Healthy lung tissue was delineated in the scans using auto-threshold contouring (0–0.7 g/cm{sup 3}). The volume of healthy lung was measured in each of the scans. Next, lung density was measured in a 6-mm{sup 2} ROI in a fixed anatomic location in each of the scans. Results: Day-to-day variability in respiratory rate with our technique was 13%. All metrics except for breath-hold lung volume were correlated with survival: lung density on free-breathing (r=−0.7482,p<0.01) and breath-hold images (r=−0.5864,p<0.01), free-breathing lung volume (r=0.7179,p<0.01), and respiratory rate (r= 0.6953,p<0.01). Lung density on free-breathing scans was correlated with respiratory rate (r=0.7142,p<0.01) and lung density on breath-hold scans (r=0.5543,p<0.01). One significant practical hurdle in the CBCT measurements was that at least one lobe of the lung was collapsed in 36% of free-breathing scans and 45% of breath-hold scans. Conclusion: Lung density and lung volume on free-breathing CBCTs and respiratory rate outperform breath-hold CBCT measurements as indicators for survival from radiation-induced pneumonitis. This work was partially funded by Elekta.« less
  • Purpose: Current precision of small animal and cell micro-irradiators has continuously increased during the past years. Currently, preclinical irradiators can deliver sub-millimeter fields with micrometric precision but there are no water equivalent dosimeters to determine small field profiles and dose in the orthovoltage range of energies with micrometric resolution and precision. We have developed a fiber based micro-dosimeter with the resolution and dosimetric accuracy required for radiobiological research. Methods: We constructed two prototypes of micro-dosimeters based on different compositions of fiber scintillators to study the spatial resolution and dosimetric precision of small animal and cell micro-irradiators. The first has greenmore » output and the second has blue output. The blue output dosimeter has the highest sensitivity because it matches the spectral sensitivity of silicon photomultipliers. A blue detector with 500um cross section was built and tested respect to a CC01 ion chamber, film, and the 1500um green output detector. Orthovoltage fields from 1×1mm2 to 5×5mm2 were used for detector characteristics comparison. Results: The blue fiber dosimeter shows great agreement with films and matches dose measurements with the gold-standard ion chamber for 5×5mm2 fields. The detector has the appropriate sensitivity to measure fields from 1×1mm2 to larger sizes with a 1% dosimetric accuracy. The spatial resolution is in the sub-millimeter range and the spectral matching with the photomultiplier allows reducing the sensor cross section even further than the presented prototype. These results suggest that scintillating fibers combined with silicon photomultipliers is the appropriate technology to pursue micro-dosimetry for small animals and disperse cell samples. Conclusion: The constructed detectors establish a new landmark for the resolution and sensitivity of fiber based microdetectors. The validation of the detector in our small animal and cell irradiator shows that they are appropriate for preclinical and micro single cell irradiation quality assurance and dosimetry.« less
  • Purpose: Radiotherapy treatment is specified by radiation dose prescriptions, but biological DNA damage actually controls treatment effectiveness. It is impractical to directly measure dose in the clinic, so we measure quantities, such as collected charge, and calculate the relationship to dose. At small fields, such as those in stereotactic radiosurgery (SRS), charged-particle equilibrium (CPE) breaks down and the accuracy of the measurement for delivered dose decreases. By measuring DNA double-strand breaks (DSB) directly, we believe treatment accuracy could improve by providing a more meaningful measurement. Methods: A DNA dosimeter, consisting of magnetic streptavidin beads attached to 4 kilobase pair DNAmore » strands labeled with biotin and fluorescein amidite (FAM) on opposing ends, was suspended in phosphate-buffered saline (PBS). Twenty µL samples were placed in plastic micro-capillary tubes inside a water tank setup and irradiated with 10 cm, 3 cm, 1.25 cm, 0.75 cm, and 0.5 cm radiation field sizes, where the three smallest sizes were cones. After irradiation, the dosimeters were mechanically separated into beads (intact DNA) and supernatant (broken DNA/FAM) using a magnet. The fluorescence was read and the probability of DSB was calculated. This was used to calculate the output factor for an SRS beam and compared to that measured using a diode detector. Results: The output factors relative to a 10 cm field were 0.89±0.07, 0.76±0.08, 0.59±0.04, and 0.78±0.12 for the field sizes of 3 cm, 1.25 cm, 0.75 cm, and 0.5 cm, respectively. Some of the diode measurements do not fall within these uncertainties. Conclusion: This was the first attempt to measure output factors in a water tank with the DNA dosimeter. Although differences compared to the diode were observed, the uncertainty analysis ignored systematic errors. For future work, we will repeat this experiment to quantify and correct systematic errors, such as those caused by positional alignment and sample contamination. This work was funded in part by CPRIT (RP140105).« less
  • Purpose: Cerium oxide nanoparticles (CONPs) have unique pH dependent properties such that they act as a radical modulator. These properties may be used in radiation therapy (RT) to protect normal tissue. This work investigates the selective radioprotection of CONPs in-vitro and potential for in-situ delivery of CONPs in prostate cancer RT. Methods: i) Normal human umbilical vein endothelial cells (HUVEC) and human prostate cancer cells (PC-3) were treated with 0 or 2 ng/mL CONPs (NP size: 5 nm). 2 Gy of 100 kVp radiation was delivered to the cells 4 hours after the CONP treatment. Cell viability was checked 48more » hours later using MTS assays. ii) A prostate tumor was modeled as a 2-cm diameter sphere. CONPs were proposed to be loaded in a hollow radiotherapy fiducial marker. The concentration profile for the CONPs within the tumor was modeled with a previously validated diffusion equation employed in other studies for nanoparticles 10 nm or less. Results: i) Without radiation, cell viability was above 90% when treated with 2 ng/mL CONPs for both HUVEC and PC-3. After irradiation, a slightly higher viability was observed in HUVEC with CONPs than the ones without CONPs, and this effect was not observed in PC-3. ii) Based on the calculations, 2 ng/mL of CONPs could be delivered to normal cells by diffusion with a 1 µg/mL initial concentration within two weeks. Conclusion: We conclude that CONPs can provide selective radioprotection. The delivery of needed concentrations of CONPs is feasible via in-situ release from radiotherapy biomaterials (e.g. fiducials) loaded with the CONPs.« less
  • Purpose: To validate the in-house developed CT Monte Carlo calculation tool GMctdospp against reference simulation sets provided by the AAPM in the new report 195. Methods: Deposited energy was calculated in four segments (test 1) and two 10 cm long cylinders (test 2) inside a CTDI phantom (following case #4 of the AAPM report 195). The x-ray point source of a given 120 kVp spectrum was collimated to a fan beam with two thicknesses (10 mm, 80 mm) for a static and a rotational setup. In addition, a given chest geometry was used to calculate deposited energy in several organsmore » for a 0° static and a rotational beam (following case #5 of the AAPM report 195). The results of GMctdospp were compared against the particular mean value of the four quoted Monte Carlo codes (EGSnrc, Geant 4, MCNP and Penelope). Results: Calculated values showed no outliers in any of the cases. Differences between GMctdospp and the particular mean Results: Calculated values showed no outliers in any of the cases. Differences between GMctdospp and the particular mean value were always at similar magnitude compared to the quoted codes. For case #4 (CTDI phantom) the relative differences were within 1.5 %, on average 0.4 % and for case #5 (chest phantom) within 2.5 % and on average 0.85 %. Conclusion: The results confirmed an overall uncertainty of the Monte-Carlo calculation chain in GMctdospp being <2.5 %, for most cases even better. This can be considered small compared to other sources of uncertainties, e.g. virtual source and patient models. The photon transport implemented in GMctdospp inside a voxel-based patient geometry was successfully verified.« less