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A novel conformal superficial high-dose-rate brachytherapy device for the treatment of nonmelanoma skin cancer and keloids
Brachytherapy
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(2016)
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A novel conformal superficial high-dose-rate brachytherapy device for the treatment of nonmelanoma skin cancer and keloids Clara Ferreira1,*, Daniel Johnson2, Karl Rasmussen3, Clinton Leinweber4, Salahuddin Ahmad2, Jae Won Jung5 1 Department of Radiation Oncology, University of Minnesota, Minneapolis, MN Department of Radiation Oncology, The University of Oklahoma, Oklahoma City, OK 3 Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX 4 Department of Radiation Oncology, East Carolina University, Greenville, NC 5 Department of Physics, East Carolina University, Greenville, NC 2
ABSTRACT
PURPOSE: To develop a novel conformal superficial brachytherapy (CSBT) device as a treatment option for the patient-specific radiation therapy of conditions including superficial lesions, postsurgical positive margins, Dupuytren’s contractures, keloid scars, and complex anatomic sites (eyelids, nose, ears, etc.). METHODS AND MATERIALS: A preliminary CSBT device prototype was designed, built, and tested using readily available radioactive seeds. Iodine-125 (125I) seeds were independently guided to the treatment surface to conform to the target. Treatment planning was performed via BrachyVision Planning System (BPS) and dose distributions measured with Gafchromic EBT3 film. Percent depth dose curves and profiles for Praseodymium-142 (142Pr), and Strontium-90/Yttrium-90 (90Sre90Y) were also investigated as potential sources. Results achieved with 90Sre90Y and electron external beam radiation therapy were compared and Monte Carlo N-Particle eXtended 2.6 simulations of 142Pr seeds were validated. RESULTS: BPS was able to predict clinical dose distributions for a multiple seeds matrix. Calculated and measured doses for the 125I seed matrix were 500 cGy and 473.5 cGy at 5 mm depth, and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively. Results of 90Sre90Y tests demonstrate a more conformal dose than electron EBRT (1.6 mm compared to 4.3 mm penumbra). Measured 142 Pr doses were 500 cGy at surface and 17.4 cGy at 5 mm depth. CONCLUSIONS: The CSBT device provides a highly conformal dose to small surface areas. Commercially available BPS can be used for treatment planning, and Monte Carlo simulation can be used for plans using beta-emitting sources and complex anatomies. Various radionuclides may be used in this device to suit prescription depths and treatment areas. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Skin cancer; High-dose-rate brachytherapy; Monte Carlo simulation; Conformal superficial applicator
Introduction Basal and squamous cell skin cancers are being diagnosed at a greater rate each year. The American Cancer
Received 4 June 2016; received in revised form 4 September 2016; accepted 6 September 2016. Conflict of interest: The authors declare no conflict of interest. * Corresponding author. Department of Radiation Oncology, University of Minnesota Medical School-Twin Cities, 420 Delaware Street Southeast, Mayo Mail Code # 494, Minneapolis, MN 55455. Tel.: þ1612-626-4484; fax: +1-612-624-5445. E-mail address: [email protected] (C. Ferreira).
Society estimates that 3.5 million new cases will occur this year alone (1). As the most widespread cancer, skin cancer includes basal cell carcinoma, squamous cell carcinoma (SCC), melanoma, and nonepithelial skin cancer. The currently available treatment modalities include traditional surgical intervention, Mohs micrographic surgery, cryosurgery, external beam radiation therapy (EBRT), high-dose-rate brachytherapy (HDR), and electronic brachytherapy (eBT) (2, 3). Mohs micrographic surgery is a well-established option for basal cell carcinoma; however, its side effects may include incision site complications and scarring (1). Although surgery is the standard treatment for
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.09.002
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nonmelanoma skin cancer, radiotherapy is oftentimes used as adjuvant to surgery. Radiotherapy as monotherapy is in some instances the preferred method for patients who choose to avoid disfiguring and painful surgery and may also be the recommended treatment for patients unable to qualify for tumor resection due to: potentially compromised organ function, tumors deemed surgically unresectable, or if surgery is contraindicated for medical reasons. Historically, orthovoltage therapy has been a common treatment modality for treating superficial tumors. While easier to shield and capable of small field sizes and a sharp dose falloff when compared to megavoltage electron beams (4), the drawback of orthovoltage therapy is the enhanced dose to the underlying bone, potentially 2 to 3 times greater due to the photoelectric effect for high Z material in the kV energy range (5). Electron EBRT is effective for treating large and flat areas in the body but may fail to deliver predictable and homogeneous coverage to small or irregular fields. Additional radiation modalities that are currently available to treat superficial lesions include the eBT devices such as Esteya, and Xoft Axxent Electronic Brachytherapy System (6). The advantages of eBT are the low-energy xray sources (continuous spectrum with maximum of 50 keV for Xoft and 69.5 keV for Esteya) and a relatively simplified treatment procedure. Field sizes in eBT present circular and flat shapes, ranging from 1 to 3 cm in diameter. Other HDR-based procedures have been developed to use applicators and molds attached to the 192Ir after-loader; including the Elekta’s Valencia, and Freiburg Flap applicators, and the Varian Leipzig surface applicator. These HDR techniques have addressed the need of a more conformal therapy, yet the higher photon energies of 192Ir sources (average energy of 0.38 MeV) result in deeper dose penetration in tissue. Recurrence rates for nonmelanoma skin cancer are reported to be very low after radiation therapy (7, 8), and current brachytherapy techniques have demonstrated local control comparable to electron EBRT (9). Conformal superficial brachytherapy (CSBT) is proposed as an alternative potential modality in small field contact therapy by: (1) Limiting exposure to healthy tissue: adverse effects of radiation to surrounding healthy tissue may include desquamation, alopecia, hypopigmentation, or hyperpigmentation, fibrosis, necrosis, radiodermatitis with nonhealing ulcerations, ocular damage, hearing loss, and secondary skin malignancies appearing several years after treatment (10); therefore, for small lesions, a more localized irradiation may be beneficial. (2) Delivering patient-specific fields: CSBT has the potential to deliver intensity-modulated radiation fields similar to a multileaf collimator used to precisely collimate photons. By the superposition of small treatment fields at the skin surface, the physician may adequately tailor the planned dose to the
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individual characteristics of each lesion with greater precision. This technique allows treatment plans to address the individualized nature of cancer (11). Balancing treatment efficacy and normal tissue complication are of fundamental importance in the practice of radiation therapy. Individualized and patient-specific treatment methodologies are at the core of both modern radiotherapy precision medicine (12). The goal of the CSBT was to offer a patient-specific and tumor-specific conformal treatment, sparing healthy tissue, and administering a therapeutic dose. The design of the device allows for the use of a variety of isotopes. Previous clinical studies on the use of Strontium-90 (90Sr) in treating skin cancer (13) make it a strong candidate for use in this device. 90Sr is a longlived, high-energy, beta-emitting radionuclide, traditionally used in treating conjunctival SCC and melanoma of the eye, and post-surgical prevention of pterygia (14e16). While the decay product of 90Sr is the short-lived Yttrium-90 (90Y), parent and daughter coexist in secular equilibrium (90Sre90Y). Another promising isotope is beta-emitter Praseodymium-142 (142Pr) having been previously studied for applications in prostate and liver cancer (17, 18). The potential of Iodine-125 (125I) seeds are supported by its common use in prostate seed implants, Collaborative Ocular Melanoma Study eye plaques, (19), and the availability of consensus dosimetric parameters presented in the report of The American Association of Physicists in Medicine (AAPM) Task Group 43 (20). While the radioisotopes used in this study are generally well established, the innovative device design enhances skin lesion targeting and healthy tissue sparing. The intent of this study is to design and construct a prototype device to test the feasibility and advantages of using different radionuclides. The prototype was designed, manufactured, and mechanically tested in-house. While the radionuclides used in this study include the beta-emitters 142 Pr and 90Sre90Y, and the gamma-emitter 125I, Monte Carlo N-Particle eXtended (MCNPX) 2.6 Monte Carlo Simulations were exclusively performed for 142Pr to determine its applicability in the device designed. Dose distributions were assessed for different radioactive seed loading patterns. Dose profiles from external electron beams were used to compare and estimate the dose conformity capable of the device. Methods and materials The device tested is designed to optimally conform to the patient-specific geometries and treat small (!3 cm), superficial tumors; delivering a localized, therapeutic dose to the lesion, ensuring favorable cosmetic outcomes, and limiting any adverse side effects. An increase in the scale area of the device design, or abutting treatment applications on the patient, may be used to treat larger fields.
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The device in addition has the potential to deliver different doses to different regions of interest; it may be gross tumor volume, clinical target volume, or planning target volume. Ouhib et al. (21) has recently reviewed margins and dose fractionations for HDR-based contact therapies. In the clinical application of the device, patient selection, dose fractionation scheme, and treatment margins should be based on the evidence reported in literature. Margins for clinical target volume expansions from gross tumor volume of 4 mm can be used for low risk and a 6 mm for high risk if lesion location allows, based on margin recommendations of Mohs surgery. A 5-mm expansion of the planning target volume is common practice. Total dose prescriptions and fractionation schemes used in custom brachytherapy molds and superficial applicators may vary (12e42 Gy). The prescription depth is selected to limit the dose to the surface and hypofractionated schedules are commonly used (5e7 fractions). Device design The CSBT device is comprised of an applicator containing several retractable rods, a radioactive seed placed at the tip of each. A shielded hollow acrylic cylinder contains the loaded rods and evenly distributes them in a 3-cm diameter grid pattern (Fig. 1). For 90Sre90Y applications, the external cylinder that lodges the seeds needs to adequately shield against both beta and generated bremsstrahlung radiations. An ideal construct for this application may be a layer of tungsten greater than 0.60 mm, shielding the 90Y daughter (22). The diameter of applicator enables the device to address a variety of skin tumor sizes. The mechanically controlled rods may move independently from one another, the length of each rod projection controlled to conform to flat or curved surfaces. Two- or three-dimensional modulated fields can be obtained through a combination of field segments (Fig. 2). A device holder was designed to permit both
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rotation and translation, allowing accurate positioning of the applicator over the tumor site (Fig. 3). In prototype testing, a gynecological HDR mechanical arm stabilizer was used to hold the device in place during irradiation using 125I seeds. Positional uncertainty was within 1 mm from the planned position. Advantages presented by the device included: (1) Short patient treatment time: radioisotopes such as 90 Sr can administer high-dose rates of radiation to the skin, allowing the procedure to be completed within a few minutes. This duration is comparable to the treatment times of current treatment techniques. (2) Reusable treatment materials: device and radioactive seeds can be reused for multiple patients and tumors. Utilization of a thin protective disposable membrane avoids direct contact of patient skin with surface of the device. (3) Precise therapy: the device allows for small field sizes to be localized to the treatment area and offers the flexibility of replanning subsequent treatment fractions to account for possible changes in target size. (4) Versatility: the geometry and physical properties of the hardware enable the device to be applicable to other types of superficial regions of interest: keloids, Dupuytren’s contractures, and other superficial conditions. (5) Treatment verification: positioning and dose distributions can be verified with high resolution using dosimeters such as radiochromic film. The delivery of the therapy can be checked against the original treatment plan and quality assurance (QA) methods can be easily implemented for the device. (6) Treatment time and QA: timing can be controlled by an automated positioning system. Linearity testing, end effect evaluation, and total time QA should be performed on a frequency recommended by AAPM Task Group 56 (23). In the present study, the theoretical model conceived and prototype built and tested were measured via Gafchromic film; 2D dose distributions measured in solid water phantoms for all radionuclides of interest. Doses were calculated in the BrachyVision Planning System (BPS) for the CSBT device using multiple 125I seeds and compared with measured doses. Conformity of doses for 90Sre90Y sources were compared with the doses delivered with the commonly used 6 MeV external beam electron cutouts. Finally, dose measurements for 142Pr were obtained and compared with Monte Carlo simulations for this nuclide. Preliminary 3D-printed prototype
Fig. 1. Conformal superficial brachytherapy (CSBT) device showing possible seed expansions for positioning in the skin surface to conform to treatment lesion. Time and position of each seed can be controlled to optimize the treatment.
A preliminary, 3D-printed prototype of the device was used in initial measurements and proof-of-concept testing. The device prototype was designed in SketchUp (Trimble
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Fig. 2. (a) Clockwise direction, starting from top left: frontal view of the template with no rods extended, field 1 (yellow), superposition of fields 1 and 2 (orange), superposition of fields 1, 2, and 3 (red). (b) Representation of total dose distribution from all fields added. ‘‘(For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)’’
Navigation) and exported to Slic3r, which translated the digital 3D model into printing instructions (gcode) for a Fusematic 3D printer (Maker’s Tool Works). The prototype was printed in-house using PLA thermoplastic via Bowden-style extrusion technique. Cylindrical brass rods (1.59 304.8 mm2) were inserted through the 3D-printed template, and 125I seeds were directly attached to the tip of each rod. The movable metal rods were free to extend and retract in the 3D-printed template to conform to the surface. Film dosimetry Often used in treatment verification and QA, selfdeveloping Gafchromic EBT3 film offers high-spatial
resolution (25 mm), a weak energy dependency, and requires no wet processing (24, 25). As it is designed for quantitative dose measurements in radiotherapy, it is widely used in intensity-modulated radiation therapy and brachytherapy; applications in which high-dose gradients occur (26). The dose response for Gafchromic film is independent of fractionation, dose rate, and depth dependence for electron beams (27). The film is water resistant, stable in room light and temperatures of up to 60 C, and has a nearly EBT tissue-equivalent electron density (Zeff 5 6.84 compared water to Zeff 5 7.42). EBT3 films were scanned using an Epson Expression 10000XL and analyzed in ImageJ (National Institute of Health). The color scanning of the film enabled the red channel to be used for the dose calibration curves, having a strong sensitivity to dose. While film sensitivity in the red channel limits the range to between 1 and 1000 cGy, film doses were derived through cross-referencing an Accredited Dosimetry Calibration Laboratory calibrated ion chamber.
Gamma-emitter Iodine-125 film measurements and planning system doses
Fig. 3. Device holder and CSBT device positioned at the target.
The CSBT device was built and tested using multiple radioactive seeds loaded at the tips of metal rods. Due to availability, OncoSeed Model 6711 (GE-Amersham) Iodine-125 seeds (half-life: 59.4 days, average gamma energy: 28 keV) were used to test the feasibility of the device. The rods were spaced 1.5 mm apart when placed through the device core. The 125I loaded rods were allowed to move independently at the treatment surface to conform to the desired geometry, measurements performed in solid water phantom for different prescription depths and surface areas.
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A computed tomography (CT) scan of the device template was performed in a GE LightSpeed 16 slice CT scanner and exported to BPS to acquire the exact seed positioning for planning purposes (Fig. 4). Treatment using eleven 125I seeds was planned in BPS and measured experimentally for a total dose of 500 cGy at 5.0 mm depth. Percent depth doses (PDD) and dose profiles were analyzed. Beta-emitter 90Sre90Y and electron cutout film measurements A HDR 90Sre90Y beta therapy source (New England Nuclear, source surface dose rate: 59.3 cGy/s; half-lives: 28.79 years, and 64.1 h and maximum beta decay energies: 0.546 MeV, and 2.279 MeV, respectively) was used to test this radionuclide as a candidate for use in the CSBT device. The beta therapy source of 1 cm diameter was used to deliver dose to a solid water phantom containing EBT3 Gafchromic films arranged both on and perpendicular to the phantom surface. Due to the HDR of the source, the total dose was delivered within 20 s. The doses delivered using the 90Sre90Y beta therapy source were compared with distributions achieved via 6 MeV (Varian 21EX Clinac) external electron beam radiation using small cutouts (1 cm diameter at 100 cm source to surface distance) in a 6 6 cm2 cone and having a 0.5cm bolus applied to the surface. The small electron cutouts are not clinically ideal; however, in some practical scenarios where the eyelids, lips and ears need to be treated, cutouts of this magnitude are oftentimes used. It was intended to compare the dose coverage and dose distributions for these small fields with the doses delivered by the CSBT device. A film calibration curve (dose range: 20e 1000 cGy) was generated using the 6 MeV electron beam and was used to calibrate both 90Sre90Y and electron cutout films. Normalized PDD and dose profiles for both techniques were analyzed.
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Beta-emitter Praseodymium-142 film measurements and Monte Carlo Simulations Beta-emitter 142Pr (decay mode: 96.3% beta and 3.7% gamma; half-life: 19.12 h; average beta energy: 809 keV, maximum beta energy: 2.162 MeV) was studied as a potential candidate for the use in the CSBT device. 141Pr glass rods (MO-SCI Corporation) of 1.5 mm diameter and a length of 5 mm (a total sample mass of 0.353 g) were activated in a research reactor (neutron absorption crosssection 11.40 barn). The glass is composed of 44.5% 141 Pr, the remainder being silicon dioxide and aluminum (Si: 15.4%, Al: 8.1%, and O: 32.1%). Activity for each rod was calculated a 76.3 mCi. Due to the low activity of the seed used for testing purposes, a long irradiation time of 2.65 days was required to obtain the desired dose delivered. Higher activities can be achieved for clinical application. Irradiation of Gafchromic film in solid water was performed for a single 142Pr seed. Experimentally assessed depth dose and surface dose profiles in solid water from a single rod in air were obtained and compared with Monte Carlo simulations of dose distributions in water. MCNPX 2.6 radiation transport code (Los Alamos National Laboratory) was used for simulations, as it has broad nuclear cross-section data libraries available for various particles and energies. The code has also been benchmarked for many applications involving radiation transport in medical physics: high-energy particle therapy, neutron detection, proton and neutron dosimetry, as well as others. MCNPX 2.6 uses the continuous-slowing-down model for electron transport simulations, taking into account factors including electron energy, total path length, and total stopping power of the electron. Simulations were performed to determine dose profiles of seeds in air, one end in contact with the phantom surface. Additional simulations for 142Pr were performed to obtain the dose profile in water to compare with experimental 3500
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Fig. 4. Scanned device template exported to BPS and used for planning different seed positions.
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Fig. 5. Profile doses at the surface for planned and measured matrix.
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I seed
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Fig. 6. (a) Plot of normalized PDD and profiles for 90Sre90Y and 6 MeV electron EBRT and isodose lines from film scans for PDD and (b) profiles for external 6 MeV electron beams and 90Sre90Y single seed and multiple adjacent 90Sre90Y placements.
results. Simulations in this study were benchmarked with published results for known dose distributions of betaemitters (28). A series of three-dimensional mesh tallies were positioned along dose tally points to map the energy deposited in the medium. The energy cutoff implemented for both electrons and photons was 0.001 MeV. The number of source electron histories per simulation (2.0 107 NPS) was selected to limit statistical error to less than 1.5% for the points of interest (points close to the source). The ‘‘ITS-style’’ energy-indexing algorithm (DBCN 18 card 5 1) was used with a default ESTEP parameter (number of substeps per energy step ranges from 2 for Z 5 3 to 15 for Z O 90) defined in the material card (29).
Results Comparisons between the BPS calculated and measured doses for the 125I seed matrix (500 cGy and 473.5 cGy at 5 mm depth and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively) demonstrate a good agreement between planned and delivered dose. The total dose resulting from the 125I seed distribution covered a surface area of 88.2 mm2. The profile demonstrated conformity to contact
area, with 50% of the total surface dose deposited at 0.65 mm from the central axis (Fig. 5). Dose distributions achieved with the 90Sre90Y sources were compared with those of external electron EBRT. Penumbra (20%e80%) for electron EBRT and 90Sre90Y were 4.3 mm and 1.6 mm, respectively. PDD values of 50% (normalized to 2 mm) were 10.1 mm and 2.8 mm for electron EBRT and 90Sre90Y, respectively. Flatness (80% of the central beam profile) was 14.1% at a 5 mm depth for electron EBRT and 4.0% at surface for the 90Sre90Y. Relative dose distributions achieved with the 90Sre90Y sources and 6 MeV external electron beam were plotted (Fig. 6). Overall, 90Sre90Y exhibited a more localized dose distribution over electron EBRT 90Sre90Y shows promise as a good candidate for application in the CSBT device. For a single 142Pr seed, a dose was measured at 500.0 cGy at surface and 17.4 cGy at 5.00 mm. The total dose covered surface area for 142Pr was 2.35 mm2. Dose profiles also demonstrate a high conformity to the contact area, 50% of the total surface dose from a single 142Pr seed being deposited 0.72 mm from the central axis. The beta dose profile (Gy/decay) found within the skin due to the glass 142Pr rod (Fig. 7) show a short-ranged dose, suitable for the treatment of superficial skin lesions. The dose at the skin surface was calculated as 85.0 Gy and
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2.95 Gy at 5.00 mm, with an error of less than 1% (i.e., 0.139% and 0.855%, respectively). Uncertainty analysis An analysis of dosimetric uncertainty for photonemitting brachytherapy sources and the recommendations for film dosimetry uncertainties are described in the report of the AAPM Task Group 138 (TG-138) (30). Uncertainties included 1.1% from film uniformity; an uncertainty of less than 1.8% originating from repeated scanning variations; 1.2% uncertainty from the curve fitting of the film calibration and conversion of net optical density to dose; an uncertainty of 1.8% in the seed strength calibration using a well chamber and in calibration reproducibility of 0.2%. The estimated uncertainty of sample handling and placement in the film and phantom is 0.5 mm, translating to a 5.1% uncertainty in the dose. Uncertainty in irradiation time was estimated as 5%. The square root of the uncertainties squared calculates a total uncertainty estimated at 7.8%.
Discussions Well-established nuclides used in prostate implants and ocular tumors (e.g., 125I) prove to be a valid selection for a proof-of-concept CSBT device. As expected, the 90 Sre90Y PDDs in water reveal practical ranges shallower than that of electron EBRT for the same field size. 90 Sre90Y can be used in CSBT to provide patient-specific treatment where relatively shallow depth doses may be clinically advantageous (e.g., eyelids, nose, lips, ears, etc.). The customizability of electron EBRT could be replicated by using multiple adjacent 90Sre90Y plaque placements. While 142Pr also presented a relatively shallow surface dose deposition, its short half-life may make its use prohibitive in CSBT devices. The CSBT device has the potential to provide an increased level of personalization to the skin brachytherapy modality. In addition, the technique illustrated could be applied to other treatment sites, including SCC of the eye. As the hardware requires no temporary surgical implantation of radioisotopes, the risk of unintended exposure to the public (patient’s family, caregivers, etc.) is eliminated, allowing for therapies to be performed on an outpatient basis. Future versions of the device may potentially include robotics for the remote placement of seeds onto the treated lesion, as well as a fully automated rod positioning and source position verification system via an integrated ring or planar dose detectors.
Conclusions Millions of new cases of skin cancer are reported each year in the United States. There is an increasing demand for cost-effective treatment options. The unique, case-by-
Fig. 7. MCNPX 2.6% depth dose and radial simulations for the dose per decay profile of model used for experimental setup using the 142Pr glass rod. The dose falloff is steep and drops to minimal values at points beyond 5 mm.
case nature of cancer mandates a need for individualized medicine in both brachytherapy specifically, and in the treatment of cancer generally. CSBT would allow for a quick, fully customized, and effective method for treating these patients without the cost of vault infrastructure. This can potentially increase the availability of radiotherapy to treat skin cancers and treatment efficacy by delivering a more localized dose to the target. The conformal superficial brachytherapy device prototype tested offered the ability to customize dose to the target and would be suitable for treating any assessable body surface. The CSBT device concept was designed to be reusable across different patients, and to
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offer a fast and nonsurgical procedure in an outpatient setting. As currently available treatment planning systems can adequately predict the clinical dose distributions for a multiple gamma-emitting seed matrix, selecting radioactive seeds specifically to suit prescription depths and treatment areas may be a possibility. The overall conformity capable of the device makes it an attractive and promising innovation in contact brachytherapy. The CSBT device concept focuses on an innovative design that emphasizes personalized medicine.
Acknowledgments Special thanks to Mr. Robert Hall, and Dr. David Robertson from the University of Missouri Research Reactor (MURR) for their support in the source production. Thanks to Dr. Joel DeWitt and Mr. Marcus Jeannette from East Carolina University for their research support. Thanks to Dr. Bruce Gerbi from the University of Minnesota for the superficial radiotherapy discussions. References [1] American Cancer Society. Skin Cancer: Basal and Squamous Cell 2015;. Available at: http://www.cancer.org/cancer/cancercauses/ sunanduvexposure/skin-cancer-facts. Accessed May 05, 2016. [2] Sim~ oes MCF, Sousa JJS, Pais AACC. Skin cancer and new treatment perspectives: a review. Cancer Lett 2015;357:8e42. [3] Bhatnagar A. Nonmelanoma skin cancer treated with electronic brachytherapy: results at 1 year. Brachytherapy 2013;12:134e140. [4] Amdur RJ, Kalbaugh KJ, Ewald LM, et al. Radiation therapy for skin cancer near the eye: kilovoltage x-rays versus electrons. Int J Radiat Oncol Biol Phys 1992;23:769e779. [5] Chowa JCL, Grigorovc GN. Effect of the bone heterogeneity on the dose prescription in orthovoltage radiotherapy: a Monte Carlo study. Rep Pract Oncol Radiother 2012;17:38e43. [6] Pai S, Patel RR, Quhib Z, et al. Comparative dosimetry of two electronic brachytherapy systems Xoft Axxent electronic brachytherapy system (50 Kvp) and Esteya (EleKta) electronic brachytherapy system (69.5 Kvp) for skin application. J Contemp Brachytherapy 2015;7:231e238. [7] Ballester-Sanchez R, Pons-Llanas O, Candela-Juan C, et al. Efficacy and safety of electronic brachytherapy for superficial and nodular basal cell carcinoma. J Contemp Brachytherapy 2015;7: 231e238. [8] Alam M, Nanda S, Mittal BB, et al. The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review. J Am Acad Dermatol 2011;65:377e388. [9] Vyas S, Palaniswaamy G, Massingill B, et al. Electrons versus surface brachytherapy for non-melanoma skin cancerda matched pair analysis. Int J Radiat Oncol Biol Phys 2014;90:S118. [10] Kauvar ANB, Cronin T, Roenigk R, et al. Consensus for nonmelanoma skin cancer treatment: basal cell carcinoma, including a cost analysis of treatment methods. Dermatol Surg 2015;0:1e22. [11] Pons-Llanas O, Ballester-Sanchez R, Celada-Alvarez FJ, et al. Clinical implementation of a new electronic brachytherapy system for skin brachytherapy. J Contemp Brachytherapy 2014;6:417e423.
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[12] Yard B, Chie EK, Adams DJ, et al. Radiotherapy in the era of precision medicine. Semin Radiat Oncol 2015;25:227e236. [13] Stewart WM, Nou€el-Midoux J, Lauret P, et al. Strontium-90 in the treatment of pre-cancerous lesions and of some superficial skin cancers. Ann Dermatol Venereol 1977;104:855e859. [14] Cohen VML, Papastefanou VP, Liu S, et al. The use of Strontium-90 beta radiotherapy as adjuvant treatment for conjunctival melanoma. J Oncol 2013;2013:349162. [15] Kearsley JH, Fitchew RS, Taylor RG. Adjunctive radiotherapy with strontium-90 in the treatment of conjunctival squamous cell carcinoma. Int J Radiat Oncol Biol Phys 1988;14:435e443. [16] Qin XJ, Chen HM, Guo L, Guo YY. Low-dose Strontium-90 irradiation is effective in preventing the recurrence of pterygia: a ten-year study. PLoS One 2012;7:1e4. [17] Jung JW, Reece WD. Dosimetric characterization of 142Pr glass seeds for brachytherapy. Appl Radiat Isot 2008;66:441e449. [18] Ferreira MC, Podder TK, Rasmussen KH, Jung JW. Praseodymium142 microspheres for brachytherapy of nonresectable hepatic tumors. Brachytherapy 2013;12:654e664. [19] Chiu-Tsao ST, Astrahan MA, Finger PT, et al. Dosimetry of (125)I and (103)Pd COMS eye plaques for intraocular tumors: report of Task Group 129 by the AAPM and ABS. Med Phys 2012;39: 6161e6184. [20] Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM radiation therapy Committee Task group No. 43. Med Phys 1995;22: 209e234. [21] Ouhib Z, Kasper M, Perez Calatayud J, et al. Aspects of dosimetry and clinical practice of skin brachytherapy: the American Brachytherapy Society working group report. Brachytherapy 2015;14: 840e858. [22] Murata T, Miwa K, Matsubayashi F, et al. Optimal radiation shielding for beta and bremsstrahlung radiation emitted by (89)Sr and (90) Y: validation by empirical approach and Monte Carlo simulations. Ann Nucl Med 2014;28:617e622. [23] Nath R, Anderson LL, Meli JA, et al. Code of practice for brachytherapy physics: report of the AAPM Radiation Therapy Committee Task Group No. 56. American Association of Physicists in Medicine. Med Phys 1997;24:1557e1598. [24] Arjomandy B, Tailor R, Anand A, et al. Energy dependence and dose response of Gafchromic EBT2 film over a wide range of photon, electron, and proton beam energies. Med Phys 2010;37: 1942e1947. [25] Massillon-JL G, Chiu-Tsao ST, Domingo-Mu~noz I, Chan MF. Energy dependence of the new Gafchromic EBT3 film: dose response curves for 50 kV, 6 and 15 MV x-ray beams. Int J Med Phys Clin Eng Radiat Oncol 2012;1:60e65. [26] Low DA, Moran JM, Dempsey JF, et al. Dosimetry tools and techniques for IMRT. Med Phys 2011;38:1313e1338. [27] Sua FC, Liub Y, Stathakisa S, et al. Dosimetry characteristics of GAFCHROMICÒ EBT film responding to therapeutic electron beams. Appl Radiat Isot 2007;65:1187e1192. [28] Berger MJ. Distribution of absorbed dose around point sources of electrons and beta particles in water and other media. J Nucl Med 1971;5:5e23. [29] Reynaert N, Palmans H, Thierens H, Jeraj R. Parameter dependence of the MCNP electron transport in determining dose distributions. Med Phys 2002;29:2446e2454. [30] DeWerd LA, Ibbott GS, Meigooni AS, et al. A dosimetric uncertainty analysis for photon-emitting brachytherapy sources: report of AAPM Task Group No. 138 and GEC-ESTRO. Med Phys 2011;38:782e801.
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A novel conformal superficial high-dose-rate brachytherapy device for the treatment of nonmelanoma skin cancer and keloids Clara Ferreira1,*, Daniel Johnson2, Karl Rasmussen3, Clinton Leinweber4, Salahuddin Ahmad2, Jae Won Jung5 1 Department of Radiation Oncology, University of Minnesota, Minneapolis, MN Department of Radiation Oncology, The University of Oklahoma, Oklahoma City, OK 3 Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX 4 Department of Radiation Oncology, East Carolina University, Greenville, NC 5 Department of Physics, East Carolina University, Greenville, NC 2
ABSTRACT
PURPOSE: To develop a novel conformal superficial brachytherapy (CSBT) device as a treatment option for the patient-specific radiation therapy of conditions including superficial lesions, postsurgical positive margins, Dupuytren’s contractures, keloid scars, and complex anatomic sites (eyelids, nose, ears, etc.). METHODS AND MATERIALS: A preliminary CSBT device prototype was designed, built, and tested using readily available radioactive seeds. Iodine-125 (125I) seeds were independently guided to the treatment surface to conform to the target. Treatment planning was performed via BrachyVision Planning System (BPS) and dose distributions measured with Gafchromic EBT3 film. Percent depth dose curves and profiles for Praseodymium-142 (142Pr), and Strontium-90/Yttrium-90 (90Sre90Y) were also investigated as potential sources. Results achieved with 90Sre90Y and electron external beam radiation therapy were compared and Monte Carlo N-Particle eXtended 2.6 simulations of 142Pr seeds were validated. RESULTS: BPS was able to predict clinical dose distributions for a multiple seeds matrix. Calculated and measured doses for the 125I seed matrix were 500 cGy and 473.5 cGy at 5 mm depth, and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively. Results of 90Sre90Y tests demonstrate a more conformal dose than electron EBRT (1.6 mm compared to 4.3 mm penumbra). Measured 142 Pr doses were 500 cGy at surface and 17.4 cGy at 5 mm depth. CONCLUSIONS: The CSBT device provides a highly conformal dose to small surface areas. Commercially available BPS can be used for treatment planning, and Monte Carlo simulation can be used for plans using beta-emitting sources and complex anatomies. Various radionuclides may be used in this device to suit prescription depths and treatment areas. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Skin cancer; High-dose-rate brachytherapy; Monte Carlo simulation; Conformal superficial applicator
Introduction Basal and squamous cell skin cancers are being diagnosed at a greater rate each year. The American Cancer
Received 4 June 2016; received in revised form 4 September 2016; accepted 6 September 2016. Conflict of interest: The authors declare no conflict of interest. * Corresponding author. Department of Radiation Oncology, University of Minnesota Medical School-Twin Cities, 420 Delaware Street Southeast, Mayo Mail Code # 494, Minneapolis, MN 55455. Tel.: þ1612-626-4484; fax: +1-612-624-5445. E-mail address: [email protected] (C. Ferreira).
Society estimates that 3.5 million new cases will occur this year alone (1). As the most widespread cancer, skin cancer includes basal cell carcinoma, squamous cell carcinoma (SCC), melanoma, and nonepithelial skin cancer. The currently available treatment modalities include traditional surgical intervention, Mohs micrographic surgery, cryosurgery, external beam radiation therapy (EBRT), high-dose-rate brachytherapy (HDR), and electronic brachytherapy (eBT) (2, 3). Mohs micrographic surgery is a well-established option for basal cell carcinoma; however, its side effects may include incision site complications and scarring (1). Although surgery is the standard treatment for
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.09.002
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nonmelanoma skin cancer, radiotherapy is oftentimes used as adjuvant to surgery. Radiotherapy as monotherapy is in some instances the preferred method for patients who choose to avoid disfiguring and painful surgery and may also be the recommended treatment for patients unable to qualify for tumor resection due to: potentially compromised organ function, tumors deemed surgically unresectable, or if surgery is contraindicated for medical reasons. Historically, orthovoltage therapy has been a common treatment modality for treating superficial tumors. While easier to shield and capable of small field sizes and a sharp dose falloff when compared to megavoltage electron beams (4), the drawback of orthovoltage therapy is the enhanced dose to the underlying bone, potentially 2 to 3 times greater due to the photoelectric effect for high Z material in the kV energy range (5). Electron EBRT is effective for treating large and flat areas in the body but may fail to deliver predictable and homogeneous coverage to small or irregular fields. Additional radiation modalities that are currently available to treat superficial lesions include the eBT devices such as Esteya, and Xoft Axxent Electronic Brachytherapy System (6). The advantages of eBT are the low-energy xray sources (continuous spectrum with maximum of 50 keV for Xoft and 69.5 keV for Esteya) and a relatively simplified treatment procedure. Field sizes in eBT present circular and flat shapes, ranging from 1 to 3 cm in diameter. Other HDR-based procedures have been developed to use applicators and molds attached to the 192Ir after-loader; including the Elekta’s Valencia, and Freiburg Flap applicators, and the Varian Leipzig surface applicator. These HDR techniques have addressed the need of a more conformal therapy, yet the higher photon energies of 192Ir sources (average energy of 0.38 MeV) result in deeper dose penetration in tissue. Recurrence rates for nonmelanoma skin cancer are reported to be very low after radiation therapy (7, 8), and current brachytherapy techniques have demonstrated local control comparable to electron EBRT (9). Conformal superficial brachytherapy (CSBT) is proposed as an alternative potential modality in small field contact therapy by: (1) Limiting exposure to healthy tissue: adverse effects of radiation to surrounding healthy tissue may include desquamation, alopecia, hypopigmentation, or hyperpigmentation, fibrosis, necrosis, radiodermatitis with nonhealing ulcerations, ocular damage, hearing loss, and secondary skin malignancies appearing several years after treatment (10); therefore, for small lesions, a more localized irradiation may be beneficial. (2) Delivering patient-specific fields: CSBT has the potential to deliver intensity-modulated radiation fields similar to a multileaf collimator used to precisely collimate photons. By the superposition of small treatment fields at the skin surface, the physician may adequately tailor the planned dose to the
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individual characteristics of each lesion with greater precision. This technique allows treatment plans to address the individualized nature of cancer (11). Balancing treatment efficacy and normal tissue complication are of fundamental importance in the practice of radiation therapy. Individualized and patient-specific treatment methodologies are at the core of both modern radiotherapy precision medicine (12). The goal of the CSBT was to offer a patient-specific and tumor-specific conformal treatment, sparing healthy tissue, and administering a therapeutic dose. The design of the device allows for the use of a variety of isotopes. Previous clinical studies on the use of Strontium-90 (90Sr) in treating skin cancer (13) make it a strong candidate for use in this device. 90Sr is a longlived, high-energy, beta-emitting radionuclide, traditionally used in treating conjunctival SCC and melanoma of the eye, and post-surgical prevention of pterygia (14e16). While the decay product of 90Sr is the short-lived Yttrium-90 (90Y), parent and daughter coexist in secular equilibrium (90Sre90Y). Another promising isotope is beta-emitter Praseodymium-142 (142Pr) having been previously studied for applications in prostate and liver cancer (17, 18). The potential of Iodine-125 (125I) seeds are supported by its common use in prostate seed implants, Collaborative Ocular Melanoma Study eye plaques, (19), and the availability of consensus dosimetric parameters presented in the report of The American Association of Physicists in Medicine (AAPM) Task Group 43 (20). While the radioisotopes used in this study are generally well established, the innovative device design enhances skin lesion targeting and healthy tissue sparing. The intent of this study is to design and construct a prototype device to test the feasibility and advantages of using different radionuclides. The prototype was designed, manufactured, and mechanically tested in-house. While the radionuclides used in this study include the beta-emitters 142 Pr and 90Sre90Y, and the gamma-emitter 125I, Monte Carlo N-Particle eXtended (MCNPX) 2.6 Monte Carlo Simulations were exclusively performed for 142Pr to determine its applicability in the device designed. Dose distributions were assessed for different radioactive seed loading patterns. Dose profiles from external electron beams were used to compare and estimate the dose conformity capable of the device. Methods and materials The device tested is designed to optimally conform to the patient-specific geometries and treat small (!3 cm), superficial tumors; delivering a localized, therapeutic dose to the lesion, ensuring favorable cosmetic outcomes, and limiting any adverse side effects. An increase in the scale area of the device design, or abutting treatment applications on the patient, may be used to treat larger fields.
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The device in addition has the potential to deliver different doses to different regions of interest; it may be gross tumor volume, clinical target volume, or planning target volume. Ouhib et al. (21) has recently reviewed margins and dose fractionations for HDR-based contact therapies. In the clinical application of the device, patient selection, dose fractionation scheme, and treatment margins should be based on the evidence reported in literature. Margins for clinical target volume expansions from gross tumor volume of 4 mm can be used for low risk and a 6 mm for high risk if lesion location allows, based on margin recommendations of Mohs surgery. A 5-mm expansion of the planning target volume is common practice. Total dose prescriptions and fractionation schemes used in custom brachytherapy molds and superficial applicators may vary (12e42 Gy). The prescription depth is selected to limit the dose to the surface and hypofractionated schedules are commonly used (5e7 fractions). Device design The CSBT device is comprised of an applicator containing several retractable rods, a radioactive seed placed at the tip of each. A shielded hollow acrylic cylinder contains the loaded rods and evenly distributes them in a 3-cm diameter grid pattern (Fig. 1). For 90Sre90Y applications, the external cylinder that lodges the seeds needs to adequately shield against both beta and generated bremsstrahlung radiations. An ideal construct for this application may be a layer of tungsten greater than 0.60 mm, shielding the 90Y daughter (22). The diameter of applicator enables the device to address a variety of skin tumor sizes. The mechanically controlled rods may move independently from one another, the length of each rod projection controlled to conform to flat or curved surfaces. Two- or three-dimensional modulated fields can be obtained through a combination of field segments (Fig. 2). A device holder was designed to permit both
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rotation and translation, allowing accurate positioning of the applicator over the tumor site (Fig. 3). In prototype testing, a gynecological HDR mechanical arm stabilizer was used to hold the device in place during irradiation using 125I seeds. Positional uncertainty was within 1 mm from the planned position. Advantages presented by the device included: (1) Short patient treatment time: radioisotopes such as 90 Sr can administer high-dose rates of radiation to the skin, allowing the procedure to be completed within a few minutes. This duration is comparable to the treatment times of current treatment techniques. (2) Reusable treatment materials: device and radioactive seeds can be reused for multiple patients and tumors. Utilization of a thin protective disposable membrane avoids direct contact of patient skin with surface of the device. (3) Precise therapy: the device allows for small field sizes to be localized to the treatment area and offers the flexibility of replanning subsequent treatment fractions to account for possible changes in target size. (4) Versatility: the geometry and physical properties of the hardware enable the device to be applicable to other types of superficial regions of interest: keloids, Dupuytren’s contractures, and other superficial conditions. (5) Treatment verification: positioning and dose distributions can be verified with high resolution using dosimeters such as radiochromic film. The delivery of the therapy can be checked against the original treatment plan and quality assurance (QA) methods can be easily implemented for the device. (6) Treatment time and QA: timing can be controlled by an automated positioning system. Linearity testing, end effect evaluation, and total time QA should be performed on a frequency recommended by AAPM Task Group 56 (23). In the present study, the theoretical model conceived and prototype built and tested were measured via Gafchromic film; 2D dose distributions measured in solid water phantoms for all radionuclides of interest. Doses were calculated in the BrachyVision Planning System (BPS) for the CSBT device using multiple 125I seeds and compared with measured doses. Conformity of doses for 90Sre90Y sources were compared with the doses delivered with the commonly used 6 MeV external beam electron cutouts. Finally, dose measurements for 142Pr were obtained and compared with Monte Carlo simulations for this nuclide. Preliminary 3D-printed prototype
Fig. 1. Conformal superficial brachytherapy (CSBT) device showing possible seed expansions for positioning in the skin surface to conform to treatment lesion. Time and position of each seed can be controlled to optimize the treatment.
A preliminary, 3D-printed prototype of the device was used in initial measurements and proof-of-concept testing. The device prototype was designed in SketchUp (Trimble
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Fig. 2. (a) Clockwise direction, starting from top left: frontal view of the template with no rods extended, field 1 (yellow), superposition of fields 1 and 2 (orange), superposition of fields 1, 2, and 3 (red). (b) Representation of total dose distribution from all fields added. ‘‘(For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)’’
Navigation) and exported to Slic3r, which translated the digital 3D model into printing instructions (gcode) for a Fusematic 3D printer (Maker’s Tool Works). The prototype was printed in-house using PLA thermoplastic via Bowden-style extrusion technique. Cylindrical brass rods (1.59 304.8 mm2) were inserted through the 3D-printed template, and 125I seeds were directly attached to the tip of each rod. The movable metal rods were free to extend and retract in the 3D-printed template to conform to the surface. Film dosimetry Often used in treatment verification and QA, selfdeveloping Gafchromic EBT3 film offers high-spatial
resolution (25 mm), a weak energy dependency, and requires no wet processing (24, 25). As it is designed for quantitative dose measurements in radiotherapy, it is widely used in intensity-modulated radiation therapy and brachytherapy; applications in which high-dose gradients occur (26). The dose response for Gafchromic film is independent of fractionation, dose rate, and depth dependence for electron beams (27). The film is water resistant, stable in room light and temperatures of up to 60 C, and has a nearly EBT tissue-equivalent electron density (Zeff 5 6.84 compared water to Zeff 5 7.42). EBT3 films were scanned using an Epson Expression 10000XL and analyzed in ImageJ (National Institute of Health). The color scanning of the film enabled the red channel to be used for the dose calibration curves, having a strong sensitivity to dose. While film sensitivity in the red channel limits the range to between 1 and 1000 cGy, film doses were derived through cross-referencing an Accredited Dosimetry Calibration Laboratory calibrated ion chamber.
Gamma-emitter Iodine-125 film measurements and planning system doses
Fig. 3. Device holder and CSBT device positioned at the target.
The CSBT device was built and tested using multiple radioactive seeds loaded at the tips of metal rods. Due to availability, OncoSeed Model 6711 (GE-Amersham) Iodine-125 seeds (half-life: 59.4 days, average gamma energy: 28 keV) were used to test the feasibility of the device. The rods were spaced 1.5 mm apart when placed through the device core. The 125I loaded rods were allowed to move independently at the treatment surface to conform to the desired geometry, measurements performed in solid water phantom for different prescription depths and surface areas.
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A computed tomography (CT) scan of the device template was performed in a GE LightSpeed 16 slice CT scanner and exported to BPS to acquire the exact seed positioning for planning purposes (Fig. 4). Treatment using eleven 125I seeds was planned in BPS and measured experimentally for a total dose of 500 cGy at 5.0 mm depth. Percent depth doses (PDD) and dose profiles were analyzed. Beta-emitter 90Sre90Y and electron cutout film measurements A HDR 90Sre90Y beta therapy source (New England Nuclear, source surface dose rate: 59.3 cGy/s; half-lives: 28.79 years, and 64.1 h and maximum beta decay energies: 0.546 MeV, and 2.279 MeV, respectively) was used to test this radionuclide as a candidate for use in the CSBT device. The beta therapy source of 1 cm diameter was used to deliver dose to a solid water phantom containing EBT3 Gafchromic films arranged both on and perpendicular to the phantom surface. Due to the HDR of the source, the total dose was delivered within 20 s. The doses delivered using the 90Sre90Y beta therapy source were compared with distributions achieved via 6 MeV (Varian 21EX Clinac) external electron beam radiation using small cutouts (1 cm diameter at 100 cm source to surface distance) in a 6 6 cm2 cone and having a 0.5cm bolus applied to the surface. The small electron cutouts are not clinically ideal; however, in some practical scenarios where the eyelids, lips and ears need to be treated, cutouts of this magnitude are oftentimes used. It was intended to compare the dose coverage and dose distributions for these small fields with the doses delivered by the CSBT device. A film calibration curve (dose range: 20e 1000 cGy) was generated using the 6 MeV electron beam and was used to calibrate both 90Sre90Y and electron cutout films. Normalized PDD and dose profiles for both techniques were analyzed.
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Beta-emitter Praseodymium-142 film measurements and Monte Carlo Simulations Beta-emitter 142Pr (decay mode: 96.3% beta and 3.7% gamma; half-life: 19.12 h; average beta energy: 809 keV, maximum beta energy: 2.162 MeV) was studied as a potential candidate for the use in the CSBT device. 141Pr glass rods (MO-SCI Corporation) of 1.5 mm diameter and a length of 5 mm (a total sample mass of 0.353 g) were activated in a research reactor (neutron absorption crosssection 11.40 barn). The glass is composed of 44.5% 141 Pr, the remainder being silicon dioxide and aluminum (Si: 15.4%, Al: 8.1%, and O: 32.1%). Activity for each rod was calculated a 76.3 mCi. Due to the low activity of the seed used for testing purposes, a long irradiation time of 2.65 days was required to obtain the desired dose delivered. Higher activities can be achieved for clinical application. Irradiation of Gafchromic film in solid water was performed for a single 142Pr seed. Experimentally assessed depth dose and surface dose profiles in solid water from a single rod in air were obtained and compared with Monte Carlo simulations of dose distributions in water. MCNPX 2.6 radiation transport code (Los Alamos National Laboratory) was used for simulations, as it has broad nuclear cross-section data libraries available for various particles and energies. The code has also been benchmarked for many applications involving radiation transport in medical physics: high-energy particle therapy, neutron detection, proton and neutron dosimetry, as well as others. MCNPX 2.6 uses the continuous-slowing-down model for electron transport simulations, taking into account factors including electron energy, total path length, and total stopping power of the electron. Simulations were performed to determine dose profiles of seeds in air, one end in contact with the phantom surface. Additional simulations for 142Pr were performed to obtain the dose profile in water to compare with experimental 3500
BrachyVision GAFCHROMIC EBT3
3000
Dose (cGy)
2500 2000 1500 1000 500 0
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Fig. 4. Scanned device template exported to BPS and used for planning different seed positions.
-1.5
-0.5 0.5 Position at Surface (cm)
1.5
Fig. 5. Profile doses at the surface for planned and measured matrix.
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I seed
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Fig. 6. (a) Plot of normalized PDD and profiles for 90Sre90Y and 6 MeV electron EBRT and isodose lines from film scans for PDD and (b) profiles for external 6 MeV electron beams and 90Sre90Y single seed and multiple adjacent 90Sre90Y placements.
results. Simulations in this study were benchmarked with published results for known dose distributions of betaemitters (28). A series of three-dimensional mesh tallies were positioned along dose tally points to map the energy deposited in the medium. The energy cutoff implemented for both electrons and photons was 0.001 MeV. The number of source electron histories per simulation (2.0 107 NPS) was selected to limit statistical error to less than 1.5% for the points of interest (points close to the source). The ‘‘ITS-style’’ energy-indexing algorithm (DBCN 18 card 5 1) was used with a default ESTEP parameter (number of substeps per energy step ranges from 2 for Z 5 3 to 15 for Z O 90) defined in the material card (29).
Results Comparisons between the BPS calculated and measured doses for the 125I seed matrix (500 cGy and 473.5 cGy at 5 mm depth and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively) demonstrate a good agreement between planned and delivered dose. The total dose resulting from the 125I seed distribution covered a surface area of 88.2 mm2. The profile demonstrated conformity to contact
area, with 50% of the total surface dose deposited at 0.65 mm from the central axis (Fig. 5). Dose distributions achieved with the 90Sre90Y sources were compared with those of external electron EBRT. Penumbra (20%e80%) for electron EBRT and 90Sre90Y were 4.3 mm and 1.6 mm, respectively. PDD values of 50% (normalized to 2 mm) were 10.1 mm and 2.8 mm for electron EBRT and 90Sre90Y, respectively. Flatness (80% of the central beam profile) was 14.1% at a 5 mm depth for electron EBRT and 4.0% at surface for the 90Sre90Y. Relative dose distributions achieved with the 90Sre90Y sources and 6 MeV external electron beam were plotted (Fig. 6). Overall, 90Sre90Y exhibited a more localized dose distribution over electron EBRT 90Sre90Y shows promise as a good candidate for application in the CSBT device. For a single 142Pr seed, a dose was measured at 500.0 cGy at surface and 17.4 cGy at 5.00 mm. The total dose covered surface area for 142Pr was 2.35 mm2. Dose profiles also demonstrate a high conformity to the contact area, 50% of the total surface dose from a single 142Pr seed being deposited 0.72 mm from the central axis. The beta dose profile (Gy/decay) found within the skin due to the glass 142Pr rod (Fig. 7) show a short-ranged dose, suitable for the treatment of superficial skin lesions. The dose at the skin surface was calculated as 85.0 Gy and
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2.95 Gy at 5.00 mm, with an error of less than 1% (i.e., 0.139% and 0.855%, respectively). Uncertainty analysis An analysis of dosimetric uncertainty for photonemitting brachytherapy sources and the recommendations for film dosimetry uncertainties are described in the report of the AAPM Task Group 138 (TG-138) (30). Uncertainties included 1.1% from film uniformity; an uncertainty of less than 1.8% originating from repeated scanning variations; 1.2% uncertainty from the curve fitting of the film calibration and conversion of net optical density to dose; an uncertainty of 1.8% in the seed strength calibration using a well chamber and in calibration reproducibility of 0.2%. The estimated uncertainty of sample handling and placement in the film and phantom is 0.5 mm, translating to a 5.1% uncertainty in the dose. Uncertainty in irradiation time was estimated as 5%. The square root of the uncertainties squared calculates a total uncertainty estimated at 7.8%.
Discussions Well-established nuclides used in prostate implants and ocular tumors (e.g., 125I) prove to be a valid selection for a proof-of-concept CSBT device. As expected, the 90 Sre90Y PDDs in water reveal practical ranges shallower than that of electron EBRT for the same field size. 90 Sre90Y can be used in CSBT to provide patient-specific treatment where relatively shallow depth doses may be clinically advantageous (e.g., eyelids, nose, lips, ears, etc.). The customizability of electron EBRT could be replicated by using multiple adjacent 90Sre90Y plaque placements. While 142Pr also presented a relatively shallow surface dose deposition, its short half-life may make its use prohibitive in CSBT devices. The CSBT device has the potential to provide an increased level of personalization to the skin brachytherapy modality. In addition, the technique illustrated could be applied to other treatment sites, including SCC of the eye. As the hardware requires no temporary surgical implantation of radioisotopes, the risk of unintended exposure to the public (patient’s family, caregivers, etc.) is eliminated, allowing for therapies to be performed on an outpatient basis. Future versions of the device may potentially include robotics for the remote placement of seeds onto the treated lesion, as well as a fully automated rod positioning and source position verification system via an integrated ring or planar dose detectors.
Conclusions Millions of new cases of skin cancer are reported each year in the United States. There is an increasing demand for cost-effective treatment options. The unique, case-by-
Fig. 7. MCNPX 2.6% depth dose and radial simulations for the dose per decay profile of model used for experimental setup using the 142Pr glass rod. The dose falloff is steep and drops to minimal values at points beyond 5 mm.
case nature of cancer mandates a need for individualized medicine in both brachytherapy specifically, and in the treatment of cancer generally. CSBT would allow for a quick, fully customized, and effective method for treating these patients without the cost of vault infrastructure. This can potentially increase the availability of radiotherapy to treat skin cancers and treatment efficacy by delivering a more localized dose to the target. The conformal superficial brachytherapy device prototype tested offered the ability to customize dose to the target and would be suitable for treating any assessable body surface. The CSBT device concept was designed to be reusable across different patients, and to
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offer a fast and nonsurgical procedure in an outpatient setting. As currently available treatment planning systems can adequately predict the clinical dose distributions for a multiple gamma-emitting seed matrix, selecting radioactive seeds specifically to suit prescription depths and treatment areas may be a possibility. The overall conformity capable of the device makes it an attractive and promising innovation in contact brachytherapy. The CSBT device concept focuses on an innovative design that emphasizes personalized medicine.
Acknowledgments Special thanks to Mr. Robert Hall, and Dr. David Robertson from the University of Missouri Research Reactor (MURR) for their support in the source production. Thanks to Dr. Joel DeWitt and Mr. Marcus Jeannette from East Carolina University for their research support. Thanks to Dr. Bruce Gerbi from the University of Minnesota for the superficial radiotherapy discussions. References [1] American Cancer Society. Skin Cancer: Basal and Squamous Cell 2015;. Available at: http://www.cancer.org/cancer/cancercauses/ sunanduvexposure/skin-cancer-facts. Accessed May 05, 2016. [2] Sim~ oes MCF, Sousa JJS, Pais AACC. Skin cancer and new treatment perspectives: a review. Cancer Lett 2015;357:8e42. [3] Bhatnagar A. Nonmelanoma skin cancer treated with electronic brachytherapy: results at 1 year. Brachytherapy 2013;12:134e140. [4] Amdur RJ, Kalbaugh KJ, Ewald LM, et al. Radiation therapy for skin cancer near the eye: kilovoltage x-rays versus electrons. Int J Radiat Oncol Biol Phys 1992;23:769e779. [5] Chowa JCL, Grigorovc GN. Effect of the bone heterogeneity on the dose prescription in orthovoltage radiotherapy: a Monte Carlo study. Rep Pract Oncol Radiother 2012;17:38e43. [6] Pai S, Patel RR, Quhib Z, et al. Comparative dosimetry of two electronic brachytherapy systems Xoft Axxent electronic brachytherapy system (50 Kvp) and Esteya (EleKta) electronic brachytherapy system (69.5 Kvp) for skin application. J Contemp Brachytherapy 2015;7:231e238. [7] Ballester-Sanchez R, Pons-Llanas O, Candela-Juan C, et al. Efficacy and safety of electronic brachytherapy for superficial and nodular basal cell carcinoma. J Contemp Brachytherapy 2015;7: 231e238. [8] Alam M, Nanda S, Mittal BB, et al. The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review. J Am Acad Dermatol 2011;65:377e388. [9] Vyas S, Palaniswaamy G, Massingill B, et al. Electrons versus surface brachytherapy for non-melanoma skin cancerda matched pair analysis. Int J Radiat Oncol Biol Phys 2014;90:S118. [10] Kauvar ANB, Cronin T, Roenigk R, et al. Consensus for nonmelanoma skin cancer treatment: basal cell carcinoma, including a cost analysis of treatment methods. Dermatol Surg 2015;0:1e22. [11] Pons-Llanas O, Ballester-Sanchez R, Celada-Alvarez FJ, et al. Clinical implementation of a new electronic brachytherapy system for skin brachytherapy. J Contemp Brachytherapy 2014;6:417e423.
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