EXPERIMENTAL EVALUATION OF DOSIMETRIC CHARACTERIZATION OF GAFCHROMIC EBT3 AND EBT-XD FILMS FOR CLINICAL CARBON ION BEAMS

EXPERIMENTAL EVALUATION OF DOSIMETRIC CHARACTERIZATION OF GAFCHROMIC EBT3 AND EBT-XD FILMS FOR... Abstract Radiochromic film is a very useful tool for 2D dosimetric measurements in radiotherapy because it is self-developing and has very high-spatial resolution. However, considerable care has to be taken in ion beam radiotherapy owing to the quenching effect of high-linear energy transfer (LET) radiation. In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated using the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba. Results showed that the relations between absorbed dose and net optical density could be expressed well using an equation proposed by Reinhardt (2015). The quenching effect was evaluated by determining their relative efficiencies for photon irradiation as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used for carbon ion radiotherapy eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic film. INTRODUCTION In radiotherapy, precise irradiation of patients is essential for achieving high-tumor control with few side effects around the tumor. Quality assurance (QA) measurements are then required to confirm the beam dosimetric characteristics and consistency of the patient’s treatment plan. Radiochromic films are widely used in photon radiotherapy as QA tools for 2D dosimetric measurements, particularly for small fields, because they are self-developing and have very high-spatial resolution(1, 2). However, considerable care has to be taken in ion beam radiotherapy because their dose responses for radiation of high-linear energy transfer (LET) are known to be significantly lower, owing to the so-called quenching effect which is attributed to polymerization mechanisms in sites with a higher density of ionization. In carbon ion radiotherapy (CIRT), LET values are widely distributed, ranging from ~10 to more than 100 keV/μm. As LET basically increases with decreasing particle energy, the production of local saturation effects in the film is accentuated for low energy carbon ion beams like the one used for eye treatments, and further increased at the end of the depth dose profile. The aim of this study was to evaluate the loss of efficiency of radiochromic films in this challenging situation, and to evaluate their use as a 2D dosimeter in CIRT. Because of the nature of damages by carbon ions, hypofractionation is used with dose/fraction ranging from ~1 to ~40 Gy (RBE), corresponding to physical doses of the order from 0.5 to 20 Gy. For uveal melanomas, four fractions of 17 Gy (RBE) are delivered using two orthogonal beams, corresponding to ~6 Gy physical dose. The current generation of radiochromic films, Gafchromic® EBT3 and EBT-XD (ISP, Wayne, NJ), are best used in dose ranges of 0.2–10 and 0.4–40 Gy, respectively, which largely cover the range of physical doses used in CIRT. The under-responses of EBT2 and EBT3 films have been investigated for proton and carbon ion beams; however, these studies were limited to the entrance region(3–6). In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated for the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba (HIMAC), and the relation between dose response and LET was evaluated. MATERIALS AND METHODS Film properties GAFchromic EBT3 and EBT-XD films were used in this study. These films are composed of a 28 and 25 μm active layer for EBT3 and EBT-XD, respectively, sandwiched between two 125 μm matte polyester substrates. The active particle size in EBT-XD is significantly smaller than that in EBT3 (length 2–4 and 15–20 μm, respectively, with a similar diameter of 1–2 μm) to achieve fewer lateral response artifacts(7–9). Irradiations Irradiations with 290 and 400 MeV/u carbon ion beams were performed using the horizontal beam line in treatment room C at HIMAC, where CIRT is routinely performed with passive beams. The films provided by the manufacturer were 20.3 cm (8 in) by 25.4 cm (10 in), and they were cut into twenty five 4 cm by 5 cm pieces. Each piece of film was placed on a thin PMMA plate at the isocenter. Dose responses were investigated for four LET values, namely, 12, 42, 48 and 169 keV/μm, corresponding to the entrance of a 400 MeV/u pristine beam and to the proximal, center and distal depth dose points of a 290 MeV/u 60-mm spread-out Bragg peak, respectively. These beams maintained a lateral dose uniformity of ±2.5% within a diameter of 10 cm with the single-ring wobbling method(10). The EBT3 films were irradiated at 10 different absorbed doses between 0.01 and 10 Gy, whereas the EBT-XD films were irradiated at eight absorbed doses between 0.5 and 15 Gy. The LET dependence was investigated using eight LET values between 12 and 169 keV/μm. Because results showed that LET is independent of absorbed dose, as mentioned below, only 1 or 4 Gy irradiations were performed for the four LET conditions. The LET value of the irradiated beam was changed using variable PMMA absorbers upstream of the film. The total absorber thicknesses to obtain 12, 42, 48 and 169 keV/μm were 0, 50.75, 63.75 and 76.75 mm, respectively. The absorbed doses were determined using a main monitor installed in the irradiation system. The monitor unit of the main monitor was calibrated for each thickness of variable PMMA absorbers before film irradiations with a parallel-plate ionization chamber (Advanced Markus®, type 34 045, PTW) set at the film position. This chamber was calibrated according to IAEA protocol (TRS-398)(11). According to TRS-398, the uncertainty in absorbed dose determination is 3.4% for plane-parallel chambers in clinical carbon ion beam. Film analysis The irradiated films were scanned 24 h after irradiation with a commercial flatbed scanner (Seiko Epson Corp. ES-10000G) with a transmission unit using the provided EPSON Scan software in professional mode with all image adjustment features turned off. To avoid any dependence on the scan position or scan direction, each piece of film was placed separately at the same position and orientation in the center of the scanner. The films were digitized as 48-bit RGB with a resolution of 150 dpi and saved as uncompressed Tagged Image File Format (TIFF) files. Due to the highest dose sensitivity among RGB colors, the pixels’ red color channel values were extracted from the TIFF files using ImageJ® (National Institutes of Health, MD, USA) and converted into net optical densities (netODs) using the following equation. netOD=ODexp−OD0=−log(PVRexpPVR0) (1) Here PVR represents the pixel’s red color channel value, and the subscripts of exp and 0 correspond to the irradiated and unirradiated films, respectively. In this study, mean values in the region of interest (a 25-mm-diameter circle in the middle of the film) were used for PVR. The uncertainties in the netODs mainly originate from reproducibility due to uniformity of active particles in film, scanner uniformity, beam uniformity in the irradiation field, and misalignment of the films. The overall uncertainty in the netOD determination was estimated by repeating the entire experiment (and film setup) three times on different days. Finally, the uncertainties of EBT3 and EBT-XD were similar to each other and the maximum uncertainty was found to be 3.0 and 4.9% for EBT3 and EBT-XD films, respectively. Dose calibration and LET correction curves Dose calibration curves, which relate the absorbed dose D and netOD, were obtained using the fitting method shown in Ref. (5), which uses the following equation for the fitting procedure. D(netOD)=A×netOD+B×netODC (2) Here, A and B are the free parameters, whereas C is fixed at an initial value of 2.0 and subsequently increased in steps of 0.1 at each iteration of the fitting process until an appropriate value is found using the least-squares method. For details, refer to Refs. (5 and 12). To quantify the under-responses of EBT3 and EBT-XD films to high-LET radiation, the relative efficiency (RE)—defined as the absorbed dose ratio that yields the same netOD for different beam qualities—was determined(3, 5). In this study, the film dose response was calibrated using 6 MV photons, considered as the standard beam quality, using a clinical linear accelerator (Clinac21-EX, Varian Medical Systems, Palo Alto, USA) at National Institute of Radiological Sciences. In total, 18 film samples of each film type were set at 10 cm depth of a solid water phantom (SSD: 90 cm) in a 10 × 10 cm2 6 MV photon field and were exposed to doses ranging from 0.1 to 8 Gy or 18 Gy for EBT3 and EBT-XD, respectively. Just before film irradiations, a measurement of the linac dose rate was performed with a Farmer® ionization chamber (type30013, PTW). Films were scanned in the same conditions and direction as for the experimental films in carbon ion. The uncertainty in D6 MV (netOD), including the X-ray absolute dose measurement with the ionization chamber (2%), the variation of optical densities (0.3%) and the fitting equation (0.2%) was estimated at 2% for both film types. RE was then calculated as follows: RE=D6MV(netODC−ion)DC−ion, (3) where, DC-ion is the actual dose delivered by carbon ions to the film and D6 MV(netODC-ion) is the 6-MV-photon dose needed to produce the netOD obtained by the carbon-ion irradiation (netODC-ion). Ref. (5) showed that RE could be expressed as a function of dose-averaged LET for protons with LET values ranging from 0.5 to 12 keV/μm(5). This study used Monte Carlo calculations with the PHITS code(13) to estimate dose-averaged LET and finally obtained the relation between RE and dose-averaged LET for LET values observed in clinical carbon ion beams. RESULTS Figure 1 shows the measured dose responses of the EBT3 and EBT-XD films, and Table 1 shows the fit parameters obtained by the fitting procedure for Eq. (2). The dose response of EBT-XD showed ~40% lower sensitivity compared with EBT3, as indicated in the manufacturer’s specifications. Figure 1. View largeDownload slide Relation between the measured netOD and absorbed dose. Each curve represents Eq. (2) with the fit parameters shown in Table 1. Figure 1. View largeDownload slide Relation between the measured netOD and absorbed dose. Each curve represents Eq. (2) with the fit parameters shown in Table 1. Table 1. Fit parameters for Eq. (2) obtained from Figure 1. LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 Table 1. Fit parameters for Eq. (2) obtained from Figure 1. LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 Figure 2 shows the relations between dose-averaged LET and RE for the EBT3 and EBT-XD films. Herein, results in the dose ranges 1–10 and 4–15 Gy are plotted for EBT3 and EBT-XD films, respectively, and these results show that RE does not depend on the absorbed dose in these dose ranges. The RE values were fitted using the following equation with free parameters a, b and c, which is a modification of the fit equation given in Ref. (5). RE(LET)=1−a×(LET−c)b(LET≥c) (4) Figure 2. View largeDownload slide (a) EBT3 and (b) EBT-XD. Relation between dose-averaged LET and RE. Each curve represents Eq. (4) with the fit parameters shown in Table 2. Figure 2. View largeDownload slide (a) EBT3 and (b) EBT-XD. Relation between dose-averaged LET and RE. Each curve represents Eq. (4) with the fit parameters shown in Table 2. The fit parameters obtained are given in Table 2, which shows that the fit parameters for EBT3 and EBT-XD agreed within their fitting errors. Moreover, the fit parameter c is considered to be the threshold of under-response to high-LET radiation. This study indicates that the threshold is ~8 keV/μm, which is similar to the results for proton irradiation of EBT2 and EBT3, as seen in Figure 3 in Ref. (5). Table 2. Fit parameters for Eq. (4) obtained from Figure 2. a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 Table 2. Fit parameters for Eq. (4) obtained from Figure 2. a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 Figure 3. View largeDownload slide Comparisons of lateral dose distributions measured with a pinpoint ion chamber and EBT3 film. Figure 3. View largeDownload slide Comparisons of lateral dose distributions measured with a pinpoint ion chamber and EBT3 film. DISCUSSION The quenching effect is a limitation in the dose determination with films for high-LET radiation such as clinical carbon ion beam. As shown by Figure 2, the relation between LET and RE is non-linear. The quenching effect increases rapidly up to LET around 40 keV/μm (demonstrated by a rapid decrease of RE) and seems to slow down when LET becomes higher. Nevertheless, radiochromic films are suitable for measurements in small irradiation fields because of their high-spatial resolution of the order of 0.1 mm, superior to other 2D detectors with resolutions ranging from 2.5 (Octavius® 1000 SRS, PTW) to 5 mm (MatriXX®, IBA, Belgium). Among the clinical targets treated with CIRT at HIMAC, uveal melanoma is one where treatment requires small irradiation fields(14). For small field QA, the PinPoint® ion chamber (type 31 006, PTW) is used because of the small size of its sensitive volume (0.015 cm2). To verify our under-response correction procedure, a lateral dose distribution was measured with a pinpoint ion chamber and compared to one measured with EBT3 film and corrected using Eq. (4). Here, uveal treatment fields with LET values distributed between 25 and 85 keV/μm were simulated using a brass collimator, a polyethylene compensator, and a 170 MeV/u carbon ion beam. In addition, the comparison was performed for a mono-LET value of ~22 keV/μm without the compensator. Figure 3 shows comparisons of the measured lateral dose distributions. For mono- and multi-LET fields, absorbed doses obtained with pinpoint chamber and EBT3 agreed well within 3 and 6%, respectively. Deviations were large for LET below 40 keV/μm, where the RE is decreasing steeply (Figure 2), suggesting that additional points below 40 keV/μm would improve our model. However, these results indicate that the under-response correction procedure using Eq. (4) can be efficiently employed. CONCLUSION The dose responses of EBT3 and EBT-XD films were experimentally obtained for a clinical carbon ion beam. The relations between absorbed dose and netOD could be expressed well using a fitting equation proposed in the literature. The quenching effect owing to the high LET of carbon ions was also evaluated by determining RE as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used in CIRT eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic films. FUNDING Funding for this work was provided by National Institute of Radiological Sciences. REFERENCES 1 Soares , C. G. Radiochromic film dosimetry . Radiat. Meas. 41 , S100 – S116 ( 2007 ). Google Scholar CrossRef Search ADS 2 Devic , S. Radiochromic film dosimetry: past, present, and future . Phys. Med. 27 , 122 – 134 ( 2011 ). Google Scholar CrossRef Search ADS PubMed 3 Martišíkovsá , M. and Jäkel , O. Dosimetric properties of Gafchromic® EBT films in monoenergetic medical ion beams . Phys. Med. Biol. 55 , 3741 – 3751 ( 2010 ). Google Scholar CrossRef Search ADS PubMed 4 Fiorini , F. , Kirby , D. , Thompson , J. , Green , S. , Parker , D. J. , Jones , B. and Hill , M. A. Under-response correction for EBT3 films in the presence of proton spread out Bragg peaks . Phys. Med. 30 , 454 – 461 ( 2014 ). Google Scholar CrossRef Search ADS PubMed 5 Reinhardt , S. , Würl , M. , Greubel , C. , Humble , N. , Wilkens , J. J. , Hillbrand , M. and Parodi , K. Investigation of EBT2 and EBT3 films for proton dosimetry in the 4–20 MeV energy range . Radiat. Environ. Biophys. 54 ( 1 ), 71 – 79 ( 2015 ). Google Scholar CrossRef Search ADS PubMed 6 Castriconi , R. , Ciocca , M. , Mirandola , A. , Sini , C. , Broggi , S. , Schwarz , M. and Russo , P. Dose–response of EBT3 radiochromic films to proton and carbon ion clinical beams . Phys. Med. Biol. 62 ( 2 ), 377 – 393 ( 2017 ). Google Scholar CrossRef Search ADS PubMed 7 Grams , M. P. , Gustafson , J. M. , Long , K. M. and Fong de los Santos , L. E. Technical note: initial characterization of the new EBT-XD Gafchromic film . Med. Phys. 42 ( 10 ), 5782 – 5786 ( 2015 ). Google Scholar CrossRef Search ADS PubMed 8 Palmer , A. L. , Dimitriadis , A. , Nisbet , A. and Clark , C. H. Evaluation of Gafchromic EBT-XD film, with comparison to EBT3 film, and application in high dose radiotherapy verification . Phys. Med. Biol. 60 , 8741 – 8752 ( 2015 ). Google Scholar CrossRef Search ADS PubMed 9 Lewis , D. F. and Chan , M. F. On GAFChromic EBT-XD film and the lateral response artifact . Med. Phys. 43 ( 2 ), 643 – 649 ( 2016 ). Google Scholar CrossRef Search ADS PubMed 10 Yonai , S. , Kanematsu , N. , Komori , M. , Kanai , T. , Takei , Y. , Takahashi , O. and Tomita , H. Evaluation of beam wobbling methods for heavy-ion radiotherapy . Med. Phys. 35 ( 3 ), 927 – 938 ( 2008 ). Google Scholar CrossRef Search ADS PubMed 11 International Atomic Energy Agency . Absorbed doe determination in external beam radiotherapy. Technical Report Series No. 398 ( 2000 ). 12 Devic , S. , Seuntjens , J. , Hegyi , G. , Podgorsak , E. B. , Soares , C. G. , Kirov , A. S. and Elizondo , A. Dosimetric properties of improved GafChromic films for seven different digitizers . Med. Phys. 31 ( 9 ), 2392 – 2401 ( 2004 ). Google Scholar CrossRef Search ADS PubMed 13 Sato , T. et al. . Particle and heavy ion transport code system PHITS, Version 2.52 . J. Nucl. Sci. Technol. 50 ( 9 ), 913 – 923 ( 2013 ). Google Scholar CrossRef Search ADS 14 Toyama , S. , Tsuji , H. , Mizoguchi , N. , Nomiya , T. , Kamada , T. , Tokumaru , S. , Mizota , A. , Ohnishi , Y. and Tsujii , H. , Working Group for Ophthalmologic Tumors . Long-term results of carbon ion radiation therapy for locally advanced or unfavorably located choroidal melanoma: usefulness of CT-based 2-port orthogonal therapy for reducing the incidence of NVG . Int. J. Radiat. Oncol. Biol. Phys. 86 , 270 – 276 ( 2013 ). 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EXPERIMENTAL EVALUATION OF DOSIMETRIC CHARACTERIZATION OF GAFCHROMIC EBT3 AND EBT-XD FILMS FOR CLINICAL CARBON ION BEAMS

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Abstract

Abstract Radiochromic film is a very useful tool for 2D dosimetric measurements in radiotherapy because it is self-developing and has very high-spatial resolution. However, considerable care has to be taken in ion beam radiotherapy owing to the quenching effect of high-linear energy transfer (LET) radiation. In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated using the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba. Results showed that the relations between absorbed dose and net optical density could be expressed well using an equation proposed by Reinhardt (2015). The quenching effect was evaluated by determining their relative efficiencies for photon irradiation as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used for carbon ion radiotherapy eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic film. INTRODUCTION In radiotherapy, precise irradiation of patients is essential for achieving high-tumor control with few side effects around the tumor. Quality assurance (QA) measurements are then required to confirm the beam dosimetric characteristics and consistency of the patient’s treatment plan. Radiochromic films are widely used in photon radiotherapy as QA tools for 2D dosimetric measurements, particularly for small fields, because they are self-developing and have very high-spatial resolution(1, 2). However, considerable care has to be taken in ion beam radiotherapy because their dose responses for radiation of high-linear energy transfer (LET) are known to be significantly lower, owing to the so-called quenching effect which is attributed to polymerization mechanisms in sites with a higher density of ionization. In carbon ion radiotherapy (CIRT), LET values are widely distributed, ranging from ~10 to more than 100 keV/μm. As LET basically increases with decreasing particle energy, the production of local saturation effects in the film is accentuated for low energy carbon ion beams like the one used for eye treatments, and further increased at the end of the depth dose profile. The aim of this study was to evaluate the loss of efficiency of radiochromic films in this challenging situation, and to evaluate their use as a 2D dosimeter in CIRT. Because of the nature of damages by carbon ions, hypofractionation is used with dose/fraction ranging from ~1 to ~40 Gy (RBE), corresponding to physical doses of the order from 0.5 to 20 Gy. For uveal melanomas, four fractions of 17 Gy (RBE) are delivered using two orthogonal beams, corresponding to ~6 Gy physical dose. The current generation of radiochromic films, Gafchromic® EBT3 and EBT-XD (ISP, Wayne, NJ), are best used in dose ranges of 0.2–10 and 0.4–40 Gy, respectively, which largely cover the range of physical doses used in CIRT. The under-responses of EBT2 and EBT3 films have been investigated for proton and carbon ion beams; however, these studies were limited to the entrance region(3–6). In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated for the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba (HIMAC), and the relation between dose response and LET was evaluated. MATERIALS AND METHODS Film properties GAFchromic EBT3 and EBT-XD films were used in this study. These films are composed of a 28 and 25 μm active layer for EBT3 and EBT-XD, respectively, sandwiched between two 125 μm matte polyester substrates. The active particle size in EBT-XD is significantly smaller than that in EBT3 (length 2–4 and 15–20 μm, respectively, with a similar diameter of 1–2 μm) to achieve fewer lateral response artifacts(7–9). Irradiations Irradiations with 290 and 400 MeV/u carbon ion beams were performed using the horizontal beam line in treatment room C at HIMAC, where CIRT is routinely performed with passive beams. The films provided by the manufacturer were 20.3 cm (8 in) by 25.4 cm (10 in), and they were cut into twenty five 4 cm by 5 cm pieces. Each piece of film was placed on a thin PMMA plate at the isocenter. Dose responses were investigated for four LET values, namely, 12, 42, 48 and 169 keV/μm, corresponding to the entrance of a 400 MeV/u pristine beam and to the proximal, center and distal depth dose points of a 290 MeV/u 60-mm spread-out Bragg peak, respectively. These beams maintained a lateral dose uniformity of ±2.5% within a diameter of 10 cm with the single-ring wobbling method(10). The EBT3 films were irradiated at 10 different absorbed doses between 0.01 and 10 Gy, whereas the EBT-XD films were irradiated at eight absorbed doses between 0.5 and 15 Gy. The LET dependence was investigated using eight LET values between 12 and 169 keV/μm. Because results showed that LET is independent of absorbed dose, as mentioned below, only 1 or 4 Gy irradiations were performed for the four LET conditions. The LET value of the irradiated beam was changed using variable PMMA absorbers upstream of the film. The total absorber thicknesses to obtain 12, 42, 48 and 169 keV/μm were 0, 50.75, 63.75 and 76.75 mm, respectively. The absorbed doses were determined using a main monitor installed in the irradiation system. The monitor unit of the main monitor was calibrated for each thickness of variable PMMA absorbers before film irradiations with a parallel-plate ionization chamber (Advanced Markus®, type 34 045, PTW) set at the film position. This chamber was calibrated according to IAEA protocol (TRS-398)(11). According to TRS-398, the uncertainty in absorbed dose determination is 3.4% for plane-parallel chambers in clinical carbon ion beam. Film analysis The irradiated films were scanned 24 h after irradiation with a commercial flatbed scanner (Seiko Epson Corp. ES-10000G) with a transmission unit using the provided EPSON Scan software in professional mode with all image adjustment features turned off. To avoid any dependence on the scan position or scan direction, each piece of film was placed separately at the same position and orientation in the center of the scanner. The films were digitized as 48-bit RGB with a resolution of 150 dpi and saved as uncompressed Tagged Image File Format (TIFF) files. Due to the highest dose sensitivity among RGB colors, the pixels’ red color channel values were extracted from the TIFF files using ImageJ® (National Institutes of Health, MD, USA) and converted into net optical densities (netODs) using the following equation. netOD=ODexp−OD0=−log(PVRexpPVR0) (1) Here PVR represents the pixel’s red color channel value, and the subscripts of exp and 0 correspond to the irradiated and unirradiated films, respectively. In this study, mean values in the region of interest (a 25-mm-diameter circle in the middle of the film) were used for PVR. The uncertainties in the netODs mainly originate from reproducibility due to uniformity of active particles in film, scanner uniformity, beam uniformity in the irradiation field, and misalignment of the films. The overall uncertainty in the netOD determination was estimated by repeating the entire experiment (and film setup) three times on different days. Finally, the uncertainties of EBT3 and EBT-XD were similar to each other and the maximum uncertainty was found to be 3.0 and 4.9% for EBT3 and EBT-XD films, respectively. Dose calibration and LET correction curves Dose calibration curves, which relate the absorbed dose D and netOD, were obtained using the fitting method shown in Ref. (5), which uses the following equation for the fitting procedure. D(netOD)=A×netOD+B×netODC (2) Here, A and B are the free parameters, whereas C is fixed at an initial value of 2.0 and subsequently increased in steps of 0.1 at each iteration of the fitting process until an appropriate value is found using the least-squares method. For details, refer to Refs. (5 and 12). To quantify the under-responses of EBT3 and EBT-XD films to high-LET radiation, the relative efficiency (RE)—defined as the absorbed dose ratio that yields the same netOD for different beam qualities—was determined(3, 5). In this study, the film dose response was calibrated using 6 MV photons, considered as the standard beam quality, using a clinical linear accelerator (Clinac21-EX, Varian Medical Systems, Palo Alto, USA) at National Institute of Radiological Sciences. In total, 18 film samples of each film type were set at 10 cm depth of a solid water phantom (SSD: 90 cm) in a 10 × 10 cm2 6 MV photon field and were exposed to doses ranging from 0.1 to 8 Gy or 18 Gy for EBT3 and EBT-XD, respectively. Just before film irradiations, a measurement of the linac dose rate was performed with a Farmer® ionization chamber (type30013, PTW). Films were scanned in the same conditions and direction as for the experimental films in carbon ion. The uncertainty in D6 MV (netOD), including the X-ray absolute dose measurement with the ionization chamber (2%), the variation of optical densities (0.3%) and the fitting equation (0.2%) was estimated at 2% for both film types. RE was then calculated as follows: RE=D6MV(netODC−ion)DC−ion, (3) where, DC-ion is the actual dose delivered by carbon ions to the film and D6 MV(netODC-ion) is the 6-MV-photon dose needed to produce the netOD obtained by the carbon-ion irradiation (netODC-ion). Ref. (5) showed that RE could be expressed as a function of dose-averaged LET for protons with LET values ranging from 0.5 to 12 keV/μm(5). This study used Monte Carlo calculations with the PHITS code(13) to estimate dose-averaged LET and finally obtained the relation between RE and dose-averaged LET for LET values observed in clinical carbon ion beams. RESULTS Figure 1 shows the measured dose responses of the EBT3 and EBT-XD films, and Table 1 shows the fit parameters obtained by the fitting procedure for Eq. (2). The dose response of EBT-XD showed ~40% lower sensitivity compared with EBT3, as indicated in the manufacturer’s specifications. Figure 1. View largeDownload slide Relation between the measured netOD and absorbed dose. Each curve represents Eq. (2) with the fit parameters shown in Table 1. Figure 1. View largeDownload slide Relation between the measured netOD and absorbed dose. Each curve represents Eq. (2) with the fit parameters shown in Table 1. Table 1. Fit parameters for Eq. (2) obtained from Figure 1. LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 Table 1. Fit parameters for Eq. (2) obtained from Figure 1. LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 LET [keV/μm] EBT3 EBT-XD A [Gy] B [Gy] C A [Gy] B [Gy] C 12 9.7 ± 0.2 31.5 ± 0.7 2.6 24.7 ± 0.3 101.6 ± 2.2 2.5 41.6 12.2 ± 0.3 40.4 ± 1.4 2.7 29.7 ± 0.3 95.6 ± 2.2 2.3 48.1 12.5 ± 0.2 42.7 ± 0.8 2.7 30.0 ± 0.7 102.5 ± 4.4 2.3 169 18.0 ± 0.3 66.2 ± 2.2 2.7 45.0 ± 1.7 195.8 ± 22.3 2.5 6 MV photon 8.3 ± 0.1 26.2 ± 0.2 2.5 22.6 ± 0.3 84.3 ± 1.5 2.5 Figure 2 shows the relations between dose-averaged LET and RE for the EBT3 and EBT-XD films. Herein, results in the dose ranges 1–10 and 4–15 Gy are plotted for EBT3 and EBT-XD films, respectively, and these results show that RE does not depend on the absorbed dose in these dose ranges. The RE values were fitted using the following equation with free parameters a, b and c, which is a modification of the fit equation given in Ref. (5). RE(LET)=1−a×(LET−c)b(LET≥c) (4) Figure 2. View largeDownload slide (a) EBT3 and (b) EBT-XD. Relation between dose-averaged LET and RE. Each curve represents Eq. (4) with the fit parameters shown in Table 2. Figure 2. View largeDownload slide (a) EBT3 and (b) EBT-XD. Relation between dose-averaged LET and RE. Each curve represents Eq. (4) with the fit parameters shown in Table 2. The fit parameters obtained are given in Table 2, which shows that the fit parameters for EBT3 and EBT-XD agreed within their fitting errors. Moreover, the fit parameter c is considered to be the threshold of under-response to high-LET radiation. This study indicates that the threshold is ~8 keV/μm, which is similar to the results for proton irradiation of EBT2 and EBT3, as seen in Figure 3 in Ref. (5). Table 2. Fit parameters for Eq. (4) obtained from Figure 2. a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 Table 2. Fit parameters for Eq. (4) obtained from Figure 2. a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 a b c EBT3 0.0732 ± 0.0034 0.388 ± 0.010 8.65 ± 0.47 EBT-XD 0.0670 ± 0.0059 0.407 ± 0.018 8.19 ± 0.93 Figure 3. View largeDownload slide Comparisons of lateral dose distributions measured with a pinpoint ion chamber and EBT3 film. Figure 3. View largeDownload slide Comparisons of lateral dose distributions measured with a pinpoint ion chamber and EBT3 film. DISCUSSION The quenching effect is a limitation in the dose determination with films for high-LET radiation such as clinical carbon ion beam. As shown by Figure 2, the relation between LET and RE is non-linear. The quenching effect increases rapidly up to LET around 40 keV/μm (demonstrated by a rapid decrease of RE) and seems to slow down when LET becomes higher. Nevertheless, radiochromic films are suitable for measurements in small irradiation fields because of their high-spatial resolution of the order of 0.1 mm, superior to other 2D detectors with resolutions ranging from 2.5 (Octavius® 1000 SRS, PTW) to 5 mm (MatriXX®, IBA, Belgium). Among the clinical targets treated with CIRT at HIMAC, uveal melanoma is one where treatment requires small irradiation fields(14). For small field QA, the PinPoint® ion chamber (type 31 006, PTW) is used because of the small size of its sensitive volume (0.015 cm2). To verify our under-response correction procedure, a lateral dose distribution was measured with a pinpoint ion chamber and compared to one measured with EBT3 film and corrected using Eq. (4). Here, uveal treatment fields with LET values distributed between 25 and 85 keV/μm were simulated using a brass collimator, a polyethylene compensator, and a 170 MeV/u carbon ion beam. In addition, the comparison was performed for a mono-LET value of ~22 keV/μm without the compensator. Figure 3 shows comparisons of the measured lateral dose distributions. For mono- and multi-LET fields, absorbed doses obtained with pinpoint chamber and EBT3 agreed well within 3 and 6%, respectively. Deviations were large for LET below 40 keV/μm, where the RE is decreasing steeply (Figure 2), suggesting that additional points below 40 keV/μm would improve our model. However, these results indicate that the under-response correction procedure using Eq. (4) can be efficiently employed. CONCLUSION The dose responses of EBT3 and EBT-XD films were experimentally obtained for a clinical carbon ion beam. The relations between absorbed dose and netOD could be expressed well using a fitting equation proposed in the literature. The quenching effect owing to the high LET of carbon ions was also evaluated by determining RE as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used in CIRT eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic films. FUNDING Funding for this work was provided by National Institute of Radiological Sciences. REFERENCES 1 Soares , C. G. Radiochromic film dosimetry . Radiat. Meas. 41 , S100 – S116 ( 2007 ). Google Scholar CrossRef Search ADS 2 Devic , S. Radiochromic film dosimetry: past, present, and future . Phys. Med. 27 , 122 – 134 ( 2011 ). Google Scholar CrossRef Search ADS PubMed 3 Martišíkovsá , M. and Jäkel , O. Dosimetric properties of Gafchromic® EBT films in monoenergetic medical ion beams . Phys. Med. Biol. 55 , 3741 – 3751 ( 2010 ). Google Scholar CrossRef Search ADS PubMed 4 Fiorini , F. , Kirby , D. , Thompson , J. , Green , S. , Parker , D. J. , Jones , B. and Hill , M. A. Under-response correction for EBT3 films in the presence of proton spread out Bragg peaks . Phys. Med. 30 , 454 – 461 ( 2014 ). Google Scholar CrossRef Search ADS PubMed 5 Reinhardt , S. , Würl , M. , Greubel , C. , Humble , N. , Wilkens , J. J. , Hillbrand , M. and Parodi , K. Investigation of EBT2 and EBT3 films for proton dosimetry in the 4–20 MeV energy range . Radiat. Environ. Biophys. 54 ( 1 ), 71 – 79 ( 2015 ). Google Scholar CrossRef Search ADS PubMed 6 Castriconi , R. , Ciocca , M. , Mirandola , A. , Sini , C. , Broggi , S. , Schwarz , M. and Russo , P. Dose–response of EBT3 radiochromic films to proton and carbon ion clinical beams . Phys. Med. Biol. 62 ( 2 ), 377 – 393 ( 2017 ). Google Scholar CrossRef Search ADS PubMed 7 Grams , M. P. , Gustafson , J. M. , Long , K. M. and Fong de los Santos , L. E. Technical note: initial characterization of the new EBT-XD Gafchromic film . Med. Phys. 42 ( 10 ), 5782 – 5786 ( 2015 ). Google Scholar CrossRef Search ADS PubMed 8 Palmer , A. L. , Dimitriadis , A. , Nisbet , A. and Clark , C. H. Evaluation of Gafchromic EBT-XD film, with comparison to EBT3 film, and application in high dose radiotherapy verification . Phys. Med. Biol. 60 , 8741 – 8752 ( 2015 ). Google Scholar CrossRef Search ADS PubMed 9 Lewis , D. F. and Chan , M. F. On GAFChromic EBT-XD film and the lateral response artifact . Med. Phys. 43 ( 2 ), 643 – 649 ( 2016 ). Google Scholar CrossRef Search ADS PubMed 10 Yonai , S. , Kanematsu , N. , Komori , M. , Kanai , T. , Takei , Y. , Takahashi , O. and Tomita , H. Evaluation of beam wobbling methods for heavy-ion radiotherapy . Med. Phys. 35 ( 3 ), 927 – 938 ( 2008 ). Google Scholar CrossRef Search ADS PubMed 11 International Atomic Energy Agency . Absorbed doe determination in external beam radiotherapy. Technical Report Series No. 398 ( 2000 ). 12 Devic , S. , Seuntjens , J. , Hegyi , G. , Podgorsak , E. B. , Soares , C. G. , Kirov , A. S. and Elizondo , A. Dosimetric properties of improved GafChromic films for seven different digitizers . Med. Phys. 31 ( 9 ), 2392 – 2401 ( 2004 ). Google Scholar CrossRef Search ADS PubMed 13 Sato , T. et al. . Particle and heavy ion transport code system PHITS, Version 2.52 . J. Nucl. Sci. Technol. 50 ( 9 ), 913 – 923 ( 2013 ). Google Scholar CrossRef Search ADS 14 Toyama , S. , Tsuji , H. , Mizoguchi , N. , Nomiya , T. , Kamada , T. , Tokumaru , S. , Mizota , A. , Ohnishi , Y. and Tsujii , H. , Working Group for Ophthalmologic Tumors . Long-term results of carbon ion radiation therapy for locally advanced or unfavorably located choroidal melanoma: usefulness of CT-based 2-port orthogonal therapy for reducing the incidence of NVG . Int. J. Radiat. Oncol. Biol. Phys. 86 , 270 – 276 ( 2013 ). Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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Radiation Protection DosimetryOxford University Press

Published: Feb 3, 2018

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