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Title: Preclinical investigation for developing injectable fiducial markers using a mixture of BaSO{sub 4} and biodegradable polymer for proton therapy

Abstract

Purpose: The aim of this study is to investigate the use of mixture of BaSO{sub 4} and biodegradable polymer as an injectable nonmetallic fiducial marker to reduce artifacts in x-ray images, decrease the absorbed dose distortion in proton therapy, and replace permanent metal markers. Methods: Two samples were made with 90 wt. % polymer phosphate buffer saline (PBS) and 10 wt. % BaSO{sub 4} (B1) or 20 wt. % BaSO{sub 4} (B2). Two animal models (mice and rats) were used. To test the injectability and in vivo gelation, a volume of 200 μl at a pH 5.8 were injected into the Sprague-Dawley rats. After sacrificing the rats over time, the authors checked the gel morphology. Detectability of the markers in the x-ray images was tested for two sizes (diameters of 1 and 2 mm) for B1 and B2. Four samples were injected into BALB/C mice. The polymer mixed with BaSO{sub 4} transform from SOL at 20 °C with a pH of 6.0 to GEL in the living body at 37 °C with a pH of 7.4, so the size of the fiducial marker could be controlled by adjusting the injected volume. The detectability of the BaSO{sub 4} marker was measured in x-raymore » images of cone beam CT (CBCT), on-board imager [anterior–posterior (AP), lateral], and fluoroscopy (AP, lateral) using a Novalis-TX (Varian Medical Systems, Palo Alto, CA) repeatedly over 4 months. The volume, HU, and artifacts for the markers were measured in the CBCT images. Artifacts were compared to those of gold marker by analyzing the HU distribution. The dose distortion in proton therapy was computed by using a Monte Carlo (MC) code. A cylindrical shaped marker (diameter: 1 or 2 mm, length: 3 mm) made of gold, stainless-steel [304], titanium, and 20 wt. % BaSO{sub 4} was positioned at the center of the spread-out Bragg peak (SOBP) in parallel or perpendicular to the beam entrance. The dose distortion was measured on the depth dose profile across the markers. Results: Transformation to GEL and the biodegradation were verified. All BaSO{sub 4} markers could be detected in the CBCT. In the OBI and fluoroscopy images, all markers visible in the AP, but only B2(2 mm) could be identified in the lateral images. Changes of BaSO{sub 4} position were not detected in vivo (mice). The volume of the markers decreased by up to 65% and the HU increased by 22%, on average. The mean HU values around the B1, B2, and gold markers were 121.30 [standard deviation (SD): 54.86], 126.31 (SD: 62.13), and 1070.7 (SD: 235.16), respectively. The MC-simulated dose distortion for the BaSO{sub 4} markers was less than that of the commercially used markers. The dose reduction due to the gold marker was largest (15.05%) followed by stainless steel (7.92%) and titanium (6.92%). Dose reduction by B2 (2 mm) was 4.75% and 0.53% in parallel and perpendicular orientations, respectively. Conclusions: BaSO{sub 4} mixed with PBS is a good contrast agent in biodegradable polymer marker because of minimal artifacts in x-ray images and minimal dose reduction in proton therapy. The flexibility of the size is considered to be an advantage of this material over solid type fiducials.« less

Authors:
 [1]; ;  [2]; ; ; ; ; ; ;  [3];  [4]; ;  [5]
  1. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710 (Korea, Republic of)
  2. Sungkyunkwan University School of Chemical Engineering, Suwon 440-746 (Korea, Republic of)
  3. Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of)
  4. Department of Radiation Oncology, Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 (United States)
  5. Department of Radiation Oncology, Samsung Medical Center, Seoul 135-710 (Korea, Republic of)
Publication Date:
OSTI Identifier:
22413567
Resource Type:
Journal Article
Resource Relation:
Journal Name: Medical Physics; Journal Volume: 42; Journal Issue: 5; Other Information: (c) 2015 American Association of Physicists in Medicine; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; 60 APPLIED LIFE SCIENCES; ABSORBED RADIATION DOSES; BARIUM SULFATES; BRAGG CURVE; CONTRAST MEDIA; DEPTH DOSE DISTRIBUTIONS; FIDUCIAL MARKERS; GOLD; MICE; PROTON BEAMS; RADIOTHERAPY; RATS; STAINLESS STEEL-304; TITANIUM; X RADIATION

Citation Formats

Ahn, Sang Hee, Gil, Moon Soo, Lee, Doo Sung, Han, Youngyih, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com, Park, Hee Chul, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com, Yu, Jeong Il, Noh, Jae Myoung, Cho, Jun Sang, Ahn, Sung Hwan, Choi, Doo Ho, Sohn, Jason W., Kim, Hye Yeong, and Shin, Eun Hyuk. Preclinical investigation for developing injectable fiducial markers using a mixture of BaSO{sub 4} and biodegradable polymer for proton therapy. United States: N. p., 2015. Web. doi:10.1118/1.4916663.
Ahn, Sang Hee, Gil, Moon Soo, Lee, Doo Sung, Han, Youngyih, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com, Park, Hee Chul, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com, Yu, Jeong Il, Noh, Jae Myoung, Cho, Jun Sang, Ahn, Sung Hwan, Choi, Doo Ho, Sohn, Jason W., Kim, Hye Yeong, & Shin, Eun Hyuk. Preclinical investigation for developing injectable fiducial markers using a mixture of BaSO{sub 4} and biodegradable polymer for proton therapy. United States. doi:10.1118/1.4916663.
Ahn, Sang Hee, Gil, Moon Soo, Lee, Doo Sung, Han, Youngyih, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com, Park, Hee Chul, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com, Yu, Jeong Il, Noh, Jae Myoung, Cho, Jun Sang, Ahn, Sung Hwan, Choi, Doo Ho, Sohn, Jason W., Kim, Hye Yeong, and Shin, Eun Hyuk. Fri . "Preclinical investigation for developing injectable fiducial markers using a mixture of BaSO{sub 4} and biodegradable polymer for proton therapy". United States. doi:10.1118/1.4916663.
@article{osti_22413567,
title = {Preclinical investigation for developing injectable fiducial markers using a mixture of BaSO{sub 4} and biodegradable polymer for proton therapy},
author = {Ahn, Sang Hee and Gil, Moon Soo and Lee, Doo Sung and Han, Youngyih, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com and Park, Hee Chul, E-mail: youngyih@skku.edu, E-mail: Hee.ro.Park@samsung.com and Yu, Jeong Il and Noh, Jae Myoung and Cho, Jun Sang and Ahn, Sung Hwan and Choi, Doo Ho and Sohn, Jason W. and Kim, Hye Yeong and Shin, Eun Hyuk},
abstractNote = {Purpose: The aim of this study is to investigate the use of mixture of BaSO{sub 4} and biodegradable polymer as an injectable nonmetallic fiducial marker to reduce artifacts in x-ray images, decrease the absorbed dose distortion in proton therapy, and replace permanent metal markers. Methods: Two samples were made with 90 wt. % polymer phosphate buffer saline (PBS) and 10 wt. % BaSO{sub 4} (B1) or 20 wt. % BaSO{sub 4} (B2). Two animal models (mice and rats) were used. To test the injectability and in vivo gelation, a volume of 200 μl at a pH 5.8 were injected into the Sprague-Dawley rats. After sacrificing the rats over time, the authors checked the gel morphology. Detectability of the markers in the x-ray images was tested for two sizes (diameters of 1 and 2 mm) for B1 and B2. Four samples were injected into BALB/C mice. The polymer mixed with BaSO{sub 4} transform from SOL at 20 °C with a pH of 6.0 to GEL in the living body at 37 °C with a pH of 7.4, so the size of the fiducial marker could be controlled by adjusting the injected volume. The detectability of the BaSO{sub 4} marker was measured in x-ray images of cone beam CT (CBCT), on-board imager [anterior–posterior (AP), lateral], and fluoroscopy (AP, lateral) using a Novalis-TX (Varian Medical Systems, Palo Alto, CA) repeatedly over 4 months. The volume, HU, and artifacts for the markers were measured in the CBCT images. Artifacts were compared to those of gold marker by analyzing the HU distribution. The dose distortion in proton therapy was computed by using a Monte Carlo (MC) code. A cylindrical shaped marker (diameter: 1 or 2 mm, length: 3 mm) made of gold, stainless-steel [304], titanium, and 20 wt. % BaSO{sub 4} was positioned at the center of the spread-out Bragg peak (SOBP) in parallel or perpendicular to the beam entrance. The dose distortion was measured on the depth dose profile across the markers. Results: Transformation to GEL and the biodegradation were verified. All BaSO{sub 4} markers could be detected in the CBCT. In the OBI and fluoroscopy images, all markers visible in the AP, but only B2(2 mm) could be identified in the lateral images. Changes of BaSO{sub 4} position were not detected in vivo (mice). The volume of the markers decreased by up to 65% and the HU increased by 22%, on average. The mean HU values around the B1, B2, and gold markers were 121.30 [standard deviation (SD): 54.86], 126.31 (SD: 62.13), and 1070.7 (SD: 235.16), respectively. The MC-simulated dose distortion for the BaSO{sub 4} markers was less than that of the commercially used markers. The dose reduction due to the gold marker was largest (15.05%) followed by stainless steel (7.92%) and titanium (6.92%). Dose reduction by B2 (2 mm) was 4.75% and 0.53% in parallel and perpendicular orientations, respectively. Conclusions: BaSO{sub 4} mixed with PBS is a good contrast agent in biodegradable polymer marker because of minimal artifacts in x-ray images and minimal dose reduction in proton therapy. The flexibility of the size is considered to be an advantage of this material over solid type fiducials.},
doi = {10.1118/1.4916663},
journal = {Medical Physics},
number = 5,
volume = 42,
place = {United States},
year = {Fri May 15 00:00:00 EDT 2015},
month = {Fri May 15 00:00:00 EDT 2015}
}
  • Purpose: Currently there are no clinically used techniques for in-vivo proton treatment/range verification. Our aim was to develop patient implantable markers that can be visualized in CT/x-ray for treatment-planning/beam-positioning, and also in PET for proton treatment/range verification. Methods: Biocompatible/biodegradable hydrogel polymers were immersed in O18-enriched water and O16 water, respectively to create O18-water hydrogels (0.5 cm3) and O16-water hydrogels (1 cm3) (both >99% water and <1% polymer). Also, 5–8 µm Zn powder was suspended in O16 water and O18-enriched water and cross-linked with hydrogel polymers to create Zn/16O-water hydrogels (30%/70% mass ratio, <1% polymer) and Zn/18O-water hydrogels (10%/90%). A blockmore » of extra-firm “wet” tofu (12.3×8.8×4.9 cm, ρ{sup =}1) immersed in water was injected with Zn/O16-water hydrogels (0.9 cm3 each) at four different depths using an 18 gauge needle. Similarly, Zn/18O-water hydrogels (0.9 cm3) were injected in a different tofu phantom. As a reference, both 16O-water and O18-water hydrogels in petri-dishes were irradiated in a “dry” environment. The hydrogels in the “wet” tofu phantoms and “dry” petri-dishes were CT-scanned and treatment-planned. Then, they were positioned at the proton distal dose fall-off region and irradiated (2 Gy) followed by PET/CT imaging. Results: Significantly high PET signals were observed only at O18-water hydrogels in the “dry” environment. Zn/O16-water hydrogels injected in the tofu phantom showed outstanding CT visibility but provided no noticeable PET signals. Zn/O18-water hydrogels in the “wet” tofu showed excellent CT visibility and moderate PET visibility, however, weaker PET signals than the “dry” environment possibly due to O18-water leaching out. Conclusion: The developed hydrogel markers can be used as universal fiducial markers due to their CT/PET/MRI/US visibility. Their PET visibility (possibly contributed more by activated O18-water than Zn) after proton irradiation can be utilized for proton therapy/range verification. More investigation is needed to slow down the leaching of O18-water.« less
  • Purpose: We examined the feasibility of using fiducial markers composed of microscopic gold particles and human-compatible polymers as a means to overcome current problems with conventional macroscopic gold fiducial markers, such as dose reduction and artifact generation, in proton therapy for prostate cancer. Methods and Materials: We examined two types of gold particle fiducial marker interactions: that with diagnostic X-rays and with a therapeutic proton beam. That is, we qualitatively and quantitatively compared the radiographic visibility of conventional gold and gold particle fiducial markers and the CT artifacts and dose reduction associated with their use. Results: The gold particle fiducialsmore » could be easily distinguished from high-density structures, such as the pelvic bone, in diagnostic X-rays but were nearly transparent to a proton beam. The proton dose distribution was distorted <5% by the gold particle fiducials with a 4.9% normalized gold density; this was the case even in the worst configuration (i.e., parallel alignment with a single-direction proton beam). In addition, CT artifacts were dramatically reduced for the gold particle mixture. Conclusion: Mixtures of microscopic gold particles and human-compatible polymers have excellent potential as fiducial markers for proton therapy for prostate cancer. These include good radiographic visibility, low distortion of the depth-dose distribution, and few CT artifacts.« less
  • Purpose: In accurate proton spot-scanning therapy, continuous target tracking by fluoroscopic x ray during irradiation is beneficial not only for respiratory moving tumors of lung and liver but also for relatively stationary tumors of prostate. Implanted gold markers have been used with great effect for positioning the target volume by a fluoroscopy, especially for the cases of liver and prostate with the targets surrounded by water-equivalent tissues. However, recent studies have revealed that gold markers can cause a significant underdose in proton therapy. This paper focuses on prostate cancer and explores the possibility that multiple-field irradiation improves the underdose effectmore » by markers on tumor-control probability (TCP). Methods: A Monte Carlo simulation was performed to evaluate the dose distortion effect. A spherical gold marker was placed at several characteristic points in a water phantom. The markers were with two different diameters of 2 and 1.5 mm, both visible on fluoroscopy. Three beam arrangements of single-field uniform dose (SFUD) were examined: one lateral field, two opposite lateral fields, and three fields (two opposite lateral fields + anterior field). The relative biological effectiveness (RBE) was set to 1.1 and a dose of 74 Gy (RBE) was delivered to the target of a typical prostate size in 37 fractions. The ratios of TCP to that without the marker (TCP{sub r}) were compared with the parameters of the marker sizes, number of fields, and marker positions. To take into account the dependence of biological parameters in TCP model, {alpha}/{beta} values of 1.5, 3, and 10 Gy (RBE) were considered. Results: It was found that the marker of 1.5 mm diameter does not affect the TCPs with all {alpha}/{beta} values when two or more fields are used. On the other hand, if the marker diameter is 2 mm, more than two irradiation fields are required to suppress the decrease in TCP from TCP{sub r} by less than 3%. This is especially true when multiple (two or three) markers are used for alignment of a patient. Conclusions: It is recommended that 1.5-mm markers be used to avoid the reduction of TCP as well as to spare the surrounding critical organs, as long as the markers are visible on x-ray fluoroscopy. When 2-mm markers are implanted, more than two fields should be used and the markers should not be placed close to the distal edge of any of the beams.« less
  • Purpose: For proton beam therapy, small fiducial markers are preferred for patient alignment due to less interference with the proton beam. Visualizing small fiducial markers can be challenging in MRI. This study intends to investigate MRI imaging protocols for better visualization of small fiducial markers. Methods: Two carbon and two coil-shaped gold markers were placed into a gel phantom. Both carbon markers had a diameter of 1mm and a length of 3mm. Both gold markers had a length of 5mm. One gold marker had a diameter of 0.5mm and the other had a diameter of 0.75mm. T1 VIBE, T2 SPACE,more » TrueFISP and susceptibility weighted (SW) images were acquired. To improve marker contrast, high spatial resolution was used to reduce partial volume effect. Slice thickness was 1.5mm for all four sequences and in-plane resolution was 0.6mm for TrueFISP, 0.7mm for T1 VIBE, and 0.8mm for T2 SPACE and SW. For comparison purpose, a 3D T1 VIBE image set at 3mm slice thickness and 1.2mm in-plane resolution was also acquired. Results: All markers were visible in all high-resolution image sets. In each image set, marker-induced signal void was the smallest (in diameter) for carbon markers, followed by the 0.5mm gold marker and the largest for the 0.75mm gold marker. The SW images had the largest marker-induced signal void. However, those might be confused by susceptibility-gradient-induced signal voids. T1 VIBE had good visualization of markers with nicely defined edges. T2 SPACE had reasonable visualization of markers but edges were slightly blurred. TrueFISP had good visualization of markers only if they were not masked by banding artifacts. As a comparison, all markers were hardly visible in the standard resolution T1 VIBE images. Conclusion: 3D high-resolution T1 VIBE and SW have great potential in providing good visualization of small fiducial markers for proton beam therapy.« less
  • Purpose: To estimate the prevalence of rectal and urinary dysfunctional symptoms using image guided radiation therapy (IGRT) with fiducials and magnetic resonance planning for prostate cancer. Methods and Materials: During the implementation stages of IGRT between September 2008 and March 2010, 367 consecutive patients were treated with prostatic irradiation using 3-dimensional conformal radiation therapy with and without IGRT (non-IGRT). In November 2010, these men were asked to report their bowel and bladder symptoms using a postal questionnaire. The proportions of patients with moderate to severe symptoms in these groups were compared using logistic regression models adjusted for tumor and treatmentmore » characteristic variables. Results: Of the 282 respondents, the 154 selected for IGRT had higher stage tumors, received higher prescribed doses, and had larger volumes of rectum receiving high dosage than did the 128 selected for non-IGRT. The follow-up duration was 8 to 26 months. Compared with the non-IGRT group, improvement was noted in all dysfunctional rectal symptoms using IGRT. In multivariable analyses, IGRT improved rectal pain (odds ratio [OR] 0.07 [0.009-0.7], P=.02), urgency (OR 0.27 [0.11-0.63], P=<.01), diarrhea (OR 0.009 [0.02-0.35], P<.01), and change in bowel habits (OR 0.18 [0.06-0.52], P<.010). No correlation was observed between rectal symptom levels and dose-volume histogram data. Urinary dysfunctional symptoms were similar in both treatment groups. Conclusions: In comparison with men selected for non-IGRT, a significant reduction of bowel dysfunctional symptoms was confirmed in men selected for IGRT, even though they had larger volumes of rectum treated to higher doses.« less