Impact of transducer arrays on deep-site dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis)

Impact of transducer arrays on deep-site dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of transducer arrays on deep-site dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis) Jiajun Zheng, Zhi Wang, Huanfeng Zhu, Wenjie Guo, Jianfeng Wu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3915746/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To study the impact of transducer arrays on the deep-site dosimetry of radiotherapy with concurrent tumor treating fields (TTFields) for glioblastoma. Methods Firstly, the covering style of transducer arrays to CIRS-038 phantom was designed to simulate the "extreme situation": four arrays were attached to the phantom as a style similar with that in clinical scene and, meanwhile, to assure that layer of interest of CIRS-038 was surrounded by twelve electrodes (three in each array). Then, eight patients undergone glioblastoma radiotherapy were selected, and the planed dose of each patient was delivered to the phantom with dosimetry film inside without and with transducer arrays. For the phantom with arrays, CBCT was used to check the dedicated covering style before dose delivery. Finally, Gamma-based consistency analysis was performed for two dose distributions for each plan (without/with arrays). Results The covering style of the TTFields array met the requirements in 8 cases before dose delivery. Gamma indexes under the four criteria (2%/2 mm, 2%/3 mm, 3%/2 mm and 3%/3 mm) were (93.16±5.16)%, (96.08±3.49)%, (96.77±2.54)% and (97.96±1.61)%, respectively. Conclusion Even in extreme situation (twelve electrodes covering the same cross-section), the perturbation of the TTFields arrays to the deep-site dose distribution of the radiotherapy for glioblastoma is weak and acceptable. Glioblastoma TTFields Radiotherapy Array Deep-site dosimetry Figures Figure 1 Figure 2 Figure 3 Introduction Tumor treating fields (TTFields) has confirmed advantages in improving overall survival (OS) and progression-free survival (PFS) in glioblastoma without significant deterioration in health-related quality of life (HRQoL) [ 1 – 3 ] . Technically, the device used to establish the treating field is a transducer array consisting of 9 button-type ceramic electrodes arranged in 3×3. The grouped four arrays are attached to the skull of patient to establish the required intracranial electric field with frequency between 100 kHz and 300 kHz and strength between 1 V/cm and 3 V/cm [ 4 ] . Although TTFields is an independent therapeutic modality, therapeutic synergies between TTfields and radiotherapy have been found in recent years, which has led to several preclinical and clinical studies about radiotherapy with concurrent TTFields for glioblastoma [ 5 – 9 ] . In addition, since TTFields arrays are designed as disposable and expensive, discarding the arrays before each radiotherapy will result in high treatment costs, which may affect the treatment compliance as well as the ultimate survival outcome [ 10 ] . Thus, it is necessary to consider the situation of patients receiving radiotherapy while wearing the TTFields arrays both in terms of clinical benefit and cost-effectiveness. Therefore, it is important to study the dosimetric effect of the TTFields arrays on glioblastoma radiotherapy, especially the deep-site dosimetry reflecting the target coverage. The metal artifacts caused by TTFields electrodes on kV-CT make it difficult to calculate the dose in the presence of electrodes in kV-CT. Straube et al focused on the calculation-based deep-site dosimetry in glioblastoma radiotherapy with concurrent TTFields [ 11 – 15 ] , which were either based on MV-CT or artificially assigned electrode HU in kV-CT (3817 or 3832, etc.). However, there is a lack of uniform standard and solid basis for the assignment of electrode HU in these calculation-based researches. In addition, the use of different dose calculation algorithms will also introduce uncertainty to the results [ 16 ] . These challenges affect the reliability of dose calculations involving electrodes and may lead to a loss of confidence in the radiotherapy centers to apply this treatment modality. Therefore, measurement-based dosimetry studies are needed to validate the results of calculation-based studies and further verify the dosimetry effects of TTFields arrays on radiotherapy for glioblastoma. In this study, the effect of the TTFields arrays on deep-site dose distribution of glioblastoma radiotherapy with concurrent TTFields was investigated based on measurements using an extreme analysis method. Method 1.1 Patient cohort Eight patients who received glioblastoma radiotherapy with concurrent TTFields were selected. The TTFields treatment plans were generated in the NovoTALTM software. The placements of the grouped arrays were optimized according to the shape and size of the patient's skull and planned target volume (PTV), as well as the positional relationship between them. In general, the four arrays were approximately located in the frontal lobe, posterior occipital, and left and right temporal lobes, respectively. The least time of wearing arrays per day was 18 hours, and arrays need be replaced by new ones with fine-tuned positions every three days to reduce scalp adverse reactions [ 2 , 17 ] . The radiotherapy plans were designed by experienced radiotherapy dosimetrists using Varian Eclipse (v15.6) treatment planning system (TPS). All radiotherapy plans used volumetric modulated arc radiotherapy (VMAT) technology with a single arc field covering an angle of 360°. All target coverage, organ at risk (OAR) sparing and other dose distribution indexes meet clinical requirements. All radiotherapy plans were delivered on the TrueBeam platform. The basic information of the involved patients, the prescribed dose and the MU of plan are shown in Table 1 . Table 1. General information of eight cases of radiotherapy with concurrent TTFields for glioblastoma. Index Age Sex PTV location PTV volume Prescription Plan Mu #1 78 Male Right occipital lobe 362.3 cc 2Gy×30f 359.4 #2 36 Female Right temporal lobe 274.1 cc 2.15Gy×28f 445.4 #3 79 Male Central parietal lobe 160.7 cc 2Gy×30f 493.3 #4 71 Male Left temporal lobe 604.2 cc 2.15Gy×28f 526.7 #5 29 Female Left frontal lobe 404.6 cc 2.15Gy×28f 574.5 #6 44 Female Right temporal lobe 371.1 cc 2Gy×30f 587 #7 68 Female Right frontal lobe 364.2 cc 2Gy×30f 635.4 #8 36 Male Central frontal lobe 339.9 cc 1.5Gy×36f 320.6 1.2 Extreme simulation The CIRS-038 anthropomorphic head & neck phantom was used to simulate patients receiving radiotherapy with concurrent TTFields. The CIRS-038 has an external profile and internal anatomy structure in CT similar to that of the human skull, and has a designated location to place dosimetry film [ 18 ] . Firstly, CT scan was performed to CIRS-038 with the layer thickness of 1 mm, and the scanned CT images were imported into Eclipse (v15.6). Then, each CT image of the eight cases was registered to the phantom and PTV, OAR and other structures were copied to the phantom. In final, new single-arc VMAT plans were generated using the same optimization objectives with the reference plans based on the phantom CT and real structures. The coverage style of the TTFields arrays on the phantom follows two principles: 1) as close as possible to the clinical coverage style; 2) a total of 12 electrodes were wrapped around the skull in the same observation transverse layer (either of the two specified transverse layers in CIRS-038 where the dosimetry film can be placed). The second principle was designed aiming to simulate the most extreme situations in electrode wrapping. Figure 1 shows the CIRS-038 phantom wearing the TTFields arrays complying with the above principles. 1.3 Dose delivery and data analysis For each selected cases, film placement and arrays coverage on the phantom were firstly completed. The EBT3 radiation dosimetry film was chosen in this study. Subsequently, the setup of the phantom was completed on the TrueBeam platform. Then, cone beam CT (CBCT) was performed to verify the phantom positioning and the dedicate coverage style. After verification, the selected radiotherapy plan was loaded and the dose was delivered to the CIRS-038 wearing the TTFields arrays as well as the film inside. After arrays removing, film replacing and positioning re-verification, the same radiotherapy plan was again performed, delivering the dose to the CIRS-038 without arrays coverage. After the dose delivery of all radiotherapy plans were completed, the obtained dosimetry films were placed in darkness for 24 hours. The films with dose patterns was scanned using the Epson V700 scanner. Then, the conversion of optical density distribution to dose distribution based on dose scale curve was completed in DoseLab software [ 19 ] . For each of the eight cases, Gamma-based consistency analysis was performed for the two dose distributions without and with coverage [ 20 ] . Results 3.1 Verification of extreme Each glioblastoma radiotherapy plan required a CBCT verification for the arrays coverage style and the phantom positioning prior to dose delivery. Figure 2 shows the CT image and the corresponding CBCT image (after registration) at the observing layer (where the film is located) in the CIRS-038 of case #2 and #4. Two marks (red arrow indicates in Fig.a- 1 and green arrow indicates in Fig.b- 1 ) can be seen in the CT image, which were used to identify the observation layers with EBT3 films. In the corresponding CBCT image, it can be seen that there were a total of 12 electrodes surrounding the skull and leading to the banded artifacts [ 21 ] . Before dose delivery of the radiotherapy plans of eight cases, the accuracy of the phantom positioning and the coverage style of the TTFields arrays were confirmed. 3.2 Dose distributions Figure 3 shows the planned dose distribution (3a) of the region of interest (deep-site) at the observation layer of case #6 and the measured dose distributions obtained by films without and with array coverage (3b and 3c). There was a slight difference between the two measured dose distributions in the region around the position of (x = 4 cm, y = 7 cm). However, the Gamma-based consistency analysis between the two showed that the Gamma index was 94.5% under the criteria of 2%/2 mm and 98.3% under the criteria of 3%/3 mm, demonstrating high consistency. Gamma indexes between the deep-site dose distributions without and with arrays coverage for all eight cases are shown in Table 2 . Under the four types of criteria (2%/ 2 mm, 2%/ 3 mm, 3%/ 2 mm and 3%/3 mm), Gamma indexes were (93.16 + 5.16)%, (96.08 + 3.49)%, (96.77 + 2.54)% and (97.96 + 1.61)%, respectively. Table 2 Gamma index reflecting consistency between the deep-site dose distributions without and with arrays coverage. Index Gamma index (10% threshold) 2%/2 mm 2%/3 mm 3%/2 mm 3%/3 mm #1 97.5% 98.8% 99.1% 99.3% #2 87.5% 96.4% 94.6% 98.4% #3 98.2% 99.2% 99.6% 99.7% #4 83.1% 87.9% 91.5% 94.3% #5 98.1% 98.7% 98.6% 98.7% #6 94.5% 96.4% 97.4% 98.3% #7 95.4% 97.3% 97.7% 98.3% #8 91% 93.9% 95.7% 96.7% \(\stackrel{-}{x}\) ±std (93.16 ± 5.16)% (96.08 ± 3.49)% (96.77 ± 2.54)% (97.96 ± 1.61)% Discussion The dosimetric effects of TTFields arrays on glioblastoma radiotherapy, especially the deep-site dosimetry related to target coverage, need to be studied in considerations of both clinical benefits and economic & convenience. The metal artifacts caused by TTFields array on kV-CT will lead to three problems: Firstly, it is difficult to give accurate electrode position and size for kV-CT. Secondly, the HU value of the electrode is ambiguous, as well as the electron density. Moreover, the banded artifacts intrude into the surrounding tissues and overlap the original values. Straube et al found that MV-CT can solve the electrode artifact problem to a certain extent, and the percent depth dose feature calculated based on MV-CT is closer to the measured value than that of kV-CT [ 11 ] . Then, they calculated the dose of radiotherapy plans with and without TTFields arrays of actual cases based on MV-CT and found that there were no clinically significant differences in target coverage and OAR sparing between the two groups. There were also some subsequent calculation-based studies [ 12 – 15 ] reaching a conclusion similar to that of Straube. In the measurement-based research, limited by the feasible means, the deep-site dose distribution that can be directly given is relatively little. Li et al used Delta4 to measure the deep-site dose distribution under the TTFields array coverage [ 12 ] . However, the geometry of the phantom and coverage style of arrays used is much different from the clinical situation. For the first time, the coverage style of arrays mimics that with the human cranial geometry and is designed so that 12 button-shaped electrodes covered the skull in the same transverse layer. In this case, if electrodes have adverse effects on the deep-site dose distribution, the distortion of the distribution in the layer wrapped by the 12 electrodes should be the most severe. Therefore, the perturbation of the TTFields electrodes to the deep-site dose distribution can be understood by observing the consistency between the dose distributions of the electrodes-wrapped layer and the corresponding electrodes-free layer. Gamma-based analysis demonstrated that the agreement between the two distributions was close to or greater than 95% under the 3%/3 mm criteria. Gamma index was less than 90% in no case under the 3%/2 mm criteria, only one case under the 2%/3mm criteria and two cases under the 2%/2mm criteria, respectively. Conventionally segmented mode is generally adopted for glioblastoma radiotherapy. Thus, taking the 3%/3 mm criteria as the standard to evaluate the consistency of the two dose distributions is generally accepted in clinical practice [ 22 – 24 ] . In other words, even when the number of wrapped electrodes reaches twelve, the distortion of the deep-site dose distribution is still small. This is consistent with other calculation-based results, further boosting the confidence in technical view of radiotherapy units to carry out this technique. The analytical method adopted in this study belongs to the "extreme case" analysis method. The presence of metal electrodes can lead to the distortion of the dose distribution in the radiotherapy patients, but the degree of influence depends on the type of metal, size and many other factors [ 25 ] . The "extreme analysis" assumes that one certain layer of the patient's brain is surrounded by 12 (reach to maximum) TTFields electrodes, at which point the electrodes are at their maximum resistance to radiation. In clinical settings, however, there is usually extremely low probability to have twelve electrodes surrounding the same layer. A retrospective examination of coverage style of the TTFields arrays in 75 cases underdone glioblastoma radiotherapy with concurrent TTFields has been carried out in our center, and no "extreme case" has been found yet. Therefore, in clinical practice, the consistency between the arrays-wearing dose distribution and the arrays-free one at any layer of the patient should be better than that in the "extreme case". On the other hand, periodic adjustment of the arrays positions (to reduce scalp adverse reactions) and the inter-fractional random fluctuations of the head position during the overall radiotherapy course may also reduce the degree to which the dose distribution at the same layer is affected by the electrode arrays. Based on the results of this study, it can be fully inferred that TTFields array has little effect on the deep-site dose of glioblastoma radiotherapy. Future dosimetry research may focus on the evaluation, inhibition and protection of skin dose enhancement in the presence of TTFields arrays [ 7 , 17 , 26 ] . There are limitations to this study. On one hand, the phantom used has a limited number of places where the film can be inserted. Therefore, only the dose distribution of the specified layer under the extreme condition of the phantom can be observed for a given glioblastoma radiotherapy plan, and situations of other layers cannot be evaluated. On the other hand, measurement-based studies using dosimetry film can only give the information of deep-site dose distribution, but not the quantitative indicators reflecting target coverage and OAR sparing. In the future, the application of 3D gels radiation dosimeters may be a potential solution [ 27 , 28 ] . Conclusion Even in the extreme case of TTFields electrodes wrapping (12 electrodes covering the same layer), the deep-site dose distribution in glioblastoma radiotherapy with concurrent TTFields is very weakly disturbed. Therefore, from the perspective of deep-site dosimetry, the presence of TTFields arrays do not diminish the enforceability of glioblastoma radiotherapy plans and the precision of dose delivery. Future dosimetry research may focus on the evaluation, inhibition and protection of skin dose enhancement in the presence of TTFields arrays. Declarations 1. Ethics approval and consent to participate All patients provided verbal informed consent prior to inclusion in the study for the research use and publishing of their clinical data. This study was approved by the Ethics Committee of Jiangsu Cancer Hospital, Jiangsu Province, China, and the corresponding Ethic number is 2022-028. 2. Conflict of Interest No conflicts of interest. 3. Funding National Key Research & Development Program of China (2022YFC2404605); Spark Basic Research Program of Jiangsu Cancer Hospital (ZJ202309) 4. Author Contribution Statement Jiajun Zheng was involved in the conception and design of the study. Zhi Wang, Huanfeng Zhu, Wenjie Guo, Jianfeng Wu, Li Sun, and Dan Zong were involved in the analysis and interpretation of the data, the drafting and critical revision of the manuscript. Jiajun Zheng and Xia He were involved in the final approval of the version submitted for publication. 5. Acknowledgements The authors wish to thank the colleagues and peers who kindly agreed to share their data and provide help: Jingjing Wu, Yuanyuan Wang and Shiyao Wang. References Stupp R, Taillibert S, Kanner A A, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial[J]. Jama, 2015, 314(23): 2535-2543. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial[J]. Jama, 2017, 318(23): 2306-2316. Taphoorn M J B, Dirven L, Kanner A A, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial[J]. JAMA oncology, 2018, 4(4): 495-504. Lok E, Swanson K D, Wong E T. 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End to end comparison of surface‐guided imaging versus stereoscopic X‐rays for the SRS treatment of multiple metastases with a single isocenter using 3D anthropomorphic gel phantoms[J]. Journal of Applied Clinical Medical Physics, 2022, 23(5): e13576. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3915746","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271294109,"identity":"cde20c99-4fe3-42a8-b6f9-42133e4d213c","order_by":0,"name":"Jiajun Zheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIie3QsQrCMBCA4QuBukS7XlHsK0SE6lB8mUJcCjo5SsW1DyDoQzg5B4ud+gAOLiI4dxCp4GAizm3dBPMPN90HuQCYTL8Y6sH0lAA590ffEbKaiqAm+URZvidRlXDXy/R86wzBXmTexeeSQiM5bMsI2aTjfkc9DGU26If81AImxLGMUAy9NupbZOa1Q36lgMwrJRZO7m/iajLkCYmqCMPQcnJFuCZQhyAKtcmQ9WQ6c2IuAqvqFncVXJ1HPO92j8kOi6c/shtJWkp0tBkDU1/2ua5qXUeKQk07qrNrMplM/9gL4GhCZWYfXs4AAAAASUVORK5CYII=","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":true,"prefix":"","firstName":"Jiajun","middleName":"","lastName":"Zheng","suffix":""},{"id":271294110,"identity":"63b11fec-d297-494d-a036-8e701c91fb00","order_by":1,"name":"Zhi Wang","email":"","orcid":"","institution":"Department of Radiation Oncology, the First Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhi","middleName":"","lastName":"Wang","suffix":""},{"id":271294111,"identity":"918286c9-dba9-4f19-a906-1d94d522b8fc","order_by":2,"name":"Huanfeng Zhu","email":"","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Huanfeng","middleName":"","lastName":"Zhu","suffix":""},{"id":271294112,"identity":"3604fef0-6bb1-4bee-a453-f5b42da0a16e","order_by":3,"name":"Wenjie Guo","email":"","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Wenjie","middleName":"","lastName":"Guo","suffix":""},{"id":271294113,"identity":"99386224-98b0-4a95-8dff-a8b9efd26d3d","order_by":4,"name":"Jianfeng Wu","email":"","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Jianfeng","middleName":"","lastName":"Wu","suffix":""},{"id":271294114,"identity":"323d2e36-ffa3-4bfc-b6d0-c1753e12f8e3","order_by":5,"name":"Li Sun","email":"","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Sun","suffix":""},{"id":271294115,"identity":"4b80b974-024e-4525-85ae-312d856edb76","order_by":6,"name":"Dan Zong","email":"","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Zong","suffix":""},{"id":271294116,"identity":"8a707e3e-f0da-48cd-a23b-72bd1bb727ee","order_by":7,"name":"Xia He","email":"","orcid":"","institution":"Department of Radiation Oncology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2024-02-01 02:44:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3915746/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3915746/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50819816,"identity":"88c82ed8-ca0e-458d-a4ce-9254681d5908","added_by":"auto","created_at":"2024-02-07 20:35:00","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":581611,"visible":true,"origin":"","legend":"\u003cp\u003eCIRS-038 wearing the TTFields arrays complying with the extreme principles (a: frontal view; b: Side view; Red arrow: TTFields array; Orange arrow: phantom)\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3915746/v1/4595f31c79f6770fcf787e71.jpg"},{"id":50819817,"identity":"4597679a-4123-4518-b448-45fefb81be52","added_by":"auto","created_at":"2024-02-07 20:35:00","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":937118,"visible":true,"origin":"","legend":"\u003cp\u003eCT image of the observation layer (a-1) of case #2 and the corresponding CBCT image (a-2); Red arrow: marker indicating the upper film-inserted place inside the phantom; The CT image of the observation layer (b-1) of case #4 and the corresponding CBCT image (b-2); Green arrow: marker indicating the lower film-inserted place inside the phantom; Red line: PTV outline.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3915746/v1/68906290f092b9881d077b8f.jpg"},{"id":50819815,"identity":"9eaa2699-b999-4b03-bc58-2c76b63fad8c","added_by":"auto","created_at":"2024-02-07 20:35:00","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":820692,"visible":true,"origin":"","legend":"\u003cp\u003ePlanned dose distribution (a) of the region of interest (deep-site) at the observation layer of case #6 and the measured dose distributions obtained by films without and with array coverage (3b and 3c).\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3915746/v1/0eb980ea97784edba86b0795.jpg"},{"id":56727020,"identity":"8d150d2b-2b93-4ea2-ace5-1c95ffbec759","added_by":"auto","created_at":"2024-05-19 09:17:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2753319,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3915746/v1/a60cdead-f642-4b37-89e3-ebaf3c612adc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of transducer arrays on deep-site dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTumor treating fields (TTFields) has confirmed advantages in improving overall survival (OS) and progression-free survival (PFS) in glioblastoma without significant deterioration in health-related quality of life (HRQoL)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Technically, the device used to establish the treating field is a transducer array consisting of 9 button-type ceramic electrodes arranged in 3\u0026times;3. The grouped four arrays are attached to the skull of patient to establish the required intracranial electric field with frequency between 100 kHz and 300 kHz and strength between 1 V/cm and 3 V/cm\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAlthough TTFields is an independent therapeutic modality, therapeutic synergies between TTfields and radiotherapy have been found in recent years, which has led to several preclinical and clinical studies about radiotherapy with concurrent TTFields for glioblastoma\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. In addition, since TTFields arrays are designed as disposable and expensive, discarding the arrays before each radiotherapy will result in high treatment costs, which may affect the treatment compliance as well as the ultimate survival outcome\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Thus, it is necessary to consider the situation of patients receiving radiotherapy while wearing the TTFields arrays both in terms of clinical benefit and cost-effectiveness. Therefore, it is important to study the dosimetric effect of the TTFields arrays on glioblastoma radiotherapy, especially the deep-site dosimetry reflecting the target coverage.\u003c/p\u003e\n\u003cp\u003eThe metal artifacts caused by TTFields electrodes on kV-CT make it difficult to calculate the dose in the presence of electrodes in kV-CT. Straube et al focused on the calculation-based deep-site dosimetry in glioblastoma radiotherapy with concurrent TTFields\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, which were either based on MV-CT or artificially assigned electrode HU in kV-CT (3817 or 3832, etc.). However, there is a lack of uniform standard and solid basis for the assignment of electrode HU in these calculation-based researches. In addition, the use of different dose calculation algorithms will also introduce uncertainty to the results\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. These challenges affect the reliability of dose calculations involving electrodes and may lead to a loss of confidence in the radiotherapy centers to apply this treatment modality. Therefore, measurement-based dosimetry studies are needed to validate the results of calculation-based studies and further verify the dosimetry effects of TTFields arrays on radiotherapy for glioblastoma. In this study, the effect of the TTFields arrays on deep-site dose distribution of glioblastoma radiotherapy with concurrent TTFields was investigated based on measurements using an extreme analysis method.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e\u003cstrong\u003e1.1 Patient cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEight patients who received glioblastoma radiotherapy with concurrent TTFields were selected. The TTFields treatment plans were generated in the NovoTALTM software. The placements of the grouped arrays were optimized according to the shape and size of the patient\u0026apos;s skull and planned target volume (PTV), as well as the positional relationship between them. In general, the four arrays were approximately located in the frontal lobe, posterior occipital, and left and right temporal lobes, respectively. The least time of wearing arrays per day was 18 hours, and arrays need be replaced by new ones with fine-tuned positions every three days to reduce scalp adverse reactions\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. The radiotherapy plans were designed by experienced radiotherapy dosimetrists using Varian Eclipse (v15.6) treatment planning system (TPS). All radiotherapy plans used volumetric modulated arc radiotherapy (VMAT) technology with a single arc field covering an angle of 360\u0026deg;. All target coverage, organ at risk (OAR) sparing and other dose distribution indexes meet clinical requirements. All radiotherapy plans were delivered on the TrueBeam platform. The basic information of the involved patients, the prescribed dose and the MU of plan are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eTable 1. General information of eight cases of radiotherapy with concurrent TTFields for glioblastoma.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIndex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePTV location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePTV volume\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePrescription\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePlan Mu\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRight occipital lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e362.3 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2Gy\u0026times;30f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e359.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRight temporal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e274.1 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.15Gy\u0026times;28f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e445.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCentral parietal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e160.7 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2Gy\u0026times;30f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e493.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLeft temporal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e604.2 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.15Gy\u0026times;28f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e526.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLeft frontal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e404.6 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.15Gy\u0026times;28f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e574.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRight temporal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e371.1 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2Gy\u0026times;30f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e587\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRight frontal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e364.2 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2Gy\u0026times;30f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e635.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e#8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCentral frontal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e339.9 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.5Gy\u0026times;36f\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e320.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e1.2 Extreme simulation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CIRS-038 anthropomorphic head \u0026amp; neck phantom was used to simulate patients receiving radiotherapy with concurrent TTFields. The CIRS-038 has an external profile and internal anatomy structure in CT similar to that of the human skull, and has a designated location to place dosimetry film\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Firstly, CT scan was performed to CIRS-038 with the layer thickness of 1 mm, and the scanned CT images were imported into Eclipse (v15.6). Then, each CT image of the eight cases was registered to the phantom and PTV, OAR and other structures were copied to the phantom. In final, new single-arc VMAT plans were generated using the same optimization objectives with the reference plans based on the phantom CT and real structures.\u003c/p\u003e\n\u003cp\u003eThe coverage style of the TTFields arrays on the phantom follows two principles: 1) as close as possible to the clinical coverage style; 2) a total of 12 electrodes were wrapped around the skull in the same observation transverse layer (either of the two specified transverse layers in CIRS-038 where the dosimetry film can be placed). The second principle was designed aiming to simulate the most extreme situations in electrode wrapping. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the CIRS-038 phantom wearing the TTFields arrays complying with the above principles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3 Dose delivery and data analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor each selected cases, film placement and arrays coverage on the phantom were firstly completed. The EBT3 radiation dosimetry film was chosen in this study. Subsequently, the setup of the phantom was completed on the TrueBeam platform. Then, cone beam CT (CBCT) was performed to verify the phantom positioning and the dedicate coverage style. After verification, the selected radiotherapy plan was loaded and the dose was delivered to the CIRS-038 wearing the TTFields arrays as well as the film inside. After arrays removing, film replacing and positioning re-verification, the same radiotherapy plan was again performed, delivering the dose to the CIRS-038 without arrays coverage.\u003c/p\u003e\n\u003cp\u003eAfter the dose delivery of all radiotherapy plans were completed, the obtained dosimetry films were placed in darkness for 24 hours. The films with dose patterns was scanned using the Epson V700 scanner. Then, the conversion of optical density distribution to dose distribution based on dose scale curve was completed in DoseLab software\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. For each of the eight cases, Gamma-based consistency analysis was performed for the two dose distributions without and with coverage\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1 Verification of extreme\u003c/h2\u003e\n\u003cp\u003eEach glioblastoma radiotherapy plan required a CBCT verification for the arrays coverage style and the phantom positioning prior to dose delivery. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the CT image and the corresponding CBCT image (after registration) at the observing layer (where the film is located) in the CIRS-038 of case #2 and #4. Two marks (red arrow indicates in Fig.a-\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and green arrow indicates in Fig.b-\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) can be seen in the CT image, which were used to identify the observation layers with EBT3 films. In the corresponding CBCT image, it can be seen that there were a total of 12 electrodes surrounding the skull and leading to the banded artifacts\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Before dose delivery of the radiotherapy plans of eight cases, the accuracy of the phantom positioning and the coverage style of the TTFields arrays were confirmed.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003e3.2 Dose distributions\u003c/h3\u003e\n\u003cp\u003eFigure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e shows the planned dose distribution (3a) of the region of interest (deep-site) at the observation layer of case #6 and the measured dose distributions obtained by films without and with array coverage (3b and 3c). There was a slight difference between the two measured dose distributions in the region around the position of (x\u0026thinsp;=\u0026thinsp;4 cm, y\u0026thinsp;=\u0026thinsp;7 cm). However, the Gamma-based consistency analysis between the two showed that the Gamma index was 94.5% under the criteria of 2%/2 mm and 98.3% under the criteria of 3%/3 mm, demonstrating high consistency. Gamma indexes between the deep-site dose distributions without and with arrays coverage for all eight cases are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Under the four types of criteria (2%/ 2 mm, 2%/ 3 mm, 3%/ 2 mm and 3%/3 mm), Gamma indexes were (93.16\u0026thinsp;+\u0026thinsp;5.16)%, (96.08\u0026thinsp;+\u0026thinsp;3.49)%, (96.77\u0026thinsp;+\u0026thinsp;2.54)% and (97.96\u0026thinsp;+\u0026thinsp;1.61)%, respectively.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eGamma index reflecting consistency between the deep-site dose distributions without and with arrays coverage.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eIndex\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eGamma index (10% threshold)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e2%/2 mm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e2%/3 mm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3%/2 mm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3%/3 mm\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.8%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e99.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e99.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e96.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e94.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98.2%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e99.2%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e99.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e99.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e87.9%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e91.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e94.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e94.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e96.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e97.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e97.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e97.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e93.9%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e95.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e96.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\stackrel{-}{x}\\)\u003c/span\u003e\u003c/span\u003e\u0026plusmn;std\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(93.16\u0026thinsp;\u0026plusmn;\u0026thinsp;5.16)%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e(96.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.49)%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e(96.77\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54)%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e(97.96\u0026thinsp;\u0026plusmn;\u0026thinsp;1.61)%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe dosimetric effects of TTFields arrays on glioblastoma radiotherapy, especially the deep-site dosimetry related to target coverage, need to be studied in considerations of both clinical benefits and economic \u0026amp; convenience. The metal artifacts caused by TTFields array on kV-CT will lead to three problems: Firstly, it is difficult to give accurate electrode position and size for kV-CT. Secondly, the HU value of the electrode is ambiguous, as well as the electron density. Moreover, the banded artifacts intrude into the surrounding tissues and overlap the original values. Straube et al found that MV-CT can solve the electrode artifact problem to a certain extent, and the percent depth dose feature calculated based on MV-CT is closer to the measured value than that of kV-CT\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Then, they calculated the dose of radiotherapy plans with and without TTFields arrays of actual cases based on MV-CT and found that there were no clinically significant differences in target coverage and OAR sparing between the two groups. There were also some subsequent calculation-based studies\u003csup\u003e[\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e reaching a conclusion similar to that of Straube.\u003c/p\u003e \u003cp\u003eIn the measurement-based research, limited by the feasible means, the deep-site dose distribution that can be directly given is relatively little. Li et al used Delta4 to measure the deep-site dose distribution under the TTFields array coverage\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. However, the geometry of the phantom and coverage style of arrays used is much different from the clinical situation. For the first time, the coverage style of arrays mimics that with the human cranial geometry and is designed so that 12 button-shaped electrodes covered the skull in the same transverse layer. In this case, if electrodes have adverse effects on the deep-site dose distribution, the distortion of the distribution in the layer wrapped by the 12 electrodes should be the most severe. Therefore, the perturbation of the TTFields electrodes to the deep-site dose distribution can be understood by observing the consistency between the dose distributions of the electrodes-wrapped layer and the corresponding electrodes-free layer.\u003c/p\u003e \u003cp\u003eGamma-based analysis demonstrated that the agreement between the two distributions was close to or greater than 95% under the 3%/3 mm criteria. Gamma index was less than 90% in no case under the 3%/2 mm criteria, only one case under the 2%/3mm criteria and two cases under the 2%/2mm criteria, respectively. Conventionally segmented mode is generally adopted for glioblastoma radiotherapy. Thus, taking the 3%/3 mm criteria as the standard to evaluate the consistency of the two dose distributions is generally accepted in clinical practice\u003csup\u003e[\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. In other words, even when the number of wrapped electrodes reaches twelve, the distortion of the deep-site dose distribution is still small. This is consistent with other calculation-based results, further boosting the confidence in technical view of radiotherapy units to carry out this technique.\u003c/p\u003e \u003cp\u003eThe analytical method adopted in this study belongs to the \"extreme case\" analysis method. The presence of metal electrodes can lead to the distortion of the dose distribution in the radiotherapy patients, but the degree of influence depends on the type of metal, size and many other factors\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. The \"extreme analysis\" assumes that one certain layer of the patient's brain is surrounded by 12 (reach to maximum) TTFields electrodes, at which point the electrodes are at their maximum resistance to radiation. In clinical settings, however, there is usually extremely low probability to have twelve electrodes surrounding the same layer. A retrospective examination of coverage style of the TTFields arrays in 75 cases underdone glioblastoma radiotherapy with concurrent TTFields has been carried out in our center, and no \"extreme case\" has been found yet. Therefore, in clinical practice, the consistency between the arrays-wearing dose distribution and the arrays-free one at any layer of the patient should be better than that in the \"extreme case\". On the other hand, periodic adjustment of the arrays positions (to reduce scalp adverse reactions) and the inter-fractional random fluctuations of the head position during the overall radiotherapy course may also reduce the degree to which the dose distribution at the same layer is affected by the electrode arrays. Based on the results of this study, it can be fully inferred that TTFields array has little effect on the deep-site dose of glioblastoma radiotherapy. Future dosimetry research may focus on the evaluation, inhibition and protection of skin dose enhancement in the presence of TTFields arrays\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere are limitations to this study. On one hand, the phantom used has a limited number of places where the film can be inserted. Therefore, only the dose distribution of the specified layer under the extreme condition of the phantom can be observed for a given glioblastoma radiotherapy plan, and situations of other layers cannot be evaluated. On the other hand, measurement-based studies using dosimetry film can only give the information of deep-site dose distribution, but not the quantitative indicators reflecting target coverage and OAR sparing. In the future, the application of 3D gels radiation dosimeters may be a potential solution\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eEven in the extreme case of TTFields electrodes wrapping (12 electrodes covering the same layer), the deep-site dose distribution in glioblastoma radiotherapy with concurrent TTFields is very weakly disturbed. Therefore, from the perspective of deep-site dosimetry, the presence of TTFields arrays do not diminish the enforceability of glioblastoma radiotherapy plans and the precision of dose delivery. Future dosimetry research may focus on the evaluation, inhibition and protection of skin dose enhancement in the presence of TTFields arrays.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e1. Ethics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients provided verbal informed consent prior to inclusion in the study for the research use and publishing of their clinical data.\u0026nbsp;This study was approved by the Ethics Committee of Jiangsu Cancer Hospital, Jiangsu Province, China, and the corresponding Ethic number is 2022-028.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Conflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Key Research \u0026amp; Development Program of China (2022YFC2404605);\u003c/p\u003e\n\u003cp\u003eSpark Basic Research Program of Jiangsu Cancer Hospital (ZJ202309)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. Author Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJiajun Zheng was involved in the conception and design of the study. Zhi Wang, Huanfeng Zhu, Wenjie Guo, Jianfeng Wu, Li Sun, and Dan Zong were involved in the analysis and interpretation of the data, the drafting and critical revision of the manuscript. Jiajun Zheng and Xia He were involved in the final approval of the version submitted for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank the colleagues and peers who kindly agreed to share their data and provide help: Jingjing Wu, Yuanyuan Wang and Shiyao Wang.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eStupp R, Taillibert S, Kanner A A, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial[J]. Jama, 2015, 314(23): 2535-2543.\u003c/li\u003e\n \u003cli\u003eStupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial[J]. Jama, 2017, 318(23): 2306-2316.\u003c/li\u003e\n \u003cli\u003eTaphoorn M J B, Dirven L, Kanner A A, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial[J]. JAMA oncology, 2018, 4(4): 495-504.\u003c/li\u003e\n \u003cli\u003eLok E, Swanson K D, Wong E T. Tumor treating fields therapy device for glioblastoma: physics and clinical practice considerations[J]. Expert review of medical devices, 2015, 12(6): 717-726.\u003c/li\u003e\n \u003cli\u003eGiladi M, Munster M, Schneiderman R S, et al. Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells[J]. Radiation Oncology, 2017, 12(1): 1-13.\u003c/li\u003e\n \u003cli\u003eBokstein F, Blumenthal D, Limon D, et al. Concurrent tumor treating fields (TTFields) and radiation therapy for newly diagnosed glioblastoma: a prospective safety and feasibility study[J]. Frontiers in oncology, 2020, 10.\u003c/li\u003e\n \u003cli\u003eSong A, Bar-Ad V, Martinez N, et al. Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma[J]. Journal of Neuro-Oncology, 2020, 147: 653-661.\u003c/li\u003e\n \u003cli\u003eAli A S, Lombardo J, Niazi M Z, et al. Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study[J]. Journal of Neuro-Oncology, 2022, 160(2): 345-350.\u003c/li\u003e\n \u003cli\u003eShi W, Roberge D, Kleinberg L, et al. Phase 3 TRIDENT study (EF-32): Tumor treating fields (TTFields; 200 kHz) concomitant with chemoradiation, and maintenance TTFields therapy/temozolomide in newly diagnosed glioblastoma[J]. 2023, 40(16).\u003c/li\u003e\n \u003cli\u003eToms S A, Kim C Y, Nicholas G, et al. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial[J]. Journal of Neuro-oncology, 2019, 141: 467-473.\u003c/li\u003e\n \u003cli\u003eStraube C, Oechsner M, Kampfer S, et al. Dosimetric impact of tumor treating field (TTField) transducer arrays onto treatment plans for glioblastomas\u0026ndash;a planning study[J]. Radiation Oncology, 2018, 13(1): 1-10.\u003c/li\u003e\n \u003cli\u003eLi T, Shukla G, Peng C, et al. Dosimetric impact of a tumor treating fields device for glioblastoma patients undergoing simultaneous radiation therapy[J]. Frontiers in Oncology, 2018, 8: 51.\u003c/li\u003e\n \u003cli\u003eGuberina N, P\u0026ouml;ttgen C, Kebir S, et al. Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial[J]. Radiation Oncology, 2020, 15(1): 1-11.\u003c/li\u003e\n \u003cli\u003eStachelek G C, Grimm J, Moore J, et al. Tumor-treating field arrays do not reduce target volume coverage for glioblastoma radiation therapy[J]. Advances in Radiation Oncology, 2020, 5(1): 62-69.\u003c/li\u003e\n \u003cli\u003eNour Y, P\u0026ouml;ttgen C, Kebir S, et al. Dosimetric impact of the positioning variation of tumor treating field electrodes in the PriCoTTF‐phase I/II trial[J]. 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Journal of Applied Clinical Medical Physics, 2022, 23(5): e13576.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glioblastoma, TTFields, Radiotherapy, Array, Deep-site dosimetry","lastPublishedDoi":"10.21203/rs.3.rs-3915746/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3915746/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e To study the impact of transducer arrays on the deep-site dosimetry of radiotherapy with concurrent tumor treating fields (TTFields) for glioblastoma.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e Firstly, the covering style of transducer arrays to CIRS-038 phantom was designed to simulate the \"extreme situation\": four arrays were attached to the phantom as a style similar with that in clinical scene and, meanwhile, to assure that layer of interest of CIRS-038 was surrounded by twelve electrodes (three in each array). Then, eight patients undergone glioblastoma radiotherapy were selected, and the planed dose of each patient was delivered to the phantom with dosimetry film inside without and with transducer arrays. For the phantom with arrays, CBCT was used to check the dedicated covering style before dose delivery. Finally, Gamma-based consistency analysis was performed for two dose distributions for each plan (without/with arrays).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e The covering style of the TTFields array met the requirements in 8 cases before dose delivery. Gamma indexes under the four criteria (2%/2 mm, 2%/3 mm, 3%/2 mm and 3%/3 mm) were (93.16±5.16)%, (96.08±3.49)%, (96.77±2.54)% and (97.96±1.61)%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e Even in extreme situation (twelve electrodes covering the same cross-section), the perturbation of the TTFields arrays to the deep-site dose distribution of the radiotherapy for glioblastoma is weak and acceptable.\u003c/p\u003e","manuscriptTitle":"Impact of transducer arrays on deep-site dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-07 20:34:55","doi":"10.21203/rs.3.rs-3915746/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b19d55a0-1a14-4cec-adda-42b9be2e9f4b","owner":[],"postedDate":"February 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-19T09:09:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-07 20:34:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3915746","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3915746","identity":"rs-3915746","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}