Prospective pilot study evaluating dental side effects of radiotherapy on subjects treated for head and neck cancer: StomRay Study

Prospective pilot study evaluating dental side effects of radiotherapy on subjects treated for head and neck cancer: StomRay Study | 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 Study protocol Prospective pilot study evaluating dental side effects of radiotherapy on subjects treated for head and neck cancer: StomRay Study Yasemin Karaca, Sylvie Beauvois, Clémence Al wardi, Mehdi Keddar, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4642483/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 Background : Head and Neck Squamous Cell Carcinoma (HNSCC) remains a significant global cause of mortality, with late-stage diagnoses contributing to unfavorable prognosis 1 . Radiotherapy (RT) is crucial in HNSCC treatment but poses risks, including osteoradionecrosis of the jaw (ORNJ) and dental issues post-irradiation 2 . Pre-RT dental restoration is recommended, yet some patients undergo unnecessary tooth removal, impacting post-treatment options like dental implants or bridges 3 . To address this, a predictive model for dental avulsions pre-RT is being developed. It aims to identify low-risk areas (50 Gy), low risk (<40 Gy), and an intermediate group (40-50 Gy). A color-coded system categorizes irradiated areas on the dental arch, simplifying assessments for molar, premolar, and incisor groups. This approach aimed to balance the need for dental interventions before RT, optimizing patient care and post-treatment quality of life. Methods: Patients diagnosed with HNSCC scheduled for RT undergo initial assessment by a stomatologist for a comprehensive dental examination prior to treatment. As part of our protocol, a dental decalcification and splint placement are conducted before the onset of RT. According to our predictive model, teeth expected to receive over 40 Gy, impacting long-term survival, are scheduled for extraction at least two weeks before RT begins. After treatment, patients undergo regular dental evaluations every six months for 36 months to detect and address potential dental issues. Additionally, patients' quality of life was assessed by three different questionnaires, both during and post-RT. The primary goal of our study is to model the risk of dental complications, particularly the likelihood of fractures and dental caries, using the concept of normal tissue complication probability (NTCP). Secondary objectives involved validating our predictive dose model for RT based on tumor location and TNM stage. We aimed to integrate our predictive dose model with dental NTCP to personalize decisions regarding tooth extraction before RT. Moreover, we investigated the impact of partial or total tooth loss and RT on the patient's quality of life. Discussion: Our study is based on the importance of preserving oral health, particularly dental structures, in survivors of HNSCC to enhance their quality of life post-treatment. It highlights the benefits of a conservative approach to dental interventions, especially for HPV-positive oropharyngeal carcinoma patients, aiming to minimize unnecessary procedures and tailor treatments based on individual risk factors. It also emphasizes the significance of identifying teeth at minimal risk of radiation exposure to prevent complications such as osteonecrosis. Additionally, it outlines ongoing research efforts to develop a predictive dose model for guiding dental interventions, aiming to safeguard dental health and overall well-being in HNSCC survivors. Trial registration : ClinicalTrials.gov NCT04452032, study protocol version 1.1_11/08/2020. Registered 25/06/2020 Head and neck squamous cell carcinoma radiotherapy radionecrosis dental health predictive model Figures Figure 1 Background Osteoradionecrosis, a well described complication of RT, frequently is due to dental extractions in areas exposed to doses exceeding 40 Gy 4 . The occurrence ranged from 5 to 15%, with tooth extraction after head and neck RT accounting for 2 to 22% of cases 4 , 5 . In a retrospective study involving 11 subjects, we observed a significant correlation between dental fractures and an average dental dose exceeding 50 Gy (p = 0.01). Similarly, an average parotids RT dose above 40 Gy correlated with caries (p = 0.05). However, the small sample size limits rigorous statistical testing, warranting cautious interpretation 6 . Based on literature 7 and our retrospective findings, we have adopted a conservative approach, using "40 Gy" as the threshold for tolerable dose for post-irradiation dental extraction to minimize osteoradionecrosis risk. Accurate predicting teeth receiving tolerable doses (< 40 Gy) could preserve more teeth, even those with questionable long-term viability. This conservative strategy, especially beneficial for human papilloma virus (HPV)-positive oropharyngeal carcinoma patients with generally better prognoses and dental status compared to alcohol- or tobacco-induced HNC patients, is pivotal 8 . Our prospective study has a dual objective: firstly, to assess the risk of dental complications—specifically fractures and caries—by utilizing the normal tissue complication probability (NTCP). Secondly, we aimed to validate a "predictive dose model" for RT based on tumor location and TNM stage (8th edition). This model's refinement and application seek to minimize unnecessary dental extractions, thereby significantly enhancing the overall quality of life post-RT for patients undergoing treatment for head and neck cancers. Methods/study design This is a multi-centric prospective one arm, phase II clinical trial evaluating the risk of dental complication (normal tissue complication probability (NTCP), especially the probability of fractures and dental caries. The study design is illustrated in Fig. 1 Study objectives and statistical analyses This study primarily aims to model the risk of dental complications post-RT, focusing on the normal tissue complication probability (NTCP), specifically the likelihood of fractures and dental caries. In addition to this primary goal, the study has several secondary objectives: Firstly, we aim to validate our "predictive dose model" for radiotherapy by considering the tumor's location and the TNM stage. This validation process aims to refine and enhance the accuracy of our predictive model. Secondly, our intention is to integrate our predictive dose model with dental NTCP. This integration seeks to personalize decisions regarding teeth avulsion before the initiation of RT. By aligning the predictive dose model with dental complications, we aim to optimize treatment planning, minimizing unnecessary dental interventions while ensuring the efficacy of RT. Lastly, we seek to explore the impact of (partial or total) edentulousness and RT on the overall quality of life of the subjects. Understanding how tooth loss and its interaction with RT affect patients' well-being is crucial for comprehensive treatment considerations and patient-centered care. Overall, this study aims to not only predict and mitigate dental complications following RT but also to refine treatment strategies, personalize dental interventions, and assess the holistic impact on patients' quality of life. Sample size calculation The study's primary objective is to construct a comprehensive model for Normal Tissue Complication Probability (NTCP). Previous research projects suggest an anticipated NTCP rate of approximately 20% per tooth, serving as the unit of analysis. The model will consider several factors for inclusion, including the actual dose to the tooth, parotid glands, pre-RT clinical tooth status, and the cT and cN stages. Up to five variables could potentially form the basis of the final model. To achieve this, a minimum of 50 teeth with complications and a total of 250 teeth must be documented. Considering an average of 10 teeth per subject, the study aims to encompass at least 25 assessable subjects. Subjects and their respective teeth will be considered evaluable if they maintain follow-up for 36 months post-RT and if all necessary data are accessible for assessing both administered and predicted RT doses. Accounting for an expected 10% rate of screening failure and 30% rate of unevaluable subjects, the study aims to enroll approximately 40 subjects to ensure a sufficient evaluable cohort for analysis. Patients’ characteristics Patients with newly diagnosed and histologically confirmed primary HNSCC planned for curative intent RT will be included. The recruiting centers are the Jules Bordet Institute, Centre Hospitalier Universitaire Saint- Pierre and Hôpital Erasme—Clinique Universitaire de Bruxelles. The inclusion and exclusion criteria are summarized in Table 1. Study interventions Dental avulsion : Before initiating RT, each subject undergoes a meticulous dental assessment. If necessary, dental avulsions are conducted for teeth at risk of compromising long-term survival and situated in areas expected to receive more than 40 Gy, potentially leading to osteoradionecrosis of the jaw. Avulsions are scheduled at least 2 weeks before the start of RT to allow mucosal healing. Tooth avulsion is performed for all teeth within irradiation fields identified "at risk" according to our developed "predictive model." This includes teeth meeting at least one of the following criteria, indicating compromised long-term viability: - Tooth mobility score > 2 (Miller’s score, 1985) - Caries severity score > 4 (ICDAS II, 2005) - Dutch periodontal screening index (DPSI) score > 2 - Periapical lesion - Root fracture - Furcation caries (in multi-rooted teeth) - Coronary reconstruction exceeding 1/3 of its total surface (except inlay, only and total crown if there are not sign of caries or lack of sealing) In addition, dental avulsions are sometimes also necessary for a more adequate prosthetic rehabilitation. For all of subjects, a dental decalcification and afterwards, a dental splint will be performed before the start of RT. Following completion of RT, subjects receive thorough clinical follow-ups, including dental evaluations every 6 months over a period of 36 months. These evaluations aim to promptly identify and address any potential dental concerns that may arise post-treatment. Each session includes a comprehensive stomatological examination and two bitewing radiographs. Additionally, an annual orthopantomogram provides a comprehensive overview of dental health. If necessary, periapical X-rays are conducted to investigate specific dental complaints or to further examine any identified abnormalities in the orthopantomogram. Patient-reported outcomes Quality of life questionnaires (EORTC: QLQ-C30 and QLQH&N43) will be completed at screening, at week 3, 7 and at the end of RT treatment. During the follow-up period, those questionnaires will be filled on month 3, 6, 12, 24 and 36 months (end of study). In addition, the Xerostomia questionnaire will be completed once a week during RT treatment and at month 3, 6, 12, 24 and 36 during follow-up visits. Radiotherapy treatment: All subjects will be treated by simultaneous integrated boost (SIB) intensity modulated RT (IMRT) / volumetric modulated arc therapy (VMAT). The dose prescription for various situations can be found in Table 2. The total radiation dose and fractionation scheme vary based on whether radiotherapy is administered as a standalone treatment or as post-operative therapy with or without extranodal extension and involved margins. Toxicity evaluation A comprehensive clinical assessment will be conducted to evaluate toxicity, distinguishing between acute occurrences during RT and up to 3 months post-RT, and late toxicity beyond this period. The intensity of all adverse events will be carefully graded on a 5-point scale (grades 1 to 5) using the National Cancer Institute (NCI)–Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) grading scale. In this study, specific adverse events of special interest included xerostomia, dental decay, dental fracture, swallowing disorders, tooth abscess, toothache, dental mobility, oral cavity ulceration, and periodontal disease. The severity and frequency of these events will be meticulously assessed, providing valuable insights into the impact of RT on various aspects of oral health. Clinical outcome evaluation Several efficacy parameters are assessed to evaluate dental outcomes, including dental decay, fracture, mobility, periodontopathy, endodontopathy, and osteoradionecrosis-free dental avulsion. These parameters will be useful as crucial benchmarks to judge the effectiveness of the "predictive model." The evaluation of these parameters aimed to validate the model's efficiency. If the dental check-ups, guided by our predictive model, revealed minimal issues post-RT, it would substantiate the legitimacy of extracting fewer teeth before RT. This approach intended to enhance the patient's quality of life by minimizing unnecessary dental interventions while ensuring effective treatment outcomes. The detailed dental outcomes, along with clinical and radiological examinations, are provided in Table 3. Ancillary and post-trial care Any patient suffering from a complication due to trial participation will be provided with medical and surgical care as per institutional standards. The participant centers will ensure post-trial care and long-term follow-up for all patients participating in the trial. Data monitoring To ensure this trial’s quality assurance, the clinical research physician is assisted by a research team. This team ensures safety, eligibility, treatment compliance and data management (for which the electronic data capture system OpenClinica will be used). Regular monitoring will be performed and observations will be documented. Discussion Supporting a better quality of life for our patients who survive HNSCC (which represents 50% of our patients), remains a paramount goal in post-treatment care 1 . The preservation of oral health, particularly dental structures, significantly contributes to an improved quality of life for our patients. Implementing a more conservative approach, one that restricts dental extractions solely to teeth deemed at risk, holds the promise of minimizing unnecessary interventions, thereby safeguarding essential oral function and positively impacting overall well-being. This conservative strategy takes on enhanced significance for individuals diagnosed with HPV-positive oropharyngeal carcinoma. These patients not only exhibit a more favorable prognosis but often also possess a superior baseline dental status compared to those with alcohol- or tobacco-induced HNSCC 8 . By tailoring dental interventions based on risk assessment, particularly considering the tumor characteristics and staging, it becomes plausible to ensure a personalized and optimized approach to oral health preservation. The identification of teeth at minimal risk of radiation exposure, receiving doses below the critical threshold of 40 Gy, emerges as a crucial focal point. This determination plays a pivotal role in mitigating the potential for osteonecrosis while reducing the need for unnecessary dental procedures, thereby enhancing the overall post-treatment quality of life. Building upon the insights garnered from our retrospective study, we have embarked on a rigorous prospective investigation. This study aims to validate and refine a "predictive dose model" meticulously designed to account for tumor localization and TNM staging. The ultimate goal is to establish a robust and reliable tool that not only predicts but also potentially prevents detrimental radiation exposure to teeth. This strategic approach is poised to safeguard dental health and, by extension, contribute substantially to the holistic well-being and quality of life for individuals navigating the complexities of HNSCC treatment and survival. Abbreviations CTV Clinical Target Volume DPSI Dutch periodontal screening index DVH Dose Volume Histogram ECOG Eastern Cooperative Oncology Group EORTC European Organization for Research and Treatment of Cancer EOS End Of Study EOT End Of Treatment GTV Gross Target Volume Gy Gray HPV Human Papillomavirus HNSCC head and neck squamous cell carcinoma ICDAS The International Caries Detection and Assessment System ICF Informed Consent Form IMRT Intensity Modulated Radiotherapy NCI-CTCAE National Cancer Institute - Common Terminology Criteria for Adverse Events NTCP Normal Tissue Complication Probability OARs Organs at risks OPG orthopantomography ORNJ osteroradionecrosis of the jaw PTV Planning Target Volume QLQ Quality of Life Questionnaire QOL Quality Of Life RT Radiotherapy RTOG Radiation Therapy Oncology Group SIB Simultaneous Integrated Boost VMAT Volumetric modulated arc therapy TNM Tumor Node Metastasis Declarations Trial status Protocol version number 1.1 and date 11/08/2020. The first participant was enrolled on 08/12/2020. The last enrolled patient was on the 23 rd March 2023. Last patient visit is scheduled on June 2026. Acknowledgements The authors wish to thank “Association Jules Bordet” for their contribution to this project and the personnel of the Clinical Support Unit of Jules Bordet Institute for their assistance in the protocol conducting. Confidentiality The principal investigator or any authorized study member staff will assure that subjects’ identity is maintained confidential and that their identities are protected from unauthorized parties. Personal medical information is always treated as confidential. The sponsor (Jules Bordet Institute, Brussels, Belgium) is the data controller of the subject’s encoded data. The investigator and the hospital are, on the one hand, subcontractors of the sponsor with regard to the processing of the subject’s encoded data and, on the other hand, data controllers of the patient’s unencoded data collected both as part of the study and outside it Plans for dissemination It is expected that the study results will be published in a peer-reviewed journal. Presentations at national and international conferences are anticipated. Publication policy The authors should have a significant role in the protocol and study design, data collection, and/or data analysis. This implies they have discussed the study in person and/or they have enrolled patients. Authors’ contributions YK is the principal investigator of the StomRay study. YK, SB and DVG designed the project. YK and SB applied for funding. YK and DVG produced the first and subsequent drafts of the manuscript. MP advised on study design, sample size analysis, and statistical design. CAW is the project coordinator . YK, TD and DD are enrolled patients in the study. YK and TD are collected dental data and RT toxicities. All authors made an important intellectual contribution to the manuscript, and all have read and approved the final version. Acknowledgments We wish to extend our heartfelt gratitude to Delphine Talmon for her help and invaluable assistance in patient recruitment for this study. Her exemplary collaboration served as a fundamental pillar in the success of this project, and we are immensely grateful for her commitment and professionalism. Funding The Jules Bordet Institute is the legal sponsor of the Study. This project was supported by a grant from “L’Association Jules Bordet asbl.” The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Availability of data and materials The datasets used and analyzed during the current study will be available from the corresponding author on reasonable request. Ethics approval and consent to participate The study was approved by the Jules Bordet Hospital Ethics Committee (StomRay; CE3113). All patients will be informed by the study investigators and included after providing written consent. The informed consent form is based on the Belgian national template and is identified by a version number and a date, and it makes reference to the associated protocol. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022;233:780–6. 10.1038/s41415-022-5166-x . Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg. 2008;46:653–60. 10.1016/j.bjoms.2008.04.006 . Buurman DJM, Speksnijder CM, Granzier ME, Timmer VCML, Hoebers FJP, Kessler P. The extent of unnecessary tooth loss due to extractions prior to radiotherapy based on radiation field and dose in patients with head and neck cancer. Radiother Oncol. 2023;187:109847. 10.1016/j.radonc.2023.109847 . Epub 2023 Aug 4. PMID: 37543058. Rosenfeld E, Eid B, Masri D, Popovtzer A, Mizrachi A, Chaushu G. Is the Risk to Develop Osteoradionecrosis of the Jaws Following IMRT for Head and Neck Cancer Related to Co-Factors? Medicina (Kaunas). 2021;57(5):468. 10.3390/medicina57050468 . Lajolo C, Rupe C, Gioco G, Troiano G, Patini R, Petruzzi M, Micciche' F, Giuliani M. Osteoradionecrosis of the Jaws Due to Teeth Extractions during and after Radiotherapy: A Systematic Review. Cancers (Basel). 2021;13(22):5798. 10.3390/cancers13225798 . PMID: 34830954; PMCID: PMC8616343. Karaca Y, Beauvois S, Paesmans M, Mokhtari Z, Dequanter D, Al Wardi C, Evrard L, Van Gestel D. Retrospective Study Evaluating Dental Side Effects of Radiotherapy in Patients Treated for Head and Neck Cancer. https://dx.doi.org/10.2139/ssrn.4672534 . Thariat J, de Mones E, Darcourt V, Poissonnet G, Marcy PY, Guevara N, Bozec A, Ortholan C, Santini J, Bensadoun RJ, Dassonville O. Teeth and irradiation: Dental care and treatment of osteoradionecrosis after irradiation in head and neck cancer. Cancer/Radiothérapie. 2010;14:137–44. 10.1016/j.canrad.2009.09.010 . Kanzow P, Mielke K, Hrasky V, Wiegand S, Schliephake H, Beutner D, Wiegand A. Oral health in HPV-positive and HPV-negative patients with oropharyngeal squamous cell carcinoma. Front Oncol. 2023;13:1083067. 10.3389/fonc.2023.1083067 . PMID: 36776286; PMCID: PMC9909218. Tables Table 1: Inclusion and exclusion criteria: Table of all inclusion and exclusion criteria Inclusion criteria Exclusion criteria Age ≥ 18 years old Subject having less than ten teeth on dental arch ECOG performance status ≤2 Life expectancy less than 12 months Female and Male History of previous head and neck irradiation Newly diagnosed, histologically or cytologically confirmed HNSCC (oropharynx, oral cavity, larynx, hypopharynx or cavum) Prior or current treatment with bisphosphonates or denosumab Results of previous pre-treatment imaging (PET-CT and cervicofacial MRI and/or CT scan) Presence of too many metal artefacts on the RT simulation scan preventing precise teeth contouring Eligible for treatment based on (chemo-)RT (with or without a surgical treatment) Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study Agree to wear, three times per week, fluoride dental splint after RT Pregnancy and/or lactating women HPV/p 16 testing results available at the time of screening (only for subjects with oropharyngeal cancer) Subjects with imperfect amelogenesis Serum pregnancy test (for subjects of childbearing potential) negative within 7 days prior to the 1st RT treatment Women of childbearing potential must agree to use of one effective method of contraception prior study entry and during the course of the study. Completion of all necessary screening procedures within 30 days prior to 1 st RT treatment. Signed Informed Consent form (ICF) obtained prior to any study related procedure. Ability to understand and complete the questionnaires (language proficiency, cognitive functioning) as judged by the principal investigator upon screening Table 2 : Radiotherapy dose prescriptions: Table of all radiotherapy dose prescriptions used in this study Dose prescription for subjects receiving radical (chemo-)RT Target volume Median dose (Gy) Nr fractions Dose/fraction (Gy) PTV high risk 69.12 32 2.16 PTV elective 56 32 1.75 Dose prescription for subjects receiving postoperative (chemoRT with extranodal extension and/or invaded margins Target volume Median dose (Gy) Nr fractions Dose/fraction (Gy) PTV high risk 66 33 2.00 PTV elective 56.1 33 1.70 Dose prescription for subjects receiving postoperative (chemo- )RT without extranodal extension and with free margins (>5mm) Target volume Median dose (Gy) Nr fractions Dose/fraction (Gy) PTV high risk 60 30 2.00 PTV elective 54 30 1.80 Table 3: Dental outcomes and their diagnosis : Table including dental outcomes and the techniques used for their diagnosis. in bold : essential for the diagnosis. Dental outcome Clinical diagnosis Radiological diagnosis (in order of importance) Dental decay Sickle probe (dental explorer): tactile verification with firm pressure to probe suspicious areas may result in the rupture of the surface layer covering early lesions allowing diagnosis1 · Bitewings : presence of sign of enamel demineralization, radiolucent · Periapical radiograph · OPG Caries severity score (ICDAS II, from 0 to 6) Dental fracture Sickle probe : tactile verification · Periapical radiograph: often possible to identify tooth cracks · (OPG) Dental mobility Tooth mobility score (from I to IV depending of the importance of the mobility) · OPG: important resorption of the alveolar bone · Periapical radiograph Periodontopathy Periodontal probe : the way of detecting and measuring periodontal pocket depths and for obtaining information about the health status of periodontium · Periapical radiograph : Periapical lesion · (OPG) (detectable only in case of bone resorption, not usually in early stages) Dental percussion: only positive (causing pain) in case of acute apical periodontis. Osteoradionecrosisfree tooth avulsion Inspection of oral cavity: presence of exposed irradiated bone that fails to heal over a period of 3 months without any evidence of persisting or recurrent tumor. · OPG · CT scans · MRI · (Doppler ultrasound) · (Nuclear medicine) · (near-infrared spectroscopy) (not usually detectable radiographically in early stages) ORNJ stage (based on Notani’s classification) 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. 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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-4642483","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":324605980,"identity":"62dc103d-d6f9-4d7d-9f0b-c238a033abaf","order_by":0,"name":"Yasemin 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11:47:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4642483/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4642483/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60929573,"identity":"47f9c73b-3eb5-42fd-8b00-015ba2306bb4","added_by":"auto","created_at":"2024-07-23 16:54:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56565,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flowchart: Schema of the study design\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4642483/v1/3fb1c2ec6242b4b964f7f12f.png"},{"id":65081048,"identity":"c7d2162c-d0b1-471e-bf8a-f64b3fb7a64d","added_by":"auto","created_at":"2024-09-23 11:57:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":695050,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4642483/v1/e01ab916-c001-44e5-89a0-afcc13f2632a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prospective pilot study evaluating dental side effects of radiotherapy on subjects treated for head and neck cancer: StomRay Study","fulltext":[{"header":"Background","content":"\u003cp\u003eOsteoradionecrosis, a well described complication of RT, frequently is due to dental extractions in areas exposed to doses exceeding 40 Gy\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The occurrence ranged from 5 to 15%, with tooth extraction after head and neck RT accounting for 2 to 22% of cases\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In a retrospective study involving 11 subjects, we observed a significant correlation between dental fractures and an average dental dose exceeding 50 Gy (p\u0026thinsp;=\u0026thinsp;0.01). Similarly, an average parotids RT dose above 40 Gy correlated with caries (p\u0026thinsp;=\u0026thinsp;0.05). However, the small sample size limits rigorous statistical testing, warranting cautious interpretation\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBased on literature\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and our retrospective findings, we have adopted a conservative approach, using \"40 Gy\" as the threshold for tolerable dose for post-irradiation dental extraction to minimize osteoradionecrosis risk.\u003c/p\u003e \u003cp\u003eAccurate predicting teeth receiving tolerable doses (\u0026lt;\u0026thinsp;40 Gy) could preserve more teeth, even those with questionable long-term viability. This conservative strategy, especially beneficial for human papilloma virus (HPV)-positive oropharyngeal carcinoma patients with generally better prognoses and dental status compared to alcohol- or tobacco-induced HNC patients, is pivotal\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur prospective study has a dual objective: firstly, to assess the risk of dental complications\u0026mdash;specifically fractures and caries\u0026mdash;by utilizing the normal tissue complication probability (NTCP). Secondly, we aimed to validate a \"predictive dose model\" for RT based on tumor location and TNM stage (8th edition). This model's refinement and application seek to minimize unnecessary dental extractions, thereby significantly enhancing the overall quality of life post-RT for patients undergoing treatment for head and neck cancers.\u003c/p\u003e"},{"header":"Methods/study design","content":"\u003cp\u003eThis is a multi-centric prospective one arm, phase II clinical trial evaluating the risk of dental complication (normal tissue complication probability (NTCP), especially the probability of fractures and dental caries.\u003c/p\u003e\n\u003cp\u003eThe study design is illustrated in Fig. 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy objectives and statistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study primarily aims to model the risk of dental complications post-RT, focusing on the normal tissue complication probability (NTCP), specifically the likelihood of fractures and dental caries.\u003c/p\u003e\n\u003cp\u003eIn addition to this primary goal, the study has several secondary objectives:\u003c/p\u003e\n\u003cp\u003eFirstly, we aim to validate our \u0026quot;predictive dose model\u0026quot; for radiotherapy by considering the tumor\u0026apos;s location and the TNM stage. This validation process aims to refine and enhance the accuracy of our predictive model.\u003c/p\u003e\n\u003cp\u003eSecondly, our intention is to integrate our predictive dose model with dental NTCP. This integration seeks to personalize decisions regarding teeth avulsion before the initiation of RT. By aligning the predictive dose model with dental complications, we aim to optimize treatment planning, minimizing unnecessary dental interventions while ensuring the efficacy of RT.\u003c/p\u003e\n\u003cp\u003eLastly, we seek to explore the impact of (partial or total) edentulousness and RT on the overall quality of life of the subjects. Understanding how tooth loss and its interaction with RT affect patients\u0026apos; well-being is crucial for comprehensive treatment considerations and patient-centered care.\u003c/p\u003e\n\u003cp\u003eOverall, this study aims to not only predict and mitigate dental complications following RT but also to refine treatment strategies, personalize dental interventions, and assess the holistic impact on patients\u0026apos; quality of life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study\u0026apos;s primary objective is to construct a comprehensive model for Normal Tissue Complication Probability (NTCP). Previous research projects suggest an anticipated NTCP rate of approximately 20% per tooth, serving as the unit of analysis. The model will consider several factors for inclusion, including the actual dose to the tooth, parotid glands, pre-RT clinical tooth status, and the cT and cN stages. Up to five variables could potentially form the basis of the final model. To achieve this, a minimum of 50 teeth with complications and a total of 250 teeth must be documented. Considering an average of 10 teeth per subject, the study aims to encompass at least 25 assessable subjects.\u003c/p\u003e\n\u003cp\u003eSubjects and their respective teeth will be considered evaluable if they maintain follow-up for 36 months post-RT and if all necessary data are accessible for assessing both administered and predicted RT doses. Accounting for an expected 10% rate of screening failure and 30% rate of unevaluable subjects, the study aims to enroll approximately 40 subjects to ensure a sufficient evaluable cohort for analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients\u0026rsquo; characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with newly diagnosed and histologically confirmed primary HNSCC planned for curative intent RT will be included. The recruiting centers are the Jules Bordet Institute, Centre Hospitalier Universitaire Saint- Pierre and H\u0026ocirc;pital Erasme\u0026mdash;Clinique Universitaire de Bruxelles.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe inclusion and exclusion criteria are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy interventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eDental avulsion\u003c/u\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBefore initiating RT, each subject undergoes a meticulous dental assessment. If necessary, dental avulsions are conducted for teeth at risk of compromising long-term survival and situated in areas expected to receive more than 40 Gy, potentially leading to osteoradionecrosis of the jaw. Avulsions are scheduled at least 2 weeks before the start of RT to allow mucosal healing.\u003c/p\u003e\n\u003cp\u003eTooth avulsion is performed for all teeth within irradiation fields identified \u0026quot;at risk\u0026quot; according to our developed \u0026quot;predictive model.\u0026quot; This includes teeth meeting at least one of the following criteria, indicating compromised long-term viability:\u003c/p\u003e\n\u003cp\u003e- Tooth mobility score \u0026gt; 2 (Miller\u0026rsquo;s score, 1985)\u003c/p\u003e\n\u003cp\u003e- Caries severity score \u0026gt; 4 (ICDAS II, 2005)\u003c/p\u003e\n\u003cp\u003e- Dutch periodontal screening index (DPSI) score \u0026gt; 2\u003c/p\u003e\n\u003cp\u003e- Periapical lesion\u003c/p\u003e\n\u003cp\u003e- Root fracture\u003c/p\u003e\n\u003cp\u003e- Furcation caries (in multi-rooted teeth)\u003c/p\u003e\n\u003cp\u003e- Coronary reconstruction exceeding 1/3 of its total surface (except inlay, only and total crown if there are not sign of caries or lack of sealing) In addition, dental avulsions are sometimes also necessary for a more adequate prosthetic rehabilitation.\u003c/p\u003e\n\u003cp\u003eFor all of subjects, a dental decalcification and afterwards, a dental splint will be performed before the start of RT.\u003c/p\u003e\n\u003cp\u003eFollowing completion of RT, subjects receive thorough clinical follow-ups, including dental evaluations every 6 months over a period of 36 months. These evaluations aim to promptly identify and address any potential dental concerns that may arise post-treatment. Each session includes a comprehensive stomatological examination and two bitewing radiographs. Additionally, an annual orthopantomogram provides a comprehensive overview of dental health. If necessary, periapical X-rays are conducted to investigate specific dental complaints or to further examine any identified abnormalities in the orthopantomogram.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient-reported outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQuality of life questionnaires (EORTC: QLQ-C30 and QLQH\u0026amp;N43) will be completed at screening, at week 3, 7 and at the end of RT treatment. During the follow-up period, those questionnaires will be filled on month 3, 6, 12, 24 and 36 months (end of study). In addition, the Xerostomia questionnaire will be completed once a week during RT treatment and at month 3, 6, 12, 24 and 36 during follow-up visits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiotherapy treatment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll subjects will be treated by simultaneous integrated boost (SIB) intensity modulated RT (IMRT) / volumetric modulated arc therapy (VMAT).\u003c/p\u003e\n\u003cp\u003eThe dose prescription for various situations can be found in Table 2.\u003c/p\u003e\n\u003cp\u003eThe total radiation dose and fractionation scheme vary based on whether radiotherapy is administered as a standalone treatment or as post-operative therapy with or without extranodal extension and involved margins.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToxicity evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive clinical assessment will be conducted to evaluate toxicity, distinguishing between acute occurrences during RT and up to 3 months post-RT, and late toxicity beyond this period. The intensity of all adverse events will be carefully graded on a 5-point scale (grades 1 to 5) using the National Cancer Institute (NCI)\u0026ndash;Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) grading scale.\u003c/p\u003e\n\u003cp\u003eIn this study, specific adverse events of special interest included xerostomia, dental decay, dental fracture, swallowing disorders, tooth abscess, toothache, dental mobility, oral cavity ulceration, and periodontal disease. The severity and frequency of these events will be meticulously assessed, providing valuable insights into the impact of RT on various aspects of oral health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical outcome evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral efficacy parameters are assessed to evaluate dental outcomes, including dental decay, fracture, mobility, periodontopathy, endodontopathy, and osteoradionecrosis-free dental avulsion. These parameters will be useful as crucial benchmarks to judge the effectiveness of the \u0026quot;predictive model.\u0026quot;\u003c/p\u003e\n\u003cp\u003eThe evaluation of these parameters aimed to validate the model\u0026apos;s efficiency. If the dental check-ups, guided by our predictive model, revealed minimal issues post-RT, it would substantiate the legitimacy of extracting fewer teeth before RT. This approach intended to enhance the patient\u0026apos;s quality of life by minimizing unnecessary dental interventions while ensuring effective treatment outcomes. The detailed dental outcomes, along with clinical and radiological examinations, are provided in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAncillary and post-trial care\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny patient suffering from a complication due to trial participation will be provided with medical and surgical care as per institutional standards. The participant centers will ensure post-trial care and long-term follow-up for all patients participating in the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure this trial\u0026rsquo;s quality assurance, the clinical research physician is assisted by a research team. This team ensures safety, eligibility, treatment compliance and data management (for which the electronic data capture system OpenClinica will be used). Regular monitoring will be performed and observations will be documented.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSupporting a better quality of life for our patients who survive HNSCC (which represents 50% of our patients), remains a paramount goal in post-treatment care\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The preservation of oral health, particularly dental structures, significantly contributes to an improved quality of life for our patients. Implementing a more conservative approach, one that restricts dental extractions solely to teeth deemed at risk, holds the promise of minimizing unnecessary interventions, thereby safeguarding essential oral function and positively impacting overall well-being.\u003c/p\u003e \u003cp\u003eThis conservative strategy takes on enhanced significance for individuals diagnosed with HPV-positive oropharyngeal carcinoma. These patients not only exhibit a more favorable prognosis but often also possess a superior baseline dental status compared to those with alcohol- or tobacco-induced HNSCC\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. By tailoring dental interventions based on risk assessment, particularly considering the tumor characteristics and staging, it becomes plausible to ensure a personalized and optimized approach to oral health preservation.\u003c/p\u003e \u003cp\u003eThe identification of teeth at minimal risk of radiation exposure, receiving doses below the critical threshold of 40 Gy, emerges as a crucial focal point. This determination plays a pivotal role in mitigating the potential for osteonecrosis while reducing the need for unnecessary dental procedures, thereby enhancing the overall post-treatment quality of life.\u003c/p\u003e \u003cp\u003eBuilding upon the insights garnered from our retrospective study, we have embarked on a rigorous prospective investigation. This study aims to validate and refine a \"predictive dose model\" meticulously designed to account for tumor localization and TNM staging. The ultimate goal is to establish a robust and reliable tool that not only predicts but also potentially prevents detrimental radiation exposure to teeth. This strategic approach is poised to safeguard dental health and, by extension, contribute substantially to the holistic well-being and quality of life for individuals navigating the complexities of HNSCC treatment and survival.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical Target Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDPSI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDutch periodontal screening index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDose Volume Histogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEORTC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEuropean Organization for Research and Treatment of Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEnd Of Study\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEOT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEnd Of Treatment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGross Target Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGy\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGray\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Papillomavirus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHNSCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehead and neck squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICDAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThe International Caries Detection and Assessment System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInformed Consent Form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIMRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensity Modulated Radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCI-CTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNational Cancer Institute - Common Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNTCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNormal Tissue Complication Probability\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOARs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOrgans at risks\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOPG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eorthopantomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORNJ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eosteroradionecrosis of the jaw\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePlanning Target Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQLQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuality of Life Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuality Of Life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRTOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadiation Therapy Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSIB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSimultaneous Integrated Boost\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVMAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVolumetric modulated arc therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumor Node Metastasis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtocol version number 1.1 and date\u0026nbsp;11/08/2020. The first participant was enrolled on 08/12/2020. The last enrolled patient was on the 23\u003csup\u003erd\u003c/sup\u003e March 2023. Last patient visit is scheduled on June 2026.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank \u0026ldquo;Association Jules Bordet\u0026rdquo; for their contribution to this project and the personnel of the Clinical Support Unit of Jules Bordet Institute for their assistance in the protocol conducting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe principal investigator or any authorized study member staff will assure that subjects\u0026rsquo; identity is maintained confidential and that their identities are protected from unauthorized parties. Personal medical information is always treated as confidential. The sponsor (Jules Bordet Institute, Brussels, Belgium) is the data controller of the subject\u0026rsquo;s encoded data. The investigator and the hospital are, on the one hand, subcontractors of the sponsor with regard to the processing of the subject\u0026rsquo;s encoded data and, on the other hand, data controllers of the patient\u0026rsquo;s unencoded data collected both as part of the study and outside it\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for dissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt is expected that the study results will be published in a peer-reviewed journal. Presentations at national and international conferences are anticipated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors should have a significant role in the protocol and study design, data collection, and/or data analysis. This implies they have discussed the study in person and/or they have enrolled patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYK is the principal investigator of the StomRay study. YK, SB and DVG designed the project. YK and SB applied for funding. YK and DVG produced the first and subsequent drafts of the manuscript. MP advised on study design, sample size analysis, and statistical design. CAW is the project coordinator\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eYK, TD and DD are enrolled patients in the study. YK and TD are collected dental data and RT toxicities. All authors made an important intellectual contribution to the manuscript, and all have read and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to extend our heartfelt gratitude to Delphine Talmon for her help and invaluable assistance in patient recruitment for this study. Her exemplary collaboration served as a fundamental pillar in the success of this project, and we are immensely grateful for her commitment and professionalism.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Jules Bordet Institute is the legal sponsor of the Study. This project was supported by a grant from \u0026ldquo;L\u0026rsquo;Association Jules Bordet asbl.\u0026rdquo; The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study will be available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Jules Bordet Hospital Ethics Committee (StomRay; CE3113). All patients will be informed by the study investigators and included after providing written consent. The informed consent form is based on the Belgian national template and is identified by a version number and a date, and it makes reference to the associated protocol.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022;233:780\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41415-022-5166-x\u003c/span\u003e\u003cspan address=\"10.1038/s41415-022-5166-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyons A, Ghazali N. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg. 2008;46:653\u0026ndash;60. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bjoms.2008.04.006\u003c/span\u003e\u003cspan address=\"10.1016/j.bjoms.2008.04.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuurman DJM, Speksnijder CM, Granzier ME, Timmer VCML, Hoebers FJP, Kessler P. The extent of unnecessary tooth loss due to extractions prior to radiotherapy based on radiation field and dose in patients with head and neck cancer. Radiother Oncol. 2023;187:109847. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.radonc.2023.109847\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2023.109847\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2023 Aug 4. PMID: 37543058.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenfeld E, Eid B, Masri D, Popovtzer A, Mizrachi A, Chaushu G. Is the Risk to Develop Osteoradionecrosis of the Jaws Following IMRT for Head and Neck Cancer Related to Co-Factors? Medicina (Kaunas). 2021;57(5):468. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/medicina57050468\u003c/span\u003e\u003cspan address=\"10.3390/medicina57050468\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLajolo C, Rupe C, Gioco G, Troiano G, Patini R, Petruzzi M, Micciche' F, Giuliani M. Osteoradionecrosis of the Jaws Due to Teeth Extractions during and after Radiotherapy: A Systematic Review. Cancers (Basel). 2021;13(22):5798. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers13225798\u003c/span\u003e\u003cspan address=\"10.3390/cancers13225798\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 34830954; PMCID: PMC8616343.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaraca Y, Beauvois S, Paesmans M, Mokhtari Z, Dequanter D, Al Wardi C, Evrard L, Van Gestel D. Retrospective Study Evaluating Dental Side Effects of Radiotherapy in Patients Treated for Head and Neck Cancer. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://dx.doi.org/10.2139/ssrn.4672534\u003c/span\u003e\u003cspan address=\"10.2139/ssrn.4672534\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThariat J, de Mones E, Darcourt V, Poissonnet G, Marcy PY, Guevara N, Bozec A, Ortholan C, Santini J, Bensadoun RJ, Dassonville O. Teeth and irradiation: Dental care and treatment of osteoradionecrosis after irradiation in head and neck cancer. Cancer/Radioth\u0026eacute;rapie. 2010;14:137\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.canrad.2009.09.010\u003c/span\u003e\u003cspan address=\"10.1016/j.canrad.2009.09.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanzow P, Mielke K, Hrasky V, Wiegand S, Schliephake H, Beutner D, Wiegand A. Oral health in HPV-positive and HPV-negative patients with oropharyngeal squamous cell carcinoma. Front Oncol. 2023;13:1083067. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2023.1083067\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2023.1083067\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 36776286; PMCID: PMC9909218.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Inclusion and exclusion criteria: Table of all inclusion and exclusion criteria\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAge \u0026ge; 18 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSubject having less than ten teeth on dental arch\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eECOG performance status \u0026le;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eLife expectancy less than 12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eFemale and Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eHistory of previous head and neck irradiation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eNewly diagnosed, histologically or cytologically confirmed HNSCC (oropharynx, oral cavity, larynx, hypopharynx or cavum)\u003c/p\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePrior or current treatment with bisphosphonates or denosumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eResults of previous pre-treatment imaging (PET-CT and cervicofacial MRI and/or CT scan)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePresence of too many metal artefacts on the RT simulation scan preventing precise teeth contouring\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eEligible for treatment based on (chemo-)RT (with or without a surgical treatment)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSubject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator\u0026rsquo;s opinion, may interfere with completion of the study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAgree to wear, three times per week, fluoride dental splint after RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePregnancy and/or lactating women\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eHPV/p 16 testing results available at the time of screening (only for subjects with oropharyngeal cancer)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSubjects with imperfect amelogenesis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSerum pregnancy test (for subjects of childbearing potential) negative within 7 days prior to the 1st RT treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eWomen of childbearing potential must agree to use of one effective method of contraception prior study entry and during the course of the study.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCompletion of all necessary screening procedures within 30 days prior to 1\u003csup\u003est\u003c/sup\u003e RT treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSigned Informed Consent form (ICF) obtained prior to any study related procedure.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAbility to understand and complete the questionnaires (language proficiency, cognitive functioning) as judged by the principal investigator upon screening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 : Radiotherapy dose prescriptions: Table of all radiotherapy dose prescriptions used in this study\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"434\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose prescription for subjects receiving radical (chemo-)RT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003eTarget volume\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003eMedian dose (Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003eNr fractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003eDose/fraction (Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTV high risk\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003e69.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003e2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTV elective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose prescription for subjects receiving postoperative (chemoRT with extranodal extension and/or invaded margins\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003eTarget volume\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003eMedian dose (Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003eNr fractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003eDose/fraction (Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTV high risk\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTV elective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003e56.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003e1.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose prescription for subjects receiving postoperative (chemo- )RT without extranodal extension and with free margins (\u0026gt;5mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003eTarget volume\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003eMedian dose (Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003eNr fractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003eDose/fraction (Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTV high risk\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.42396313364055%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTV elective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.649769585253456%\" valign=\"top\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.5852534562212%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.341013824884794%\" valign=\"top\"\u003e\n \u003cp\u003e1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3: \u003cstrong\u003eDental outcomes and their diagnosis\u003c/strong\u003e: Table including dental outcomes and the techniques used for their diagnosis. in bold : essential for the diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003ctable\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"154\"\u003e\n\u003cp\u003e\u003cstrong\u003eDental outcome\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical\u003c/strong\u003e \u003cstrong\u003ediagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003eRadiological diagnosis (in order of importance)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"154\"\u003e\n\u003cp\u003eDental decay\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eSickle probe\u003c/strong\u003e (dental explorer): tactile verification with firm pressure to probe suspicious areas may result in the rupture of the surface layer covering early lesions allowing diagnosis1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"158\"\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cstrong\u003eBitewings\u003c/strong\u003e : presence of sign of enamel demineralization, radiolucent\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Periapical radiograph\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;OPG\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eCaries severity score\u003c/strong\u003e (ICDAS II, from 0 to 6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"154\"\u003e\n\u003cp\u003eDental fracture\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eSickle probe\u003c/strong\u003e: tactile verification\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"158\"\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cstrong\u003ePeriapical radiograph:\u003c/strong\u003e often possible to identify tooth cracks\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; (OPG)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"154\"\u003e\n\u003cp\u003eDental mobility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eTooth mobility score\u003c/strong\u003e (from I to IV depending of the importance of the mobility)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"158\"\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; OPG: important resorption of the alveolar bone\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Periapical radiograph\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"154\"\u003e\n\u003cp\u003ePeriodontopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003ePeriodontal probe\u003c/strong\u003e: the way of detecting and measuring periodontal pocket depths and for obtaining information about the health status of periodontium\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"158\"\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cstrong\u003ePeriapical radiograph\u003c/strong\u003e: Periapical lesion\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;(OPG)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(detectable only in case of bone resorption, not usually in early stages)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eDental percussion:\u003c/strong\u003e only positive (causing pain) in case of acute apical periodontis.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"154\"\u003e\n\u003cp\u003eOsteoradionecrosisfree tooth avulsion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eInspection\u003c/strong\u003e of oral cavity: presence of exposed irradiated bone that fails to heal over a period of 3 months without any evidence of persisting or recurrent tumor.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"158\"\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cstrong\u003eOPG \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; CT scans\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; MRI\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; (Doppler ultrasound)\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; (Nuclear medicine)\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; (near-infrared spectroscopy) (not usually detectable radiographically in early stages)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eORNJ stage\u003c/strong\u003e (based on Notani\u0026rsquo;s classification)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Head and neck squamous cell carcinoma, radiotherapy, radionecrosis, dental health, predictive model","lastPublishedDoi":"10.21203/rs.3.rs-4642483/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4642483/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eBackground\u003c/u\u003e\u003cu\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eHead and Neck Squamous Cell Carcinoma (HNSCC) remains a significant global cause of mortality, with late-stage diagnoses contributing to unfavorable prognosis\u003csup\u003e1\u003c/sup\u003e. Radiotherapy (RT) is crucial in HNSCC treatment but poses risks, including osteoradionecrosis of the jaw (ORNJ) and dental issues post-irradiation\u003csup\u003e2\u003c/sup\u003e. Pre-RT dental restoration is recommended, yet some patients undergo unnecessary tooth removal, impacting post-treatment options like dental implants or bridges\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eTo address this, a predictive model for dental avulsions pre-RT is being developed. It aims to identify low-risk areas (\u0026lt;40 Gy) for ORNJ based on tumor location and clinical tumor classification. Three risk groups are considered based on radiation doses: high risk (\u0026gt;50 Gy), low risk (\u0026lt;40 Gy), and an intermediate group (40-50 Gy). A color-coded system categorizes irradiated areas on the dental arch, simplifying assessments for molar, premolar, and incisor groups.\u003c/p\u003e\n\u003cp\u003eThis approach aimed to balance the need for dental interventions before RT, optimizing patient care and post-treatment quality of life.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003ePatients diagnosed with HNSCC scheduled for RT undergo initial assessment by a stomatologist for a comprehensive dental examination prior to treatment. As part of our protocol, a dental decalcification and splint placement are conducted before the onset of RT. According to our predictive model, teeth expected to receive over 40 Gy, impacting long-term survival, are scheduled for extraction at least two weeks before RT begins. After treatment, patients undergo regular dental evaluations every six months for 36 months to detect and address potential dental issues. Additionally, patients' quality of life was assessed by three different questionnaires, both during and post-RT.\u003c/p\u003e\n\u003cp\u003eThe primary goal of our study is to model the risk of dental complications, particularly the likelihood of fractures and dental caries, using the concept of normal tissue complication probability (NTCP).\u003c/p\u003e\n\u003cp\u003eSecondary objectives involved validating our predictive dose model for RT based on tumor location and TNM stage. We aimed to integrate our predictive dose model with dental NTCP to personalize decisions regarding tooth extraction before RT. Moreover, we investigated the impact of partial or total tooth loss and RT on the patient's quality of life.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eDiscussion:\u003c/u\u003e\u003cu\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/u\u003eOur study is based on the importance of preserving oral health, particularly dental structures, in survivors of HNSCC to enhance their quality of life post-treatment. It highlights the benefits of a conservative approach to dental interventions, especially for HPV-positive oropharyngeal carcinoma patients, aiming to minimize unnecessary procedures and tailor treatments based on individual risk factors. It also emphasizes the significance of identifying teeth at minimal risk of radiation exposure to prevent complications such as osteonecrosis. Additionally, it outlines ongoing research efforts to develop a predictive dose model for guiding dental interventions, aiming to safeguard dental health and overall well-being in HNSCC survivors.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTrial registration\u003c/u\u003e\u003cu\u003e\u003cstrong\u003e: \u003c/strong\u003e\u003c/u\u003eClinicalTrials.gov NCT04452032, study protocol version 1.1_11/08/2020. Registered 25/06/2020\u003c/p\u003e","manuscriptTitle":"Prospective pilot study evaluating dental side effects of radiotherapy on subjects treated for head and neck cancer: StomRay Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-23 16:54:01","doi":"10.21203/rs.3.rs-4642483/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":"a75314c6-033c-4e22-a5c5-13b935310e01","owner":[],"postedDate":"July 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-23T11:48:56+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-23 16:54:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4642483","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4642483","identity":"rs-4642483","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}