J Dugas

A technique for pediatric total skin electron irradiation

BackgroundTotal skin electron irradiation (TSEI) is a special radiotherapy technique which has generally been used for treating adult patients with mycosis fungoides. Recently, two infants presented with leukemia cutis isolated to the skin requiring TSEI. This work discusses the commissioning and quality assurance (QA) methods for implementing a modified Stanford technique using a rotating harness system to position sedated pediatric patients treated with electrons to the total skin.Methods and ResultsCommissioning of pediatric TSEI consisted of absolute calibration, measurement of dosimetric parameters, and subsequent verification in a pediatric patient sized cylindrical phantom using radiographic film and optically stimulated luminance (OSL) dosimeters. The depth of dose penetration under TSEI treatment condition was evaluated using radiographic film sandwiched in the phantom and demonstrated a 2 cm penetration depth with the maximum dose located at the phantom surface. Dosimetry measurements on the cylindrical phantom and in-vivo measurements from the patients suggested that, the factor relating the skin and calibration point doses (i.e., the B-factor) was larger for the pediatric TSEI treatments as compared to adult TSEI treatments. Custom made equipment, including a rotating plate and harness, was fabricated and added to a standard total body irradiation stand and tested to facilitate patient setup under sedated condition. A pediatric TSEI QA program, consisting of daily output, energy, flatness, and symmetry measurements as well as in-vivo dosimetry verification for the first cycle was developed. With a long interval between pediatric TSEI cases, absolute dosimetry was also repeated as part of the QA program. In-vivo dosimetry for the first two infants showed that a dose of ± 10% of the prescription dose can be achieved over the entire patient body.ConclusionThough pediatric leukemia cutis and the subsequent need for TSEI are rare, the ability to commission the technique on a modified TBI stand is appealing for clinical implementation and has been successfully used for the treatment of two pediatric patients at our institution.

Dosimetry intercomparison using a 35-keV x-ray synchrotron beam

The purpose of this study was to compare dose measurements using ion chamber and radiochromic film dosimetry for a 35-keV synchrotron beam useful for Auger electron therapy. A 1.3-GeV electron beam, transported through a 3-pole superconducting wiggler magnet, produced a polychromatic photon beam from which a 35-keV beam (3.3 mm Al HVL) was selected using a monochromator. A 2.8 cm x 2.5 cm field was produced by vertically oscillating a polymethylmethacrylate phantom in which dose to water was measured as a function of depth. Charge, measured using a 0.23-cm(3) cylindrical, air-equivalent ionization chamber, was converted to dose using American Association of Physicists in Medicine TG-61 protocol for 40-300 kV X-ray beam dosimetry with minor assumptions. Optical density of radiochromic film (Gafchromic EBT) was converted to dose using a 125 kVp X-ray beam (2.9 mm Al HVL) calibration curve. Fractional depth-dose curves measured using ion chamber and film agreed well with each other, the maximum difference being 4.5% at 8.85 cm. Both agreed well with that predicted by MCNP5 Monte Carlo calculations. At 2.0-cm depth, film doses from five independent measurements predicted 0.952+/-0.022 of dose measured using the ion chamber. Dose measurements using two independent methods, ionization chamber and radiochromic film dosimetry, showed good agreement and should be suitable for future dosimetry necessary for cell and small animal irradiations. Improving agreement will require additional investigations of methods for converting ionization and film optical density to dose.

Monochromatic beam characterization for Auger electron dosimetry and radiotherapy

Dosimetry for Auger electron radiotherapy using monochromatic photon beams requires knowledge of beam characteristics. This study characterized a 35-keV photon beam generated at the LSU/CAMD synchrotron. Beam energy was measured by Compton spectroscopy and Si640c powder diffraction. Photon spatial distribution and virtual source position were measured using radiochromic film. Central-axis fluence was determined from Compton scattering measurements and application of the Klein-Nishina cross-section with percent polarization fit to results at 2-4 scattering angles. Broad-beam fluence was combined with MCNP5 Monte Carlo dose per fluence calculations to generate dose versus depth in a polymethylmethacrylate phantom, which was compared to ionization chamber and radiochromic film depth-dose measurements. For 22-41 keV beams, diffraction-based and Compton-based energy measurements agreed to within -0.1+/-0.3 and 0.6+/-0.3 keV, respectively, of monochromator calibrated energies. At 35 eV and 0.66 cm depth, dose uniformity over 80% of the 2.8 cm x 2.5 cm beam varied from 105 to 78% of the central-axis value horizontally and from 90 to 100% vertically. Narrow-beam divergence yielded vertical and horizontal virtual source-to-surface distances of 3.8+/-0.2 and 15.7+/-1.0m, respectively. Incident fluence rates for a 35-keV beam (100 mA ring current) ranged from 1.181+/-0.011 x 10(11) to 3.053+/-0.004 x 10(11)photons cm(-2)s(-1) with approximately 100% polarization in the horizontal plane. Ion chamber and film dose measurements underestimated MCNP5-based dose by an average of 6.4+/-0.8 and 9.1+/-0.8%, respectively, over measured depths. These practical beam characterization methods should allow subsequent Monte Carlo dose calculations needed for planning future radiotherapy studies. Although simulated and measured depth-dose curves agree well in shape, improvement in absolute dose is desirable.

Dependence of Cell Survival on Iododeoxyuridine Concentration in 35-keV Photon-Activated Auger Electron Radiotherapy

PURPOSE To measure and compare Chinese hamster ovary cell survival curves using monochromatic 35-keV photons and 4-MV x-rays as a function of concentration of the radiosensitizer iododeoxyuridine (IUdR). METHODS AND MATERIALS IUdR was incorporated into Chinese hamster ovary cell DNA at 16.6 ± 1.9%, 12.0 ± 1.4%, and 9.2 ± 1.3% thymidine replacement. Cells were irradiated from 1 to 8 Gy with 35-keV synchrotron-generated photons and conventional radiotherapy 4-MV x-rays. The effects of the radiation were measured via clonogenic survival assays. Surviving fraction was plotted vs. dose and fit to a linear quadratic model. Sensitization enhancement ratios (SER(10)) were calculated as the ratio of doses required to achieve 10% surviving fraction for cells without and with DNA-incorporated IUdR. RESULTS At 4 MV, SER(10) values were 2.6 ± 0.1, 2.2 ± 0.1, and 1.5 ± 0.1 for 16.6%, 12.0%, and 9.2% thymidine replacement, respectively. At 35 keV, SER(10) values were 4.1 ± 0.2, 3.0 ± 0.1, and 2.0 ± 0.1, respectively, which yielded SER(10) ratios (35 keV:4 MV) of 1.6 ± 0.1, 1.4 ± 0.1, and 1.3 ± 0.1, respectively. CONCLUSIONS SER(10) increases monotonically with percent thymidine replacement by IUdR for both modalities. As compared to 4-MV x-rays, 35-keV photons produce enhanced SER(10) values whose ratios are linear with percent thymidine replacement and assumed to be due to Auger electrons contributing to enhanced dose to DNA. Although this Auger effectiveness factor is less than the radiosensitization factor of IUdR, both could be important for the clinical efficacy of IUdR radiotherapy.

Impact of IUdR on Rat 9L Glioma Cell Survival for 25-35 keV Photon- Activated Auger Electron Therapy

The goal of the current study was to measure the energy dependence of survival of rat 9L glioma cells labeled with iododeoxyuridine (IUdR) that underwent photon-activated Auger electron therapy using 25–35 keV monochromatic X rays, i.e., above and below the K-edge energy of iodine. Rat 9L glioma cells were selected because of their radioresistance, ability to be implanted for future in vivo studies and analogy to radioresistant human gliomas. Survival curves were measured for a 4 MV X-ray beam and synchrotron produced monochromatic 35, 30 and 25 keV X-ray beams. IUdR was incorporated into the DNA at levels of 0, 9 and 18% thymidine replacement for 4 MV and 35 keV and 0 and 18% thymidine replacement for 30 and 25 keV. For 10 combinations of beam energy and thymidine replacement, 62 data sets (3–13 per combination) provided 776 data points (47–148 per combination). Survival versus dose data taken for the same combination, but on different days, were merged by including the zero-dose points in the nonlinear, chi-squared data fitting using the linear-quadratic model and letting the best estimate to the zero-dose plating efficiency for each of the different days be a fitting parameter. When comparing two survival curves, the ratio of doses resulting in 10% survival gave sensitization enhancement ratios (SER10) from which contributions due to linear energy transfer (LET) (SER10,LET), IUdR radiosensitization (SER10,RS), the Auger effect (SER10,AE) and the total of all effects (SER10,T) were determined. At 4 MV and 35, 30 and 25 keV, SER10,LET values were 1.00, 1.08 ± 0.03, 1.22 ± 0.02 and 1.37 ± 0.02, respectively. At 4 MV SER10,RS values for 9 and 18% IUdR were 1.28 ± 0.02 and 1.40 ± 0.02, respectively. Assuming LET effects were independent of percentage IUdR and radiosensitization effects were independent of energy, SER10,AE values for 18% IUdR at 35, 30 and 25 keV were 1.35 ± 0.05, 1.06 ± 0.03 and 0.98 ± 0.03, respectively. The value for 9% IUdR at 35 keV was 1.01 ± 0.04. First, we found the radioresistant rat 9L glioma cell line exhibited an SER10 due to the Auger effect of 1.35 at (35 keV, 18% IUdR) and an SER10 due to the radiosensitizing effect of 1.40 at (4 MV, 18% IUdR), both significantly less than values for previously reported cell lines. These low individual values emphasize the benefit of their combined value (SER10 of approximately 1.9) for achieving clinical benefit. Second, as expected, we observed that energies below the K-edge of iodine (25 and 30 keV), for which there are L, M and higher shell photoelectric events creating Auger electrons, show no promise for Auger electron therapy. Third, to proceed with future in vivo studies, additional data from 35–65 keV are needed to determine the optimal X-ray energy for IUdR Auger electron therapy. Only then can there be an answer to the question, how well the energy dependence of in vitro survival data supports the potential for photon-activated Auger electron therapy with IUdR in cancer radiotherapy.

SU‐E‐T‐155: Dose Response Curve of EBT2 and EBT3 Radiochromic Films to a Synchrotron‐Produced Monochromatic X‐Ray Beam

PURPOSE This work investigates the dose-response curves of Gafchromic EBT2 and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. These dosimeters are being utilized for dose verification in photoactivated Auger electron therapy at the LSU Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. METHODS Monochromatic beams of 25, 30 and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to calculate the dose delivered to films irradiated simultaneously at depths from 0.7 - 8.5 cm in a 10×10×10-cms polymethylmethacrylate phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Calibrations of films at 4 MV were obtained for comparison using a Clinac 21 EX radiotherapy accelerator at Mary Bird Perkins Cancer Center. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the optical density (OD) derived from the red channel. RESULTS For EBT2 film the average sensitivity (OD/dose) at 50, 100, and 200 cGy relative to that for 4-MV x- rays was 1.07, 1.20, and 1.23 for 25, 30, and 35 keV, respectively. For EBT3 film the average sensitivity was within 3 % of unity for all three monochromatic beams. CONCLUSIONS EBT2 film sensitivity shows strong energy dependence over an energy range of 25 keV - 4 MV. EBT3 film shows weak energy dependence, indicating that it would be the better dosimeter for Auger electron therapy. This research was supported by contract W81XWH-10-1-0005 awarded by The U.S. Army Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014. This report does not necessarily reflect the position or policy of the Government, and no official endorsement should be inferred.

SU‐FF‐T‐367: Radiochromic Film and Ion Chamber Dosimetry for Monochromatic X‐Rays in PMMA

Purpose: K‐edge capture radiotherapy using monochromatic, keV x‐ray beams necessitates accompanying dosimetry methods. This work compares radiochromic film and ion chamberdosimetry methods potentially suitable for use with monochromatic x‐ray beams. Method and Materials: X‐rays were produced at the LSU CAMD synchrotron by passing a 1.3‐GeV electron beam (≈200‐mA) through a 7‐T superconductingwiggler. The resulting polychromatic beam was passed through a double multilayermonochromator to generate an approximately 0.1×2.8‐cm2, 35‐keV x‐ray beam. A 2.5×2.8‐cm2 broad beam was produced via oscillation of phantom and dosimeters by a triangular waveform. Central‐axis depth dose was measured in a 10×10×12.5‐cm3 PMMA slab phantom using 5.12×5.12‐cm2 GAFChromic® EBT films and an air‐equivalent, cylindrical ion chamber (0.23‐cm3). Films were digitized using the red channel of a flatbed scanner, and pixel values were converted to dose using both 6‐MV x‐ray and 125 I brachytherapy seed calibration curves. 125 I doses were calculated using AAPM TG‐43 formalism. Ion chamber charge readings were converted to dose using the AAPM TG‐61 protocol for kilovoltage x‐ray beam dosimetry.Results: Measurements in a PMMA phantom yielded film depth‐dose curves from film that were 2.5–4.4% higher than those from the ion chamber for depths of 0 to 9 cm when using the 125 I seed calibration. Using the 6‐MV x‐ray dosecalibration for film resulted in doses approximately 35% lower due to a significantly different film calibration curve compared to that using 125 I seeds. Conclusion: These methods should be suitable for future dose measurements required for cell and small animal irradiations. The discrepancy between 6‐MV x‐rays and 125 I seeds is contrary to previously reported results and currently under investigation.

WE-E-BRE-08: Impact of IUdR in Rat 9L Glioma Cell Survival for 25–35 KeV Photo-Activated Auger Electron Therapy

PURPOSE To determine the biological effect from Auger electrons with 9% and 18% iododeoxyuridine (IUdR) incorporated into the DNA of rat 9L glioma cells at photon energies above and below the K-edge of iodine (33.2 keV). METHODS Rat 9L glioma cell survival versus dose curves with 0%, 9%, and 18% thymidine replacement with IUdR were measured using four irradiation energies (4 MV x-rays; monochromatic 35, 30, and 25 keV synchrotron photons). For each of 11 conditions (Energy, %IUdR) survival curves were fit to the data (826 cell cultures) using the linear-quadratic model. The ratio of doses resulting in 10% survival gave sensitization enhancement ratios (SER10) from which contributions due to linear-energy transfer (LET), radiosensitization (RS), and Auger effect (AE) were extracted. RESULTS At 35, 30, and 25 keV, SER10,LET values were 1.08±0.03, 1.22±0.02, and 1.37±0.02, respectively. At 4 MV SER10,RS values for 9% and 18% IUdR were 1.28±0.02 and 1.40±0.02, respectively. Assuming LET effects are independent of %IUdR and radiosensitization effects are independent of energy, SER10,AE values for 18% IUdR at 35, 30, and 25 keV were 1.35±0.05, 1.06±0.03, and 0.98±0.03, respectively; values for 9% IUdR at 35 and 25 keV were 1.01±0.04 and 0.82±0.02, respectively. CONCLUSION For 18% IUdR the radiosensitization effect of 1.40 and the Auger effect of 1.35 at 35 keV are equally important to the combined effect of 1.90. No measureable Auger effect was observed for energies below the K-edge at 20 and 25 keV, as expected. The insignificant Auger effect at 9% IUdR was not expected. Additional data (40-70 keV) and radiobiological modeling are being acquired to better understand the energy dependence of Auger electron therapy with IUdR. Funding support in part by the National Science Foundation Graduate Research Fellowship Program and in part by Contract No. W81XWH-10-1-0005 awarded by the U.S. Army Research Acquisition Activity. This paper does not necessarily reflect the position or policy of the Government, and no official endorsement should be inferred.

TH-D-BRD-09: Dependence of CHO Cell Survival On IUdR Uptake for 35-KeV Photoactivated Auger Electron Therapy

Purpose: To characterize sensitization enhancement ratios (SER) obtainable using monochromatic x‐ray activated Auger electron radiotherapy as a function of radiosensitizer concentration for a 35‐keV x‐ray beam and compare those results to measurements made using conventional 4 MV x‐rays in order to separate effects due to dose enhancement from effects due to other (chemical) mechanisms. Methods and Materials: IUdR was incorporated into CHO cell DNA through incubation in growth media containing 0, 5, 10, or 20 μM IUdR concentrations for 27 hours. Percent thymidine replacement was determined in separate tests using radiolabeled 125I‐IUdR. IUdR‐loaded cells were irradiated to 1–8 Gy with 35 keV x‐rays, generated at LSUs CAMD synchrotron, using a 2.8×2.5‐cm2 effective field size.Dose was determined from ionization chamber‐measured dose rates (∼18 cGy⋅min−1 at 100 mA) and verified with GAFCHROMIC® EBT film. 4 MV irradiations were performed using a Varian Clinac 21EX (30×30‐cm2 field, 0.5‐cm depth). Irradiated cells were incubated for 1 week, then fixed and stained with crystal violet. Colonies of 50 or more cells were scored as survivors. Survival fraction (SF) was plotted versus dose with results fit to a linear quadratic model. SER10 was calculated as the ratio of dose required to achieve 10% SF for cells without and with DNA‐incorporated IUdR. Results:SERs of 2.7 at 16.6±1.9% thymidine replacement (20 μM), 2.3 at 12.0±1.4% (10 μM), and 1.6 at 9.2±1.3% (5 μM) following 4‐MV irradiations illustrate IUdRs effect as a chemical radiosensitizer. Following 35‐keV irradiations, SERs of 4.3, 3.1, and 2.1 at 16.6%, 12.0%, and 9.2% replacement, respectively, indicate dose enhancement due to increased local DNAdose resulting from photoelectric interactions with DNA‐incorporated iodine. Conclusions: SER depends on percent thymidine replacement by IUdR. Compared to 4 MV x‐rays, 35 keV photons produce an additional SER, linear with percent thymidine replacement.

WE‐C‐332‐04: Computed Tomography Imaging to Quantify Iodine Distribution in IUdR‐Labeled DNA

Purpose:Treatment planning for X‐ray Activated Auger electron radiotherapy requires CTdata sets correlated to the distribution of preloaded high Z radiosensitizer molecules in cellular DNA. The studys aim was to evaluate a polychromatic microCT scanner and a synchrotron monochromatic CT system for their ability to measure the spatial distribution of iodine incorporated in DNA.Method and Materials: The Skyscan 1074 microCT system produces images at 20–40 kVp with a 736×512 element CCDcamera.CTimages were acquired at 40 kVp and 1000 μA. The synchrotron produces a tunable (6–35 keV) monochromatic beam with a beam profile of 0.1×2.8 cm2 and a 1.5k×1k CCDcamera with focusing lenses to obtain CTimages with pixel sizes of 4.5–9.0 μm. CTimages were acquired above (33.8 keV) and below (32.5 keV) iodines K‐edge binding energy of 33.169 keV. Phantoms were constructed from acrylic for the benchtop microCT system or glass micro‐hematocrit capillary tubes for the synchrotron based monochromatic CT system. Iodine contrast agent (Reno‐30) was diluted with distilled‐deionized water in concentrations 0.05–25 mg I ml−1. Results: Results from the microCT system and the synchrotron K‐edge subtraction data were fit using linear regression. The fit parameters for the Skyscan and CAMD (33.8 keV) data were CT♯ =2.39 + 29.7×[I] with χν 2=0.282 and CT♯ =6.80 + 82.74×[I] with χν 2=1.37 respectively. The fit parameters for the K‐edge subtraction were [I]meas= − 0.00968 + 0.677×[I]known with χν 2=1.61. Conclusion: Noise limited the microCTs accuracy at low iodine concentrations. K‐edge subtraction using monochromatic x‐rays is promising but the glass capillary tubes have proved too attenuating for test measurements. Measurement of 0.06 mg I ml−1 (corresponding to 18% thymidine replacement) appeared feasible. The imaging methods are being applied to studying Chinese hamster ovary cells containing iododeoxyuridine‐labeled DNA to verify the magnitude and distribution of iodine incorporation in cell samples.