The Risk of Osteoradionecrosis Associated With Dental Extractions Prior to Radiotherapy: A Systematic Review

The Risk of Osteoradionecrosis Associated With Dental Extractions Prior to Radiotherapy: A Systematic Review | 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 The Risk of Osteoradionecrosis Associated With Dental Extractions Prior to Radiotherapy: A Systematic Review Peter Fine, Alex Sabonchian, Colin Hopper, Robert Blizard This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8796363/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background : Head and Neck Cancer (HNC) patients have a risk of developing osteoradionecrosis (ORN) following radiotherapy (RT). Dental extractions are a recognised risk factor. The primary aim of this systematic review was to estimate the risk associated with pre-RT extractions. The secondary aim was to investigate the risk associated with post-RT extractions and both pre- and post-RT extractions in the studies identified. Methods: A systematic review was conducted using a PRISMA protocol. Electronic searches of Cochrane Library and OVID via Medline were undertaken between 2002-2023. Data extraction from the studies related to incidence of ORN and type of extraction was conducted by the authors to produce odds ratio values (OR) for each study and type of extraction. A meta-analysis was performed using a random effects model. Heterogeneity was investigated by sub-group analysis. Findings: Thirteen articles were included in this review. The odds ratio (OR) values for ORN following RT was calculated for each study, dependent on the type of extraction. Substantial heterogeneity was observed (I 2 =62.1%(p=0.002)) for the Pre-RT analyses but not for the post-RT and both types of extractions. In the presence of this heterogeneity, an increased risk of ORN following pre-RT extractions was observed (OR= 2.77, 95% CI = 1.66-4.62). There was an increased risk of ORN associated with post-RT extractions (OR = 4.19, 95% CI = 2.917-8.08) and Both extractions (OR=7.96, 95% CI = 3.91,16.20). Subgroup analyses corroborated these findings. The study population attributable risk for the association of Pre-RT extractions with ORN is 28.53%(95%CI:21.34,31.73) Interpretation: This review suggests that Pre-RT extractions increase the risk of ORN compared to no extractions. Post-RT and both extractions further increase the risk of ORN. This supports current RCS guidelines. Health sciences/Diseases Health sciences/Diseases/Cancer/Oral cancer Health sciences/Health care/Dentistry/Oral medicine/Orofacial pain Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Head and neck cancer (HNC) is the seventh most frequently occurring cancer worldwide 26 ; over 400,000 estimated new cases of oral cancer are diagnosed each year globally. 17 Head and neck cancer (HNC) is a medical term encompassing various malignant tumours that form in and around the mouth, nose, throat and larynx. Almost 90% of HNC cases are reported to be squamous cell carcinomas (SCC). 14 Surgical resection followed by radiotherapy (RT) has been the preferred treatment method for oropharyngeal cancers; however, notable modifications have been made. Multiple studies suggest that early termination of adjuvant RT or prolonged interruptions have negative impacts on survival outcomes in older HNSCC patients. 8 Significant risk factors that can lead to oropharyngeal cancers include alcohol and tobacco abuse, betel nut chewing and chronic inflammation; also prevalent is HPV-associated (mainly HPV type 16) oral and oropharyngeal cancer. 14 The incidence of oropharyngeal cancers has been reported to be linked to educational and socioeconomic status, making those of a low socioeconomic group more prone to oral cancers. 16 The importance of regular oral screening to identify oral/dental pathology cannot be overstated. 29 Prior to initiating cancer treatment, it is essential to conduct a comprehensive evaluation of both hard and soft oral tissues. Additionally, radiographs should be taken to identify any potential sources of infection or pathology. 30 This screening aims to identify existing oral/dental diseases and assess the potential risks associated with oral health prior to the commencement of cancer treatment. It holds significant importance for the dental team to inform the patient of the crucial role of maintaining excellent oral hygiene throughout their cancer treatment. Dental caries should be treated and teeth restored with either a permanent or long-term temporary restoration, and sharp teeth or restorations should be smoothed to prevent mucositis or soft tissue damage. Dental extractions for any non-vital teeth or teeth with deep periodontal pockets of poor prognosis are also recommended at this stage by the guidelines entitled The Oral Management of Oncology Patients requiring radiotherapy, chemotherapy and/or bone marrow transplantation by the Royal College of Surgeons of England (RCS). 17 One significant consequence of RT is osteoradionecrosis (ORN), a severe complication often observed in HNC patients undergoing RT. 10 After RT, the soft tissues and bone fail to heal adequately or remodel, rendering bone exposed to the oral cavity and devitalised, ultimately leading to ORN. 10 ORN involves a combination of four factors: radiation, hypoxia, hypo-vascularisation, and hypo-cellularisation, resulting in bone necrosis. The presence of poor dental health associated with ORN was reported to be particularly prevalent in males and most common in the posterior region of the mandible. 10 ORN is typically characterised by profound bone pain, frequently accompanied by a purulent discharge that might contain sequestrated bone fragments, and can lead to substantial bone loss. ORN is usually found in the mandible due to the mandible’s limited blood supply. 31 The need to regularly update scientific evidence for the good of patients is paramount. This has been recently demonstrated with the issues surrounding endocarditis prevention, when antibiotic prophylaxis was once considered necessary for all but the most trivial dental procedures. Subsequent review of the literature has brought about a seismic shift in this approach and now indications for antibiotic use have reduced dramatically. It has become widely accepted that preventive dental treatment mitigates the risk of ORN. 10 A significant risk factor for ORN is dental extractions, which should be carefully planned by the clinician responsible. 19 The prevailing guidelines recommend avoiding dental extractions post-RT whenever feasible for patients who are at risk of developing ORN. 17 Currently, the accepted standard of care is to provide any necessary dental treatment prior to starting RT, as mentioned in the guidelines by the RCS. 17 Now is an appropriate time to do a systematic review looking at this topic because of the increasing use of RT in HNC. As survival rates improve, more patients are living long enough to experience complications such as ORN, making it a more relevant issue than ever. Current guidelines worldwide vary widely regarding the safety of extractions before, during, or after RT. Royal College of Surgeons (Eng) guidelines have not been reviewed since 2018, and therefore a review is appropriate. The primary aim of this systematic review was to assess whether HNC patients who had tooth extractions pre-RT have an increased risk of developing ORN. The secondary aim investigated whether post-RT extractions and both pre-RT and post-RT extractions together modified this risk. Material and Methods This systematic review was designed and reported within the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. An electronic literature search was conducted using Cochrane Library and OVID via Medline. The full list of search terms can be found in Table 1 . Other databases including Embase and Web of science were consulted during the original scoping review but showed no additional studies to those found on Cochrane Library and OVID via Medline. Whilst using only two databases could be seen as a limitation, in the literature searches for this topic, it was considered appropriate. Table 1 Outline of the order of search terms using MEDLINE. 1 (("head and neck" or mouth or tongue or pharynx* or lanryn* or lips or lip or palate or lingual or sublingual or submandibular or tonsil*) adj3 (cancer* or neoplasm* or tumo?r* or carcinoma* or malignan* or metasti*)). 376,164 2 (radiotherap* or radiation or irradiat* or radiochemotherap* or radio chemotherap*) 2,714,536 3 (jaw* or maxill* or mandib* or alveolar or hard palate) 889,244 4 ((tooth or teeth or dental or oral) adj3 (extract* or treatment or surg*)) 335,085 5 1 and 2 and 3 and 4 665 6 remove duplicates from 5 415 7 remove duplicates from 6 415 The search strategy was based on a Population, Intervention, Comparison and Outcome (PICO) framework. Population - adults (> 18 years) with head and neck cancer undergoing radiotherapy alone or in conjunction with chemotherapy or surgical treatment. Intervention - pre-RT dental extractions ONLY or pre- and post-RT extractions mentioned in the same study. Comparison - No dental extractions. Outcome - Incidence of ORN. Following the PRISMA protocol a search of the literature was undertaken by multiple reviewers (AS, PF, CH); relevant titles and abstracts and finally appropriate articles were considered. Any discrepancies amongst the articles considered for inclusion were resolved by the three authors re-reading the full article and discussing each article's merits for inclusion. A consensus was accepted. Table 2 illustrates the inclusion/exclusion criteria used to decipher the relevant studies that were considered. Inclusion criteria: Exclusion criteria: Study types : randomised controlled trials (RCTs), observational studies (cohort, case-control) Study types : non-analytical studies, literature reviews Population : adults (>18 years) with head and neck cancer undergoing radiotherapy alone or in conjunction with chemotherapy or surgical treatment Population : non-head and neck cancer related studies, patients not undergoing radiotherapy treatment Intervention : pre-RT dental extraction ONLY or pre- and post-RT extractions mentioned in the same study Intervention : Studies only mentioning post-radiotherapy extractions Non-extraction dental interventions such as oral prophylaxis or dental fillings, studies looking at different interventions Comparison: No dental extractions Comparison : - Outcome : ORN of the jaws Outcome : not of interest, such as Medication-related osteonecrosis of the jaw (MRONJ), quality of life or inflammation response Studies published between 2002-2023 Studies where only the abstract is available Studies in English Studies not in English Studies published in a peer reviewed journal Table 2 . Inclusion and Exclusion criteria Data regarding the characteristics of the studies included study design, year of publication, study type, cancer type, radiation technique, radiation dose, follow-up time, cases of ORN. Specific information within each study, regarding patients who underwent tooth extractions (i.e. whether pre-RT or post-RT extraction or both), no. of patients receiving tooth extraction, cases of ORN due to tooth extraction were collected into a customisable table (See Table 3). The studies were numbered from 1-13 (See Table 3) and are referred to within this paper by their assigned number in some instances. Many of the included studies had separate data on both pre- and post-RT extractions; this is outlined in the table by an ‘a’ or ‘b’ after the study name with ‘a’ implying pre-RT extractions and ‘b’ implying post-RT extractions. Where there was data on both types of extractions, this was not included in the table so as not to overcomplicate it visually. Table 3 Characteristics of the included studies Authors Number label Year Study type No. of people in the study Cancer type Radiation technique Dosage Follow-up average (months) Patients receiving tooth extraction Dental exposure Cases of ORN (patients) Cases of ORN due to tooth extraction (patients) Quality score of study (Newcastle-Ottawa scale) P. R. F. Bonan et al. 7 1 2006 Cohort (prospective) 40 Squamous cell carcinoma Conventional RT 67Gy 28.7 23 pre-RT extractions 5 5 7 M. A. Ben-David et al. 6 a 2 2007 Cohort (retrospective) 188 Oropharyngeal cancer IMRT > 70Gy 34 31 pre-RT extractions 0 0 7 M. A. Ben-David et al. 6 b 2 2007 Cohort (retrospective) 188 Oropharyngeal cancer IMRT > 70Gy 34 13 post-RT extractions 0 0 7 D. T. Chang et al. 9 a 3 2007 Cohort (retrospective) 413 Squamous cell carcinoma Conventional RT 76Gy 45.6 163 pre-RT extractions 33 26 7 D. T. Chang et al. 9 b 3 2007 Cohort (retrospective) 413 Squamous cell carcinoma Conventional RT 76Gy 45.6 51 post-RT extractions 19 12 7 N. M. Beech et al. 5 a 4 2017 Cohort (retrospective) 190 Squamous cell carcinoma n/s 68Gy 72 129 pre-RT extractions 27 25 8 N. M. Beech et al. 5 b 4 2017 Cohort (retrospective) 190 Squamous cell carcinoma n/s 68Gy 72 30 post-RT extractions 9 7 8 D.H. Moon et al. 20 5 2017 Cohort (retrospective) 252 Oropharyngeal cancer IMRT/3D CRT 60-74Gy 25 88 pre-RT extractions 14 10 8 S. Aarup-Kristensen et al . 1 6 2019 Cohort (retrospective) 1224 All HNC IMRT 66-68Gy 22.8 100 pre-RT extractions 56 43 8 Y. Muraki et al. 22 a 7 2019 Cohort (prospective) 67 Squamous cell carcinoma Conventional RT/IMRT 60Gy 24 40 pre-RT extractions 5 3 8 Y. Muraki et al. 22 b 7 2019 Cohort (prospective) 67 Squamous cell carcinoma Conventional RT/IMRT 60Gy 24 5 post-RT extractions 3 1 8 R. Kabir et al. 15 a 8 2020 Cohort (retrospective) 620 Squamous cell carcinoma IMRT 20-70Gy 22.3 266 pre-RT extractions 14 10 7 R. Kabir et al. 15 b 8 2020 Cohort (retrospective) 620 Squamous cell carcinoma IMRT 20-70Gy 22.3 20 post-RT extractions 4 0 7 S. Dumoulin et al. 11 a 9 2021 Cohort (retrospective) 376 Squamous cell carcinoma IMRT 50-70Gy > 36 222 pre-RT extractions 22 16 7 S. Dumoulin et al. 11 b 9 2021 Cohort (retrospective) 376 Squamous cell carcinoma IMRT 50-70Gy > 36 39 post-RT extractions 13 7 7 F. M. Girardi et al. 13 a 10 2022 Cohort (retrospective) 57 Squamous cell carcinoma Conventional RT/3D CRT 65-70Gy 84.7 6 pre-RT extractions 6 1 8 F. M. Girardi et al. 13 b 10 2022 Cohort (retrospective) 57 Squamous cell carcinoma Conventional RT/3D CRT 65-70Gy 84.7 27 post-RT extractions 17 12 8 Y. J. Shih et al. 24 11 2022 Cohort (retrospective) 24353 All HNC n/s 60Gy 60 11689 pre-RT extractions 1014 605 7 R. Ward et al. 28 12 2022 Cohort (retrospective) 154 All HNC n/s 55Gy or 65Gy > 20 102 pre-RT extractions 2 1 6 S. Slettvoll et al. 25 a 13 2023 Cohort (retrospective) 75 Oropharyngeal cancer n/s 70Gy > 60 36 pre-RT extractions 8 6 8 S. Sletvoll et al . 25 b 13 2023 Cohort (retrospective) 75 Oropharyngeal cancer n/s 70Gy > 60 24 post-RT extractions 5 3 8 Data from the studies were assigned into 3 groups based on the exposure within each study: Pre-RT extractions only, Post-RT extractions only and Both pre- and post-RT extractions where data was available. The quality of the included studies (See Table 5 ) was assessed by two reviewers, AS and PF, who used the modified Newcastle-Ottawa scale for cohort studies. A Modified Newcastle-Ottawa quality score was used to assess the quality of scientific studies, adapting the original Newcastle-Ottawa Scale for specific research areas including retrospective studies, which this systematic review highlights. By using a modified scoring algorithm, which may vary depending on the specific modification used, study quality can be assessed. Intraclass Correlation Coefficients (ICC) score was 0.44 (p = 0.17) indicating poor agreement. These differences were resolved through mutual discussion amongst the three reviewers, until full agreement was achieved. With two reviewers all scoring each study a consensus was reached. Meta-Analysis was carried out using the METAN procedure in STATA17 (StataCorp. 2023. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC.). Odds Ratios were calculated to compare the proportion of patients who developed ORN following extractions with those who did not have extractions. Where zero events were observed, 0.5 was added to each cell to facilitate calculations. Odds Ratios were converted to Log-odds for analysis. Where necessary, sub-group analyses were performed to investigate the heterogeneity. These comprised examination of (a) Study Type: prospective, retrospective, (b) Cancer type: SCC, oropharyngeal, all HNCs, (c) Radio-Therapy techniques: conventional RT, IMRT, not specified, (d) Radiotherapy dose: 20-80Gy, > 50 Gy, not specified and (e) Follow-up period: 20–50 months, 50–90 months, not specified. Results are reported where these analyses resulted in a reduction of heterogeneity of at least 20% and retained a minimum of four studies. Results are presented as Odds Ratios using the e-form option. Cumulative meta-analysis was undertaken. The results of the meta-analysis were presented as forest plots and a table for the sub-group analyses. Results A total of 437 articles were identified through the electronic search; 425 records after the duplicates were removed. For some articles the titles warranted further examination, but no abstracts were available. A total of 375 articles were excluded leaving 50 articles to assess for eligibility. 37 articles were excluded based on study design, outcome or exposure. Finally, 13 full text articles were included in the analysis, which clearly described the relation between pre and post – RT extractions (See Fig. 1 ). General information on the selected study characteristics can be found in Table 3 . Pre-RT extractions were performed on 22,920 patients who had HNC, among these patients 1464 patients received a diagnosis of ORN. Table 3 shows the data for the number of patients who had tooth extractions, the overall number of patients who developed ORN in total, as well as the number of cases of ORN within those patients who had tooth extractions. The odds ratio values were calculated for 13 of the pre-RT extraction studies (1,2,3,4,5,6,7,8,9,10,11,12,13) (See Fig. 2 ) The meta-analysis revealed a value of 2.77 (95% CI = 1.66–4.62, p = 0.002) for the shared OR value. The analysis showed the rate of heterogeneity between the studies (I 2 = 62.1%). The pooled estimate OR value of 2.77 indicates that pre-RT extractions exacerbated ORN by almost 2.8 times compared to those who did not have pre-RT extractions. The odds ratios for the studies of post-RT extractions were calculated for 8 of the studies (2,3,4,7,8,9,10,13) (See Fig. 3 ). The meta-analysis revealed a pooled OR value of 4.19 (95% CI = 2.17–8.08, p = 0.678). The analysis showed the presence of homogeneity between these 8 studies (I 2 = 0.00%). This finding indicates that post-RT extractions increase the risk of ORN at a rate of more than four times. The odds ratios for the studies where both pre- and post-RT extractions were carried out on the same individuals within the study sample. This data was present for 5 of the studies (3,4,7,9,13) (Fig. 4). The meta-analysis revealed a pooled OR value of 7.96 (95%CI = 3.91–16.2). The analysis showed the presence of homogeneity between the studies (I 2 = 0.00%). This finding indicates that having both pre- and post-RT extractions increase the risk of ORN by almost eight times. No statistically significant differences were observed between the risk associated with types of extractions and the incidence of ORN with the exception of the comparison between Pre-RT extractions and Both extractions (z = 2.15; p = 0.03). To assess the impact of confounding factors and find potential sources of the high heterogeneity for the Pre-RT OR subgroup analyses were undertaken looking at study design, cancer type, RT technique, RT dose and follow-up time. Table 4 shows the results of sub-group analyses for pre-RT groups with the reported results in bold and the non-reported results in italics. For the Pre-RT studies, the subgroups which successfully lowered the rate of heterogeneity by 20% and retained more than 4 studies were SCC (cancer type), 20-80Gy (RT dose) and 20–50 months (follow-up period). Table 4. Sub-group analysis for pre-RT extractions The subgroup analysis of pre-RT extraction studies reported a statistically significant increase in risk for: 20-80Gy (RT dose) and 20–50 months (follow-up time). Both subgroups displayed a marked reduction in heterogeneity of 0% with an OR of 4.7 and 4.91, respectively. A cumulative meta-analysis demonstrated the effect of all types of extractions on ORN more precisely over time. Taken together, all three analyses demonstrate a gradual reduction in risk. (See Fig. 3). Using the accumulated figures, the study population attributable risk for the association of any extraction with the development of ORN is 27%(95%CI:22.6%,32.29%). The risk for Pre-RT, Post-RT, Both-RT extractions are 28.53%(95%CI:21.34,31.73), 37.40%( 95%CI:22.40,52.38), 42.84%(95%CI:25.10,60.59) respectively. Regarding the sensitivity analysis, the studies with final quality ratings of 8 were compared with those studies with quality ratings of less than 8 using a sub-group analysis. The OR for the studies scoring ‘8’ was OR 2.71 (95%CI 1.30,5.87) and for the studies scoring ‘less than 8’ was OR 2.82 (95%CI 1.39,5.78). The result simply demonstrates no difference based on the comparison of interest. The Newcastle-Ottawa scale was used to investigate the quality of the included studies (See Table 5). Table 5 Modified Newcastle-Ottawa Scale for measuring the quality and risk of bias for included studies. Representativeness of the exposed cohort Selection of the non- exposed cohort Ascertainment of exposure Demonstration that outcome of interest was not present at the start of the study Comparability of cohorts on the basis of the design or analysis Assessment of outcome Was follow-up long enough for outcomes to occur Adequacy of follow up of cohorts Total: Bonan et al. (2006) * * * * * * * 7 Ben-David et al. (2007) * * * * * * * 7 Chang et al. (2007) * * * * * * * 7 Beech et al. (2017) * * * * * * * * 8 Moon et al. (2017) * * * * * * * * 8 Aarup-Kristensen et al. (2019) * * * * * * * * 8 Muraki et al. (2019) * * * * * * * * 8 Kabir et al. (2020) * * * * * * * 7 Dumoulin et al. (2021) * * * * * * * 7 Girardi et al. (2022) * * * * * * * * 8 Shih et al. (2022) * * * * * * * * 8 Ward et al. (2022) * * * * * * 6 Slettvoll et al. (2023) * * * * * * * * 8 Discussion Current evidence on this topic suggests that while extractions before radiation can increase the risk of ORN, the overall risk remains relatively low, and the timing of extractions within this context is crucial. Specifically, Kumar et al. 17 suggest that extractions performed very close to the start of radiation therapy (within a week) may be associated with a higher risk of ORN. However, other reviews suggest that pre-RT extractions don't significantly reduce the risk of ORN compared to post-RT extractions. Most studies indicate that pre-RT extractions should be carried out 2–3 weeks before treatment, when possible, to allow bone and soft tissue healing. 17 Preliminary scoping searches were undertaken through PubMed, Embase and Web of Science to identify evidence related to this topic. The search was limited to systematic reviews published between 2002–2023 not limited to studies only in English. This ensured the most updated evidence on the topic. The search terms used were ‘systematic review’ AND ‘osteoradionecrosis’ AND ‘dental extraction’. The constant development of treatment protocols requires ongoing regular systematic reviews of the management of these patients. Therefore, this systematic review adds to the current literature as the current Royal College of Surgeons (Eng) guidelines appear to be in line with the findings of this review. A sample of recent systematic reviews on this topic are found in Table 5 . The main outcome of this systematic review is that there is a general indication for pre-RT extractions to exacerbate ORN in the study population; this finding was statistically significant with an overall shared OR value of 2.77, with a substantial degree of heterogeneity amongst the studies. These findings need to be considered in the light of the high degree of heterogeneity and the less-than-ideal quality of the selected studies, in light of the low ICC score. The quality aspect is particularly of concern as major changes in clinical practice are unlikely due to the quality aspect. More studies need to be undertaken looking into quality and study design. Therefore, any conclusions that are drawn from this study need to be considered with caution based on the quality of those studies in this review. The finding for post-RT extractions from this meta-analysis was a pooled OR value of 4.19, which was found to be statistically significant. The clinical implication of this finding is that post-RT extractions have more potentiating effect for ORN compared to pre-RT extractions. The updated guidelines by the RCS (2018) state that ‘teeth with doubtful prognosis (deep caries, deep periodontal pockets, non-vital teeth) should be extracted as soon as possible before radiotherapy’. The evidence of this current systematic review corroborates the RCS guidelines by indicating a lower OR for pre-RT extractions than for post-RT extractions. 17 Studies reporting both pre- and post-RT extractions showed an increased risk, OR value of 7.96. From a clinical perspective, this would indicate that clinicians should not consider extraction of sub-optimal teeth on patients undergoing RT for HNC without due consideration of the real risk of the patient developing ORN. Where an extraction is unavoidable, it must be performed with appropriate precautions and potentially within a hospital environment. 20 Prior to the original guidelines from the RCS (Eng) in 1997, the finding for post-RT extractions can be compared with the study by Morrish et al. (1981), who reported an OR value of 5.3 (95% CI: 1.77–15.9). 21 Epstein et al. (1987) conducted a similar study but reported a non-significant OR value of 1.02. 12 Modern techniques of IMRT could influence the risk of ORN in today’s HNC population. IMRT limits the field of radiation to a smaller, more specific area than previous radiation techniques, thus reducing the potential for patients to develop ORN. This rapidly developing field necessitates the multi-disciplinary approach to patient care and individual patient risk assessment. Cancer treatment planning, including dose, staging of tumour, site of tumour, co-morbidities and current medication review should all be included in the patient care. The need for the general dental practitioner to work alongside the oncologists, maxilla-facial surgeon and other specialists is paramount as is the need to consider patients’ choices for treatment. The subgroup analyses resulted in the criterion reduction of heterogeneity for several groups in the pre-RT analyses, including more reliable estimates for SCC (2.64); 20–80 Gy of 4.70; 20–50 months of 4.91. This reinforces the findings that the OR of 2.77 is still reliable for the pre-RT extraction group. This represents a significant risk of patients developing ORN by a factor of 3 compared to patients who don’t undergo extractions. The impact of variable definitions of ORN could affect the pooled estimates as these minor variations in definition act as a limiting factor despite undertaking sub-group analyses. Radiation doses and follow-up variability also potentially has an effect on the pooled estimate. The cumulative analysis demonstrated the significance of time in relation to knowledge and research. The gradual reduction in risk between 2006 and 2023 was observed in all categories of extractions. This corresponds to more precise targeted delivery of radiation. The increased knowledge available over time needs to be disseminated to GDPs, so that they are operating within contemporary guidelines to offer patients the best possible care. Those guidelines need to be regularly updated to reflect the most current evidence from the literature. RCS guidelines suggest that ‘where possible, extraction of teeth from irradiated sites should be avoided due to the risk of ORN’. Within this systematic review, chosen articles revealed a consistent lack of detail associated with the specific timing of extractions. The time interval is known to be quite important in determining whether a patient gets ORN, as it is heavily discussed in the guidelines for the oral management of oncology patients by the RCS. 17 The guidelines suggest that teeth with a questionable prognosis, or the teeth in the direct path of the radiation beam, should be extracted prior to RT to prevent future dental extractions. A minimum of 2–3 weeks between extractions and commencement of RT should be followed as a guide. 18 The mechanism for diagnosing ORN within these studies has a huge impact on the outcomes of the studies. The Notani and Common Terminology Criteria for Adverse Events v5.0 (CTCAE) classifications have been mentioned for grading ORN for five of the studies (2,3,6,10,13) in which a grade of 2 or above was needed. Furthermore, four of the studies included in the analysis diagnosed ORN by an area of exposed bone for at least three months (4,5,7,9). Three studies (1,8,12) that didn’t mention how they diagnosed ORN. Considering exposed bone as the only sign of ORN could result in underestimating the real rate of ORN due to misdiagnosis. Future studies looking at the incidence of ORN will need to provide a clear definition of ORN so that results can be compared reliably. Another area where there was a lack of detail in the included studies was the number of teeth extracted, the number of sites of ORN, and whether the site of ORN was at an extraction site or not. Given the studies were mainly retrospective through reviewing patient records rather than prospective and directly involved with the patients, the detail regarding extractions and ORN was limited to the number of patients who had received extractions and number of patients who developed ORN. The lack of detail in this area puts into question the causal link between extractions and ORN, and so future studies will need this level of detail to ascertain whether a direct causal link can be found rather than just an association. Many authors report that poor oral health and dental pathology predispose patients to ORN, as this is the reason why patients need to have dental extractions. 4 , 14 The use of screening for HNCs would seem to be a positive step forward in early diagnosis and treatment. Careful management of these patients necessitates careful planning with a multidisciplinary team (MDT) once the HNC diagnosis is known. Careful dental treatment to reduce the possibilities of bacterial infection before the beginning of RT includes periodontal and/or endodontic treatment, as well as supportive therapies like oral hygiene recalls and professional fluoride therapy. This degree of management of these patients should result in fewer extractions per patient, improved oral health, and fewer inflamed/infected foci. The role of the dental team in caring for these patients is fundamental for their long-term health and survival. Instigating regular dental visits to monitor oral health should be encouraged in this population of patients who previously have only attended sporadically. Cancer patients having dental extractions are at a particular risk of ORN if undertaken close to the start of RT, whether before or after. 17 If tooth extractions are conducted before RT, the swift bone regeneration in the healing socket becomes vulnerable to the effects of RT. In such cases, the cancer treatment cannot be postponed until the socket has fully healed; therefore, dental professionals need to be aware of the increased risk from extractions in these patients. On the other hand, if extractions are performed after RT, they take place in an environment with impaired healing. According to Beaumont et al. 4 , there is no conclusive evidence to determine the optimal timing for the extraction of these compromised teeth. This current study was unable to systematically review all confounding variables between all categories of extractions because of inadequate coverage in the literature. For example, poor oral health/hygiene, tobacco and alcohol misuse, and primary wound closure of extraction sites were not consistently reported. If almost all the confounding variables are present in all categories of extractions, can there really be a case made for the timing of the extractions to be the ultimate predictor of ORN? Or are the other variables more influential? The clinical implications of this study suggest that GDPs and oncologists need to work closely when dealing with HNC patients in relation to all extractions and to decide the optimum time for said extractions in relation to RT for HNC. A team approach, which should include regular preventative oral hygiene appointments for these patients, is essential for the best possible outcome. The Newcastle-Ottawa scale indicated the selected articles were of high quality. However, it proved to have limitations as a generic scale because it didn’t consider that many of the studies were missing important clinical details such as RT technique and dosage, and follow-up time. Subgroup analysis demonstrated just how many of the articles didn’t specify these important clinical details when looking at each of the subgroups. There are some discrepancies between this study and other systematic reviews mentioned in Table 5 . Beaumont et al. 4 concluded a slightly lower incidence of ORN from post-RT extractions compared to pre-RT extractions. Beaumont et al. 4 only included articles up to 2020, whereas this current study is more contemporary in including studies up to 2023. The fact that there were very little significant differences between the two studies may indicate that little research has been done in this field in the interim years. In addition, this study looked at dose of radiation, follow-up period, types of radiotherapy and type of cancer, but did not look specifically at age as Beaumont et al did. The majority of recent systematic reviews look at incidence of ORN, as their metric whereas this current study uses OR as a measure, which gives a more specific, relevant finding. The other systematic reviews mentioned in Table 5 only looked at pre-RT extractions and all infer that they present a risk factor for ORN, much like this study confirms. The inclusion of pre & post RT extractions in this current study given a more holistic picture of the situation, which allows governing bodies to modify their advice to practitioners based on contemporary knowledge. However, whenever both pre- and post-RT extractions are compared from Balermpas et al. 3 and Costa Normando et al., 23 post-RT extractions are more significantly associated with ORN. Despite the heterogeneity of the six studies mentioned in Table 5 , the consensus from the studies is that pre-RT extractions are potentially safer than post-RT extractions but still carry some risk of ORN; this agrees with the main finding of this current study. Further studies related to this topic should have larger sample sizes with better reporting standards, especially for the time interval between extraction and the start of RT. It would be advantageous if future studies reported on whether post-extraction sites were the location of the ORN, as opposed to just mentioning the number of patients who were diagnosed with ORN. Further studies are needed to consider the implications for ORN due to IMRT as a radiation technique. It would be helpful if a standardised definition of ORN was adopted for future research. Smoking, alcohol and poor oral health can be associated with ORN but are not reported as causative factors. Causation is possibly a factor of inadequate bone healing following radiotherapy and extractions but is not a direct causation. Future prospective studies with comprehensive data collection on patient comorbidities, oral health status, and timing of extractions are essential. Limitations of this systematic review include: i) it didn’t investigate the patient’s characteristics such as gender, age, smoking status, stage of cancer, dental health, and general health, which could act as significant risk factors for the development of ORN; ii) A limited number of data bases were used; iii) there was a predominance of retrospective observational data; iv) variability in ORN definitions and diagnostic criteria; v) lack of detailed data on confounders; and vi) potential publication bias. The high degree of heterogeneity and limited data on timing of extractions relative to RT in some studies constrain definitive conclusions. The strengths of this review included: 1) a twenty-year observation period; 2) looking at studies of both pre- and post-RT extractions, as well as pre- or post-RT extractions; and 3) subgroup analysis stratified by cancer type, RT technique, RT dose, and follow-up time. This review demonstrates a limitation of the evidence available, as it is based only on observational studies that illustrate an association rather than a direct causal link. Conclusion The guidelines from the RCS about extraction of unsound teeth either prior to or after RT for HNC patients are consistent with the current available literature. 17 The timings of extractions could be a critical factor when considering these patients, and therefore the continued review of guidelines based on current knowledge is essential. Declarations Funding Statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work the author(s) used ChatGPT in order to convert original Harvard referencing into the Vancouver referencing style. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication. References Aarup-Kristensen S, Hansen CR, Forner L, Brink C, Eriksen JG, Johansen J. Osteoradionecrosis of the mandible after radiotherapy for head and neck cancer: risk factors and dose-volume correlations. Acta Oncol. 2019;58(10):1373–7. de Almeida-Silva LA, Lupp J dos S, Sobral-Silva LA, dos Santos LAR, Marques TO, da Silva DBR, et al. The incidence of osteoradionecrosis of the jaws in oral cavity cancer patients treated with intensity-modulated radiotherapy: a systematic review and meta-analysis. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2024;138(1):66–78. Balermpas P, van Timmeren JE, Knierim DJ, Guckenberger M, Ciernik IF. Dental extraction, intensity-modulated radiotherapy of head and neck cancer, and osteoradionecrosis: A systematic review and meta-analysis. Strahlenther Onkol. 2022;198(3):219–228. Beaumont S, Bhatia N, McDowell L, Fua T, McCullough M, Celentano A, et al. Timing of dental extractions in patients undergoing radiotherapy and the incidence of osteoradionecrosis: a systematic review and meta-analysis. British Journal of Oral and Maxillofacial Surgery. 2021;59(5):511–23. Beech NM, Porceddu S, Batstone MD. Radiotherapy-associated dental extractions and osteoradionecrosis. Head Neck. 2017;39(1):128–32. Ben-David MA, Diamante M, Radawski JD, Vineberg KA, Stroup C, Murdoch-Kinch CA, et al. Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions. Int J Radiat Oncol Biol Phys . 2007;68(2):396–402. Bonan PRF, Lopes MA, Pires FR, Almeida OPD. Dental management of low socioeconomic level patients before radiotherapy of the head and neck with special emphasis on the prevention of osteoradionecrosis. Braz Dent J. 2006;17(4):336–42. Butkus JM, Crippen M, Bar-Ad V, Luginbuhl A. Impact of adjuvant radiation therapy after definitive surgery in senior adults > 80 years old with advanced head and neck squamous cell carcinoma on overall survival. Front Oncol . 2022. Chang DT, Sandow PR, Morris CG, Hollander R, Scarborough L, Amdur RJ, et al. Do pre-irradiation dental extractions reduce the risk of osteoradionecrosis of the mandible? Head Neck. 2007;29(6):528–36. Corrao G, Mazzola GC, Lombardi N, Marvaso G, Pispero A, Baruzzi E, Decani S, Tarozzi M, Bergamaschi L, Lorubbio C, Repetti I, Starzyńska A, Alterio D, Ansarin M, Orecchia R, D'Amore F, Franchini R, Nicali A, Castellarin P, Sardella A, Lodi G, Varoni EM, Jereczek-Fossa BA. Oral Surgery and Osteoradionecrosis in Patients Undergoing Head and Neck Radiation Therapy: An Update of the Current Literature. Biomedicines. 2023;11(12):3339. doi: 10.3390/biomedicines11123339 . PMID: 38137559; PMCID: PMC10742198. Dumoulin S, Van Maanen A, Magremanne M. Dental prevention of maxillo-mandibular osteoradionecrosis: a ten-year retrospective study. J Stomatol Oral Maxillofac Surg. 2021;122(2):127–34. Epstein JB, Rea G, Wong FLW, Spinelli J, Stevenson-Moore P. Osteonecrosis: Study of the relationship of dental extractions in patients receiving radiotherapy. Head Neck Surg. 1987;10(1):48–54. Girardi FM, Wagner VP, Martins MD, Abentroth AL, Hauth LA, Kraether Neto L, et al. Risk factors for jaw osteoradionecrosis: a case control study. Braz Oral Res. 2022;36:132. 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(9):780–6. Kabir R, Durand R, Roberge D, Dufresne E, Nguyen-Tân PF, Schmittbuhl M. Incidence of osteoradionecrosis of the jaws: A retrospective study of 620 head and neck cancer patients treated by radiotherapy. Gen Dent. 2022;70(4):72–7. Karanth S, Mistry S, Wheeler M, Akinyemiju T, Divaker J, Yang JJ, Yoon HS, Braithwaite D. Persistent poverty disparities in incidence and outcomes among oral and pharynx cancer patients. Cancer Causes Control . 2024;35(7):1063–1073. Kumar N, Brooke M, Chan F, Ali S, Doughty J, Cho H, et al. The oral management of oncology patients requiring radiotherapy, chemotherapy and/or bone marrow transplantation: clinical guideline. Royal College of Surgeons of England & British Society for Disability and Oral Health ; 2018. https://doi.org/10.1308/204268513X13776914744952 Lajolo C, Gioco G, Rupe C, Troiano G, Cordaro M, Lucchese A, Paludetti G, Giuliani M. Tooth extraction before radiotherapy is a risk factor for developing osteoradionecrosis of the jaws: A systematic review. Oral Dis. 2021;27(7):1595–1605. Leeder J, Modabber A, Hölzle F, Eble MJ, Mohamed AA. Predictive modelling of mandibular osteoradionecrosis in head and neck cancer patients: clinical and dosimetric insights. Clin Oral Investig . 2025;29(6):313. Moon DH, Moon SH, Wang K, Weissler MC, Hackman TG, Zanation AM, et al. Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers. Oral Oncol. 2017;72:98–103. Morrish RB Jr, Chan E, Silverman S Jr, Meyer J, Fu KK, Greenspan D. Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer. 1981;47(8):1980–3. Muraki Y, Akashi M, Ejima Y, Hasegawa T, Miyawaki D, Shinomiya H, et al. Dental intervention against osteoradionecrosis of the jaws in irradiated patients with head and neck malignancy: a single-arm prospective study. Oral Maxillofac Surg. 2019;23(3):297–305. Normando AGC, Pérez-de-Oliveira ME, Guerra ENS, Lopes MA, Rocha AC, Brandão TB, Prado-Ribeiro AC, Gueiros LAM, Epstein JB, Migliorati CA, Santos-Silva AR; Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). To extract or not extract teeth prior to head and neck radiotherapy? A systematic review and meta-analysis. Support Care Cancer. 2022;30(11):8745–8759. doi: 10.1007/s00520-022-07215-y . Epub 2022 Jun 17. PMID: 35713725. Shih YJ, Huang JY, Lai YC, Lin HM, Kuo TJ. Tooth extraction within 2 weeks before radiotherapy and osteoradionecrosis: a nationwide cohort study. Oral Dis. 2022. Slettvoll S, Thaning RC, Pedersen TØ. Tooth extraction prior to radiotherapy for oropharyngeal cancer increases the risk of osteoradionecrosis. J Oral Sci. 2023;65(2):87–9. Sun H, Yu M, An Z, Liang F, Sun B, Liu Y, Zhang S. Global burden of head and neck cancer: Epidemiological transitions, inequities, and projections to 2050. Front Oncol . 2025. Urquhart O, DeLong HR, Ziegler KM, Pilcher L, Pahlke S, Tampi MP, et al. Effect of preradiation dental intervention on incidence of osteoradionecrosis in patients with head and neck cancer. The Journal of the American Dental Association. 2022;153(10):931–942.e32. Ward R, Kanani R, Shihab A. An audit into the timing of dental extractions pre-head and neck radiotherapy and the prevalence of osteoradionecrosis. Br Dent J. 2022. Warnakulasuriya S, Kerr AR. Oral cancer screening: past, present, and future. J Dent Res. 2021;100(12). Yong CW, Robinson A, Hong C. Dental Evaluation Prior to Cancer Therapy. Front Oral Health. 2022;3:876941. doi: 10.3389/froh.2022.876941 . PMID: 35510226; PMCID: PMC9058061.. Zehr LJ, Cooper JS. Mandible Osteoradionecrosis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Additional Declarations There is no duality of interest Cite Share Download PDF Status: Under Review Version 1 posted Review # 3 received at journal 11 May, 2026 Reviewer # 3 agreed at journal 17 Apr, 2026 Review # 1 received at journal 19 Feb, 2026 Reviewer # 2 agreed at journal 19 Feb, 2026 Reviewer # 1 agreed at journal 19 Feb, 2026 Reviewers invited by journal 12 Feb, 2026 Editor assigned by journal 10 Feb, 2026 Submission checks completed at journal 10 Feb, 2026 First submitted to journal 10 Feb, 2026 Unknown event 05 Feb, 2026 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-8796363","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":589118351,"identity":"771ea9f5-2172-477f-a924-f54292b16242","order_by":0,"name":"Peter Fine","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYFACxgcHGBhsGBjYIVwDIrQwGwC1pAFpUrQAicMkaDFnYGY8XFBxPrG/mYHxww+Gw8YEtVg2MDMcnnHmduKMwwzMkj0Mh80IajE4wH/gMG/b7cQNQIdJA11oQ4QWoC28/86BtDD/JkFLwwGQFjaQLYQdZtkM1MJzLNl4xmHGNsseg3TC3jdnb2b+zFNjJ9vf3nz4xo8Ka8MGgg5jhjMZG4iLSGLUjIJRMApGwUgHAMK4NHR2O74TAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7228-2743","institution":"UCL Eastman Dental Institute","correspondingAuthor":true,"prefix":"","firstName":"Peter","middleName":"","lastName":"Fine","suffix":""},{"id":589118352,"identity":"3660fa10-a981-4218-863c-6f91b3e559df","order_by":1,"name":"Alex Sabonchian","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Alex","middleName":"","lastName":"Sabonchian","suffix":""},{"id":589118353,"identity":"4d293b52-a17e-498d-af27-6635a464855a","order_by":2,"name":"Colin Hopper","email":"","orcid":"https://orcid.org/0000-0002-4710-5921","institution":"Eastman Dental Institute for Oral Health Care Sciences","correspondingAuthor":false,"prefix":"","firstName":"Colin","middleName":"","lastName":"Hopper","suffix":""},{"id":589118354,"identity":"ca1b5ebd-07e6-47d7-98f0-30c48e48e8ad","order_by":3,"name":"Robert Blizard","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Blizard","suffix":""}],"badges":[],"createdAt":"2026-02-05 11:36:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8796363/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8796363/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102981988,"identity":"c03f5329-42ce-40f8-9dac-2113a0b2d054","added_by":"auto","created_at":"2026-02-19 09:12:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":188667,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA flow diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8796363/v1/5368ef449b694f765cd9d81b.png"},{"id":102981951,"identity":"b2cf7f20-4bd4-4ad0-9dd0-5f6c51816695","added_by":"auto","created_at":"2026-02-19 09:11:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":601806,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of pre, post and both-RT extractions.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8796363/v1/d189d344f088eb432d2d6ebc.png"},{"id":102981913,"identity":"1b7012f4-b2e9-4f73-97d9-7c0931cc538e","added_by":"auto","created_at":"2026-02-19 09:11:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1713873,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative forest plot for each class of extraction\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8796363/v1/df803340d744c778337224eb.png"},{"id":102981986,"identity":"c05e61bc-c6e9-4149-b6c6-4bfd596844ee","added_by":"auto","created_at":"2026-02-19 09:12:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4493,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"fig.png","url":"https://assets-eu.researchsquare.com/files/rs-8796363/v1/242149b2988fd9d8af43cc38.png"},{"id":102982097,"identity":"6f2bb51a-9873-4a68-94a6-e448051b07e5","added_by":"auto","created_at":"2026-02-19 09:12:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3975618,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8796363/v1/a2f7e7b6-7089-4351-92ca-8dbc9fd77a17.pdf"}],"financialInterests":"There is no duality of interest","formattedTitle":"The Risk of Osteoradionecrosis Associated With Dental Extractions Prior to Radiotherapy: A Systematic Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHead and neck cancer (HNC) is the seventh most frequently occurring cancer worldwide \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e; over 400,000 estimated new cases of oral cancer are diagnosed each year globally.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Head and neck cancer (HNC) is a medical term encompassing various malignant tumours that form in and around the mouth, nose, throat and larynx. Almost 90% of HNC cases are reported to be squamous cell carcinomas (SCC).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Surgical resection followed by radiotherapy (RT) has been the preferred treatment method for oropharyngeal cancers; however, notable modifications have been made. Multiple studies suggest that early termination of adjuvant RT or prolonged interruptions have negative impacts on survival outcomes in older HNSCC patients.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Significant risk factors that can lead to oropharyngeal cancers include alcohol and tobacco abuse, betel nut chewing and chronic inflammation; also prevalent is HPV-associated (mainly HPV type 16) oral and oropharyngeal cancer.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The incidence of oropharyngeal cancers has been reported to be linked to educational and socioeconomic status, making those of a low socioeconomic group more prone to oral cancers.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe importance of regular oral screening to identify oral/dental pathology cannot be overstated.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Prior to initiating cancer treatment, it is essential to conduct a comprehensive evaluation of both hard and soft oral tissues. Additionally, radiographs should be taken to identify any potential sources of infection or pathology.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e This screening aims to identify existing oral/dental diseases and assess the potential risks associated with oral health prior to the commencement of cancer treatment. It holds significant importance for the dental team to inform the patient of the crucial role of maintaining excellent oral hygiene throughout their cancer treatment. Dental caries should be treated and teeth restored with either a permanent or long-term temporary restoration, and sharp teeth or restorations should be smoothed to prevent mucositis or soft tissue damage. Dental extractions for any non-vital teeth or teeth with deep periodontal pockets of poor prognosis are also recommended at this stage by the guidelines entitled \u003cem\u003eThe Oral Management of Oncology Patients requiring radiotherapy, chemotherapy and/or bone marrow transplantation\u003c/em\u003e by the Royal College of Surgeons of England (RCS).\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne significant consequence of RT is osteoradionecrosis (ORN), a severe complication often observed in HNC patients undergoing RT.\u003csup\u003e10\u003c/sup\u003e After RT, the soft tissues and bone fail to heal adequately or remodel, rendering bone exposed to the oral cavity and devitalised, ultimately leading to ORN.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e ORN involves a combination of four factors: radiation, hypoxia, hypo-vascularisation, and hypo-cellularisation, resulting in bone necrosis. The presence of poor dental health associated with ORN was reported to be particularly prevalent in males and most common in the posterior region of the mandible.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e ORN is typically characterised by profound bone pain, frequently accompanied by a purulent discharge that might contain sequestrated bone fragments, and can lead to substantial bone loss. ORN is usually found in the mandible due to the mandible\u0026rsquo;s limited blood supply.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe need to regularly update scientific evidence for the good of patients is paramount. This has been recently demonstrated with the issues surrounding endocarditis prevention, when antibiotic prophylaxis was once considered necessary for all but the most trivial dental procedures. Subsequent review of the literature has brought about a seismic shift in this approach and now indications for antibiotic use have reduced dramatically. It has become widely accepted that preventive dental treatment mitigates the risk of ORN.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA significant risk factor for ORN is dental extractions, which should be carefully planned by the clinician responsible.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The prevailing guidelines recommend avoiding dental extractions post-RT whenever feasible for patients who are at risk of developing ORN.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Currently, the accepted standard of care is to provide any necessary dental treatment prior to starting RT, as mentioned in the guidelines by the RCS.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNow is an appropriate time to do a systematic review looking at this topic because of the increasing use of RT in HNC. As survival rates improve, more patients are living long enough to experience complications such as ORN, making it a more relevant issue than ever. Current guidelines worldwide vary widely regarding the safety of extractions before, during, or after RT. Royal College of Surgeons (Eng) guidelines have not been reviewed since 2018, and therefore a review is appropriate.\u003c/p\u003e \u003cp\u003eThe primary aim of this systematic review was to assess whether HNC patients who had tooth extractions pre-RT have an increased risk of developing ORN. The secondary aim investigated whether post-RT extractions and both pre-RT and post-RT extractions together modified this risk.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eThis systematic review was designed and reported within the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. An electronic literature search was conducted using Cochrane Library and OVID via Medline. The full list of search terms can be found in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Other databases including Embase and Web of science were consulted during the original scoping review but showed no additional studies to those found on Cochrane Library and OVID via Medline. Whilst using only two databases could be seen as a limitation, in the literature searches for this topic, it was considered appropriate.\u0026nbsp;\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutline of the order of search terms using MEDLINE.\u003c/strong\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e((\u0026quot;head and neck\u0026quot; or mouth or tongue or pharynx* or lanryn* or lips or lip or palate or lingual or sublingual or submandibular or tonsil*) adj3 (cancer* or neoplasm* or tumo?r* or carcinoma* or malignan* or metasti*)).\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e376,164\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\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(radiotherap* or radiation or irradiat* or radiochemotherap* or radio chemotherap*)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2,714,536\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(jaw* or maxill* or mandib* or alveolar or hard palate)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e889,244\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e((tooth or teeth or dental or oral) adj3 (extract* or treatment or surg*))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e335,085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 and 2 and 3 and 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e665\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eremove duplicates from 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e415\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eremove duplicates from 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e415\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eThe search strategy was based on a Population, Intervention, Comparison and Outcome (PICO) framework. \u003cstrong\u003ePopulation -\u003c/strong\u003e adults (\u0026gt;\u0026thinsp;18 years) with head and neck cancer undergoing radiotherapy alone or in conjunction with chemotherapy or surgical treatment. \u003cstrong\u003eIntervention\u003c/strong\u003e - pre-RT dental extractions ONLY or pre- and post-RT extractions mentioned in the same study. \u003cstrong\u003eComparison\u003c/strong\u003e - No dental extractions. \u003cstrong\u003eOutcome\u003c/strong\u003e - Incidence of ORN.\u003c/p\u003e\n\u003cp\u003eFollowing the PRISMA protocol a search of the literature was undertaken by multiple reviewers (AS, PF, CH); relevant titles and abstracts and finally appropriate articles were considered. Any discrepancies amongst the articles considered for inclusion were resolved by the three authors re-reading the full article and discussing each article\u0026apos;s merits for inclusion. A consensus was accepted.\u003c/p\u003e\n\u003cp\u003eTable 2 illustrates the inclusion/exclusion criteria used to decipher the relevant studies that were considered.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\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 valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy types\u003c/strong\u003e: randomised controlled trials (RCTs), observational studies (cohort, case-control)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy types\u003c/strong\u003e: non-analytical studies, literature reviews\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e: adults (\u0026gt;18 years) with head and neck cancer undergoing radiotherapy alone or in conjunction with chemotherapy or surgical treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e: non-head and neck cancer related studies, patients not undergoing radiotherapy treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e: pre-RT dental extraction ONLY or pre- and post-RT extractions mentioned in the same study\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eStudies only mentioning post-radiotherapy extractions\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNon-extraction dental interventions such as oral prophylaxis or dental fillings, studies looking at different interventions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparison:\u0026nbsp;\u003c/strong\u003eNo dental extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparison\u003c/strong\u003e: -\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e: ORN of the jaws\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e: not of interest, such as Medication-related osteonecrosis of the jaw (MRONJ), quality of life or inflammation response\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eStudies published between 2002-2023\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eStudies where only the abstract is available\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eStudies in English\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eStudies not in English\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eStudies published in a peer reviewed journal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. \u003cstrong\u003eInclusion and Exclusion criteria\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eData regarding the characteristics of the studies included study design, year of publication, study type, cancer type, radiation technique, radiation dose, follow-up time, cases of ORN. Specific information within each study, regarding patients who underwent tooth extractions (i.e. whether pre-RT or post-RT extraction or both), no. of patients receiving tooth extraction, cases of ORN due to tooth extraction were collected into a customisable table (See Table 3). The studies were numbered from 1-13 (See Table 3) and are referred to within this paper by their assigned number in some instances. Many of the included studies had separate data on both pre- and post-RT extractions; this is outlined in the table by an \u0026lsquo;a\u0026rsquo; or \u0026lsquo;b\u0026rsquo; after the study name with \u0026lsquo;a\u0026rsquo; implying pre-RT extractions and \u0026lsquo;b\u0026rsquo; implying post-RT extractions. Where there was data on both types of extractions, this was not included in the table so as not to overcomplicate it visually.\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of the included studies\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber label\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYear\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo. of people in the study\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCancer type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRadiation technique\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDosage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFollow-up average (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatients receiving tooth extraction\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDental exposure\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCases of ORN (patients)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCases of ORN due to tooth extraction (patients)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQuality score of study (Newcastle-Ottawa scale)\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\u003eP. R. F. Bonan \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e7\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (prospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM. A. Ben-David \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOropharyngeal cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM. A. Ben-David \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOropharyngeal cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD. T. Chang \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e9\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD. T. Chang \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN. M. Beech \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e5\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN. M. Beech \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD.H. Moon \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e252\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOropharyngeal cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT/3D CRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60-74Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS. Aarup-Kristensen \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAll HNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66-68Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY. Muraki \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e22\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (prospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT/IMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;60 and \u0026gt;\u0026thinsp;60Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY. Muraki \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e22\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (prospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT/IMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;60 and \u0026gt;\u0026thinsp;60Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR. Kabir \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e15\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20-70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR. Kabir \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e15\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20-70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS. Dumoulin \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e11\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e376\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50-70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS. Dumoulin \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e11\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e376\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50-70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF. M. Girardi \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT/3D CRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65-70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF. M. Girardi \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e13\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConventional RT/3D CRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65-70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY. J. Shih \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAll HNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;60 and \u0026gt;\u0026thinsp;60Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11689\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e605\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR. Ward \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cem\u003e28\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAll HNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55Gy or 65Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS. Slettvoll \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOropharyngeal cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epre-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS. Sletvoll \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e25\u003c/sup\u003e \u003cstrong\u003eb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCohort (retrospective)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOropharyngeal cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en/s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epost-RT extractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eData from the studies were assigned into 3 groups based on the exposure within each study: Pre-RT extractions only, Post-RT extractions only and Both pre- and post-RT extractions where data was available.\u003c/p\u003e\n\u003cp\u003eThe quality of the included studies (See Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e) was assessed by two reviewers, AS and PF, who used the modified Newcastle-Ottawa scale for cohort studies. A Modified Newcastle-Ottawa quality score was used to assess the quality of scientific studies, adapting the original Newcastle-Ottawa Scale for specific research areas including retrospective studies, which this systematic review highlights. By using a modified scoring algorithm, which may vary depending on the specific modification used, study quality can be assessed. Intraclass Correlation Coefficients (ICC) score was 0.44 (p\u0026thinsp;=\u0026thinsp;0.17) indicating poor agreement. These differences were resolved through mutual discussion amongst the three reviewers, until full agreement was achieved. With two reviewers all scoring each study a consensus was reached.\u003c/p\u003e\n\u003cp\u003eMeta-Analysis was carried out using the METAN procedure in STATA17 (StataCorp. 2023. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC.). Odds Ratios were calculated to compare the proportion of patients who developed ORN following extractions with those who did not have extractions. Where zero events were observed, 0.5 was added to each cell to facilitate calculations. Odds Ratios were converted to Log-odds for analysis.\u003c/p\u003e\n\u003cp\u003eWhere necessary, sub-group analyses were performed to investigate the heterogeneity. These comprised examination of (a) Study Type: prospective, retrospective, (b) Cancer type: SCC, oropharyngeal, all HNCs, (c) Radio-Therapy techniques: conventional RT, IMRT, not specified, (d) Radiotherapy dose: 20-80Gy, \u0026gt;\u0026thinsp;50 Gy, not specified and (e) Follow-up period: 20\u0026ndash;50 months, 50\u0026ndash;90 months, not specified. Results are reported where these analyses resulted in a reduction of heterogeneity of at least 20% and retained a minimum of four studies. Results are presented as Odds Ratios using the e-form option. Cumulative meta-analysis was undertaken.\u003c/p\u003e\n\u003cp\u003eThe results of the meta-analysis were presented as forest plots and a table for the sub-group analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 437 articles were identified through the electronic search; 425 records after the duplicates were removed. For some articles the titles warranted further examination, but no abstracts were available. A total of 375 articles were excluded leaving 50 articles to assess for eligibility. 37 articles were excluded based on study design, outcome or exposure. Finally, 13 full text articles were included in the analysis, which clearly described the relation between pre and post \u0026ndash; RT extractions (See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGeneral information on the selected study characteristics can be found in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Pre-RT extractions were performed on 22,920 patients who had HNC, among these patients 1464 patients received a diagnosis of ORN. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the data for the number of patients who had tooth extractions, the overall number of patients who developed ORN in total, as well as the number of cases of ORN within those patients who had tooth extractions.\u003c/p\u003e \u003cp\u003eThe odds ratio values were calculated for 13 of the pre-RT extraction studies (1,2,3,4,5,6,7,8,9,10,11,12,13) (See Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) The meta-analysis revealed a value of 2.77 (95% CI\u0026thinsp;=\u0026thinsp;1.66\u0026ndash;4.62, p\u0026thinsp;=\u0026thinsp;0.002) for the shared OR value. The analysis showed the rate of heterogeneity between the studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;62.1%). The pooled estimate OR value of 2.77 indicates that pre-RT extractions exacerbated ORN by almost 2.8 times compared to those who did not have pre-RT extractions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe odds ratios for the studies of post-RT extractions were calculated for 8 of the studies (2,3,4,7,8,9,10,13) (See Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The meta-analysis revealed a pooled OR value of 4.19 (95% CI\u0026thinsp;=\u0026thinsp;2.17\u0026ndash;8.08, p\u0026thinsp;=\u0026thinsp;0.678). The analysis showed the presence of homogeneity between these 8 studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%). This finding indicates that post-RT extractions increase the risk of ORN at a rate of more than four times.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe odds ratios for the studies where both pre- and post-RT extractions were carried out on the same individuals within the study sample. This data was present for 5 of the studies (3,4,7,9,13) (Fig.\u0026nbsp;4). The meta-analysis revealed a pooled OR value of 7.96 (95%CI\u0026thinsp;=\u0026thinsp;3.91\u0026ndash;16.2). The analysis showed the presence of homogeneity between the studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00%). This finding indicates that having both pre- and post-RT extractions increase the risk of ORN by almost eight times.\u003c/p\u003e \u003cp\u003eNo statistically significant differences were observed between the risk associated with types of extractions and the incidence of ORN with the exception of the comparison between Pre-RT extractions and Both extractions (z\u0026thinsp;=\u0026thinsp;2.15; p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eTo assess the impact of confounding factors and find potential sources of the high heterogeneity for the Pre-RT OR subgroup analyses were undertaken looking at study design, cancer type, RT technique, RT dose and follow-up time. Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the results of sub-group analyses for pre-RT groups with the reported results in bold and the non-reported results in italics. For the Pre-RT studies, the subgroups which successfully lowered the rate of heterogeneity by 20% and retained more than 4 studies were SCC (cancer type), 20-80Gy (RT dose) and 20\u0026ndash;50 months (follow-up period).\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 4. Sub-group analysis for pre-RT extractions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cimg 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\"\u003e\u003c/strong\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe subgroup analysis of pre-RT extraction studies reported a statistically significant increase in risk for: 20-80Gy (RT dose) and 20\u0026ndash;50 months (follow-up time). Both subgroups displayed a marked reduction in heterogeneity of 0% with an OR of 4.7 and 4.91, respectively.\u003c/p\u003e\n\u003cp\u003eA cumulative meta-analysis demonstrated the effect of all types of extractions on ORN more precisely over time. Taken together, all three analyses demonstrate a gradual reduction in risk. (See Fig.\u0026nbsp;3).\u003c/p\u003e\n\u003cp\u003eUsing the accumulated figures, the study population attributable risk for the association of any extraction with the development of ORN is 27%(95%CI:22.6%,32.29%). The risk for Pre-RT, Post-RT, Both-RT extractions are 28.53%(95%CI:21.34,31.73), 37.40%(\u003c/p\u003e\n\u003cp\u003e95%CI:22.40,52.38), 42.84%(95%CI:25.10,60.59) respectively.\u003c/p\u003e\n\u003cp\u003eRegarding the sensitivity analysis, the studies with final quality ratings of 8 were compared with those studies with quality ratings of less than 8 using a sub-group analysis. The OR for the studies scoring \u0026lsquo;8\u0026rsquo; was OR 2.71 (95%CI 1.30,5.87) and for the studies scoring \u0026lsquo;less than 8\u0026rsquo; was OR 2.82 (95%CI 1.39,5.78). The result simply demonstrates no difference based on the comparison of interest.\u003c/p\u003e\n\u003cp\u003eThe Newcastle-Ottawa scale was used to investigate the quality of the included studies (See Table 5).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 5\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eModified Newcastle-Ottawa Scale for measuring the quality and risk of bias for included studies.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRepresentativeness of the exposed cohort\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSelection of the non- exposed cohort\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAscertainment of exposure\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDemonstration that outcome of interest was not present at the start of the study\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eComparability of cohorts on the basis of the design or analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAssessment of outcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWas follow-up long enough for outcomes to occur\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdequacy of follow up of cohorts\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal:\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\u003cstrong\u003eBonan et al. (2006)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBen-David et al. (2007)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChang et al. (2007)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBeech et al. (2017)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMoon et al. (2017)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAarup-Kristensen et al. (2019)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMuraki et al. (2019)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eKabir et al. (2020)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDumoulin et al. (2021)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGirardi et al. (2022)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eShih et al. (2022)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWard et al. (2022)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSlettvoll et al. (2023)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eCurrent evidence on this topic suggests that while extractions before radiation can increase the risk of ORN, the overall risk remains relatively low, and the timing of extractions within this context is crucial. Specifically, Kumar et al. \u003csup\u003e17\u003c/sup\u003e suggest that extractions performed very close to the start of radiation therapy (within a week) may be associated with a higher risk of ORN. However, other reviews suggest that pre-RT extractions don't significantly reduce the risk of ORN compared to post-RT extractions. Most studies indicate that pre-RT extractions should be carried out 2\u0026ndash;3 weeks before treatment, when possible, to allow bone and soft tissue healing. \u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePreliminary scoping searches were undertaken through PubMed, Embase and Web of Science to identify evidence related to this topic. The search was limited to systematic reviews published between 2002\u0026ndash;2023 not limited to studies only in English. This ensured the most updated evidence on the topic. The search terms used were \u0026lsquo;systematic review\u0026rsquo; AND \u0026lsquo;osteoradionecrosis\u0026rsquo; AND \u0026lsquo;dental extraction\u0026rsquo;.\u003c/p\u003e \u003cp\u003eThe constant development of treatment protocols requires ongoing regular systematic reviews of the management of these patients. Therefore, this systematic review adds to the current literature as the current Royal College of Surgeons (Eng) guidelines appear to be in line with the findings of this review.\u003c/p\u003e \u003cp\u003eA sample of recent systematic reviews on this topic are found in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe main outcome of this systematic review is that there is a general indication for pre-RT extractions to exacerbate ORN in the study population; this finding was statistically significant with an overall shared OR value of 2.77, with a substantial degree of heterogeneity amongst the studies. These findings need to be considered in the light of the high degree of heterogeneity and the less-than-ideal quality of the selected studies, in light of the low ICC score. The quality aspect is particularly of concern as major changes in clinical practice are unlikely due to the quality aspect. More studies need to be undertaken looking into quality and study design. Therefore, any conclusions that are drawn from this study need to be considered with caution based on the quality of those studies in this review.\u003c/p\u003e \u003cp\u003eThe finding for post-RT extractions from this meta-analysis was a pooled OR value of 4.19, which was found to be statistically significant. The clinical implication of this finding is that post-RT extractions have more potentiating effect for ORN compared to pre-RT extractions.\u003c/p\u003e \u003cp\u003e The updated guidelines by the RCS (2018) state that \u0026lsquo;teeth with doubtful prognosis (deep caries, deep periodontal pockets, non-vital teeth) should be extracted as soon as possible before radiotherapy\u0026rsquo;. The evidence of this current systematic review corroborates the RCS guidelines by indicating a lower OR for pre-RT extractions than for post-RT extractions.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eStudies reporting both pre- and post-RT extractions showed an increased risk, OR value of 7.96. From a clinical perspective, this would indicate that clinicians should not consider extraction of sub-optimal teeth on patients undergoing RT for HNC without due consideration of the real risk of the patient developing ORN. Where an extraction is unavoidable, it must be performed with appropriate precautions and potentially within a hospital environment.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e Prior to the original guidelines from the RCS (Eng) in 1997, the finding for post-RT extractions can be compared with the study by Morrish et al. (1981), who reported an OR value of 5.3 (95% CI: 1.77\u0026ndash;15.9).\u003csup\u003e21\u003c/sup\u003e Epstein et al. (1987) conducted a similar study but reported a non-significant OR value of 1.02.\u003csup\u003e12\u003c/sup\u003e Modern techniques of IMRT could influence the risk of ORN in today\u0026rsquo;s HNC population. IMRT limits the field of radiation to a smaller, more specific area than previous radiation techniques, thus reducing the potential for patients to develop ORN. This rapidly developing field necessitates the multi-disciplinary approach to patient care and individual patient risk assessment. Cancer treatment planning, including dose, staging of tumour, site of tumour, co-morbidities and current medication review should all be included in the patient care. The need for the general dental practitioner to work alongside the oncologists, maxilla-facial surgeon and other specialists is paramount as is the need to consider patients\u0026rsquo; choices for treatment.\u003c/p\u003e \u003cp\u003eThe subgroup analyses resulted in the criterion reduction of heterogeneity for several groups in the pre-RT analyses, including more reliable estimates for SCC (2.64); 20\u0026ndash;80 Gy of 4.70; 20\u0026ndash;50 months of 4.91. This reinforces the findings that the OR of 2.77 is still reliable for the pre-RT extraction group. This represents a significant risk of patients developing ORN by a factor of 3 compared to patients who don\u0026rsquo;t undergo extractions. The impact of variable definitions of ORN could affect the pooled estimates as these minor variations in definition act as a limiting factor despite undertaking sub-group analyses. Radiation doses and follow-up variability also potentially has an effect on the pooled estimate.\u003c/p\u003e \u003cp\u003eThe cumulative analysis demonstrated the significance of time in relation to knowledge and research. The gradual reduction in risk between 2006 and 2023 was observed in all categories of extractions. This corresponds to more precise targeted delivery of radiation. The increased knowledge available over time needs to be disseminated to GDPs, so that they are operating within contemporary guidelines to offer patients the best possible care. Those guidelines need to be regularly updated to reflect the most current evidence from the literature.\u003c/p\u003e \u003cp\u003e RCS guidelines suggest that \u0026lsquo;where possible, extraction of teeth from irradiated sites should be avoided due to the risk of ORN\u0026rsquo;. Within this systematic review, chosen articles revealed a consistent lack of detail associated with the specific timing of extractions. The time interval is known to be quite important in determining whether a patient gets ORN, as it is heavily discussed in the guidelines for the oral management of oncology patients by the RCS.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The guidelines suggest that teeth with a questionable prognosis, or the teeth in the direct path of the radiation beam, should be extracted prior to RT to prevent future dental extractions. A minimum of 2\u0026ndash;3 weeks between extractions and commencement of RT should be followed as a guide.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe mechanism for diagnosing ORN within these studies has a huge impact on the outcomes of the studies. The Notani and Common Terminology Criteria for Adverse Events v5.0 (CTCAE) classifications have been mentioned for grading ORN for five of the studies (2,3,6,10,13) in which a grade of 2 or above was needed. Furthermore, four of the studies included in the analysis diagnosed ORN by an area of exposed bone for at least three months (4,5,7,9). Three studies (1,8,12) that didn\u0026rsquo;t mention how they diagnosed ORN. Considering exposed bone as the only sign of ORN could result in underestimating the real rate of ORN due to misdiagnosis. Future studies looking at the incidence of ORN will need to provide a clear definition of ORN so that results can be compared reliably.\u003c/p\u003e \u003cp\u003eAnother area where there was a lack of detail in the included studies was the number of teeth extracted, the number of sites of ORN, and whether the site of ORN was at an extraction site or not. Given the studies were mainly retrospective through reviewing patient records rather than prospective and directly involved with the patients, the detail regarding extractions and ORN was limited to the number of patients who had received extractions and number of patients who developed ORN. The lack of detail in this area puts into question the causal link between extractions and ORN, and so future studies will need this level of detail to ascertain whether a direct causal link can be found rather than just an association.\u003c/p\u003e \u003cp\u003eMany authors report that poor oral health and dental pathology predispose patients to ORN, as this is the reason why patients need to have dental extractions.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The use of screening for HNCs would seem to be a positive step forward in early diagnosis and treatment. Careful management of these patients necessitates careful planning with a multidisciplinary team (MDT) once the HNC diagnosis is known. Careful dental treatment to reduce the possibilities of bacterial infection before the beginning of RT includes periodontal and/or endodontic treatment, as well as supportive therapies like oral hygiene recalls and professional fluoride therapy. This degree of management of these patients should result in fewer extractions per patient, improved oral health, and fewer inflamed/infected foci. The role of the dental team in caring for these patients is fundamental for their long-term health and survival. Instigating regular dental visits to monitor oral health should be encouraged in this population of patients who previously have only attended sporadically.\u003c/p\u003e \u003cp\u003eCancer patients having dental extractions are at a particular risk of ORN if undertaken close to the start of RT, whether before or after.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e If tooth extractions are conducted before RT, the swift bone regeneration in the healing socket becomes vulnerable to the effects of RT. In such cases, the cancer treatment cannot be postponed until the socket has fully healed; therefore, dental professionals need to be aware of the increased risk from extractions in these patients. On the other hand, if extractions are performed after RT, they take place in an environment with impaired healing. According to Beaumont et al.\u003csup\u003e4\u003c/sup\u003e, there is no conclusive evidence to determine the optimal timing for the extraction of these compromised teeth.\u003c/p\u003e \u003cp\u003eThis current study was unable to systematically review all confounding variables between all categories of extractions because of inadequate coverage in the literature. For example, poor oral health/hygiene, tobacco and alcohol misuse, and primary wound closure of extraction sites were not consistently reported. If almost all the confounding variables are present in all categories of extractions, can there really be a case made for the timing of the extractions to be the ultimate predictor of ORN? Or are the other variables more influential?\u003c/p\u003e \u003cp\u003eThe clinical implications of this study suggest that GDPs and oncologists need to work closely when dealing with HNC patients in relation to all extractions and to decide the optimum time for said extractions in relation to RT for HNC. A team approach, which should include regular preventative oral hygiene appointments for these patients, is essential for the best possible outcome.\u003c/p\u003e \u003cp\u003eThe Newcastle-Ottawa scale indicated the selected articles were of high quality. However, it proved to have limitations as a generic scale because it didn\u0026rsquo;t consider that many of the studies were missing important clinical details such as RT technique and dosage, and follow-up time. Subgroup analysis demonstrated just how many of the articles didn\u0026rsquo;t specify these important clinical details when looking at each of the subgroups.\u003c/p\u003e \u003cp\u003eThere are some discrepancies between this study and other systematic reviews mentioned in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Beaumont et al.\u003csup\u003e4\u003c/sup\u003e concluded a slightly lower incidence of ORN from post-RT extractions compared to pre-RT extractions. Beaumont et al. \u003csup\u003e4\u003c/sup\u003e only included articles up to 2020, whereas this current study is more contemporary in including studies up to 2023. The fact that there were very little significant differences between the two studies may indicate that little research has been done in this field in the interim years. In addition, this study looked at dose of radiation, follow-up period, types of radiotherapy and type of cancer, but did not look specifically at age as Beaumont et al did. The majority of recent systematic reviews look at incidence of ORN, as their metric whereas this current study uses OR as a measure, which gives a more specific, relevant finding. The other systematic reviews mentioned in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e5\u003c/span\u003e only looked at pre-RT extractions and all infer that they present a risk factor for ORN, much like this study confirms. The inclusion of pre \u0026amp; post RT extractions in this current study given a more holistic picture of the situation, which allows governing bodies to modify their advice to practitioners based on contemporary knowledge. However, whenever both pre- and post-RT extractions are compared from Balermpas et al.\u003csup\u003e3\u003c/sup\u003e and Costa Normando et al.,\u003csup\u003e23\u003c/sup\u003e post-RT extractions are more significantly associated with ORN. Despite the heterogeneity of the six studies mentioned in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the consensus from the studies is that pre-RT extractions are potentially safer than post-RT extractions but still carry some risk of ORN; this agrees with the main finding of this current study.\u003c/p\u003e \u003cp\u003eFurther studies related to this topic should have larger sample sizes with better reporting standards, especially for the time interval between extraction and the start of RT. It would be advantageous if future studies reported on whether post-extraction sites were the location of the ORN, as opposed to just mentioning the number of patients who were diagnosed with ORN. Further studies are needed to consider the implications for ORN due to IMRT as a radiation technique. It would be helpful if a standardised definition of ORN was adopted for future research. Smoking, alcohol and poor oral health can be associated with ORN but are not reported as causative factors. Causation is possibly a factor of inadequate bone healing following radiotherapy and extractions but is not a direct causation. Future prospective studies with comprehensive data collection on patient comorbidities, oral health status, and timing of extractions are essential.\u003c/p\u003e \u003cp\u003eLimitations of this systematic review include: i) it didn\u0026rsquo;t investigate the patient\u0026rsquo;s characteristics such as gender, age, smoking status, stage of cancer, dental health, and general health, which could act as significant risk factors for the development of ORN; ii) A limited number of data bases were used; iii) there was a predominance of retrospective observational data; iv) variability in ORN definitions and diagnostic criteria; v) lack of detailed data on confounders; and vi) potential publication bias. The high degree of heterogeneity and limited data on timing of extractions relative to RT in some studies constrain definitive conclusions. The strengths of this review included: 1) a twenty-year observation period; 2) looking at studies of both pre- and post-RT extractions, as well as pre- or post-RT extractions; and 3) subgroup analysis stratified by cancer type, RT technique, RT dose, and follow-up time.\u003c/p\u003e \u003cp\u003eThis review demonstrates a limitation of the evidence available, as it is based only on observational studies that illustrate an association rather than a direct causal link.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe guidelines from the RCS about extraction of unsound teeth either prior to or after RT for HNC patients are consistent with the current available literature.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The timings of extractions could be a critical factor when considering these patients, and therefore the continued review of guidelines based on current knowledge is essential.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding Statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI and AI-assisted technologies in the writing process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work the author(s) used ChatGPT in order to convert original Harvard referencing into the Vancouver referencing style. \u0026nbsp;After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAarup-Kristensen S, Hansen CR, Forner L, Brink C, Eriksen JG, Johansen J. 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Strahlenther Onkol. 2022;198(3):219\u0026ndash;228.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeaumont S, Bhatia N, McDowell L, Fua T, McCullough M, Celentano A, et al. Timing of dental extractions in patients undergoing radiotherapy and the incidence of osteoradionecrosis: a systematic review and meta-analysis. British Journal of Oral and Maxillofacial Surgery. 2021;59(5):511\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeech NM, Porceddu S, Batstone MD. Radiotherapy-associated dental extractions and osteoradionecrosis. Head Neck. 2017;39(1):128\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBen-David MA, Diamante M, Radawski JD, Vineberg KA, Stroup C, Murdoch-Kinch CA, et al. 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Support Care Cancer. 2022;30(11):8745\u0026ndash;8759. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00520-022-07215-y\u003c/span\u003e\u003cspan address=\"10.1007/s00520-022-07215-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2022 Jun 17. PMID: 35713725.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShih YJ, Huang JY, Lai YC, Lin HM, Kuo TJ. Tooth extraction within 2 weeks before radiotherapy and osteoradionecrosis: a nationwide cohort study. Oral Dis. 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlettvoll S, Thaning RC, Pedersen T\u0026Oslash;. Tooth extraction prior to radiotherapy for oropharyngeal cancer increases the risk of osteoradionecrosis. J Oral Sci. 2023;65(2):87\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun H, Yu M, An Z, Liang F, Sun B, Liu Y, Zhang S. 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Dental Evaluation Prior to Cancer Therapy. Front Oral Health. 2022;3:876941. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/froh.2022.876941\u003c/span\u003e\u003cspan address=\"10.3389/froh.2022.876941\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 35510226; PMCID: PMC9058061..\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZehr LJ, Cooper JS. Mandible Osteoradionecrosis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"british-dental-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bdj","sideBox":"Learn more about [British Dental Journal](http://www.nature.com/bdj/)","snPcode":"41415","submissionUrl":"https://mts-bdj.nature.com/cgi-bin/main.plex","title":"British Dental Journal","twitterHandle":"@the_bdj","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8796363/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8796363/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Head and Neck Cancer (HNC) patients have a risk of developing osteoradionecrosis (ORN) following radiotherapy (RT). Dental extractions are a recognised risk factor. The primary aim of this systematic review was to estimate the risk associated with pre-RT extractions. The secondary aim was to investigate the risk associated with post-RT extractions and both pre- and post-RT extractions in the studies identified.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA systematic review was conducted using a PRISMA protocol. Electronic searches of Cochrane Library and OVID via Medline were undertaken between 2002-2023. Data extraction from the studies related to incidence of ORN and type of extraction was conducted by the authors to produce odds ratio values (OR) for each study and type of extraction. A meta-analysis was performed using a random effects model. Heterogeneity was investigated by sub-group analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings:\u003c/strong\u003e\u0026nbsp; Thirteen articles were included in this review. The odds ratio (OR) values for ORN following RT was calculated for each study, dependent on the type of extraction. Substantial heterogeneity was observed (I\u003csup\u003e2\u003c/sup\u003e=62.1%(p=0.002)) for the Pre-RT analyses but not for the post-RT and both types of extractions.\u003c/p\u003e\n\u003cp\u003eIn the presence of this heterogeneity, an increased risk of ORN following pre-RT extractions was observed (OR= 2.77, 95% CI = 1.66-4.62). There was an increased risk of ORN associated with post-RT extractions (OR = 4.19, 95% CI = 2.917-8.08) and Both extractions (OR=7.96, 95% CI = 3.91,16.20). Subgroup analyses corroborated these findings.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study population attributable risk for the association of Pre-RT extractions with ORN is 28.53%(95%CI:21.34,31.73)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation: \u003c/strong\u003eThis review suggests that Pre-RT extractions increase the risk of ORN compared to no extractions. Post-RT and both extractions further increase the risk of ORN. This supports current RCS guidelines.\u003c/p\u003e","manuscriptTitle":"The Risk of Osteoradionecrosis Associated With Dental Extractions Prior to Radiotherapy: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-19 09:09:20","doi":"10.21203/rs.3.rs-8796363/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T15:26:22+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-17T17:09:48+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-19T18:11:00+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-19T17:13:34+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-19T16:57:50+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-02-12T08:16:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-10T16:31:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-10T16:31:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"British Dental Journal","date":"2026-02-10T09:12:06+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2026-02-05T14:00:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"british-dental-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bdj","sideBox":"Learn more about [British Dental Journal](http://www.nature.com/bdj/)","snPcode":"41415","submissionUrl":"https://mts-bdj.nature.com/cgi-bin/main.plex","title":"British Dental Journal","twitterHandle":"@the_bdj","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1a18e66c-77df-4654-8c22-ab7be482659b","owner":[],"postedDate":"February 19th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T15:26:22+00:00","index":3,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":62683096,"name":"Health sciences/Diseases"},{"id":62683097,"name":"Health sciences/Diseases/Cancer/Oral cancer"},{"id":62683098,"name":"Health sciences/Health care/Dentistry/Oral medicine/Orofacial pain"}],"tags":[],"updatedAt":"2026-02-19T09:09:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-19 09:09:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8796363","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8796363","identity":"rs-8796363","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}