Osteoradionecrosis of mandible bone in patients with oral cancer Associated factors and treatment outcomes

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1 ORIGINAL ARTICLE Osteoradionecrosis of mandible bone in patients with oral cancer Associated factors and treatment outcomes Jyun-An Chen, MD, 1 Chen-Chi Wang, MD, 1,4 Yong-Kie Wong, BDS, MSc, 2 Ching-Ping Wang, MD, 1 Rong-San Jiang, MD, PhD, 1 Jin-Ching Lin, MD, PhD, 3,4 Chien-Chih Chen, MD, 3 Shih-An Liu, MD, PhD 1,4 * 1 Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan, 2 Department of Oral and Maxillofacial Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, 3 Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan, 4 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Accepted 10 December 2014 Published online 20 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to investigate factors associated with osteoradionecrosis (ORN) of the mandible bone in a large cohort of patients with oral cancer. Methods. We reviewed the medical records of patients with oral cancer and identified those with ORN of the mandible bone. Variables of patients with and without ORN were compared and associated factors were investigated by logistic regression model. Results. A total of 1692 patients were included in the final analysis and 105 patients (6.2%) developed ORN in the mandible bone. Primary site, including mouth floor, buccal mucosa, retromolar trigone, or gum, segmental mandibulectomy, and total radiation dose to the primary site 75 Gy were independent factors associated with ORN. After aggressive treatment using surgical intervention with/without hyperbaric oxygen, 93.3% of the patients healed completely. Conclusion. Among patients with oral cancer after radiation, ORN is an uncommon and dreaded complication. Recognition of associated factors can help physicians to identify those at risk. VC 2015 Wiley Periodicals, Inc. Head Neck 38: , 2016 KEY WORDS: oral cancer, osteoradionecrosis, irradiation, surgery, logistic regression model *Corresponding author: S.-A. Liu, Department of Otolaryngology, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Taichung 40705, Taiwan. saliu@vghtc.gov.tw Contract grant sponsor: The study was partially supported by grants from Taichung Veterans General Hospital (TCVGH C), Taichung, Taiwan, Republic of China. INTRODUCTION Osteoradionecrosis (ORN) is one of the most serious complications in patients with head and neck cancer after radiation therapy. 1 It is a region of exposed necrotic bone without mucosal coverage in the maxillary or mandibular alveolar process that fails to heal after 3 months. 2 The etiology of ORN has been thought to be an avascular necrosis induced by the effects of radiation to the bone. Hypoxia, hypovascularity, and hypocellularity occur when bone is exposed to radiation. 3 In the past decade, radiation-induced fibrosis (RIF), an irreversible pathological process, was also proposed to play a crucial role in the progress of ORN. 4 The reported incidences of ORN of the mandible ranged from 1% to 30% in recent studies. 1,3,5,6 At present, there is no consensus on the optimal management of ORN. The treatment protocol varied from local wound care, empiric antibiotic, and hyperbaric oxygen (HBO) to more aggressive resection of diseased tissues plus freetissue transfer. Few prospective randomized controlled trials of ORN management have been conducted. Therefore, there is scant scientific evidence for management of ORN in the literature. 7 Several risk factors of ORN have been reported, including tumor site, 4,8,9 tumor stage, 4,5,9,10 radiation dose, 1,4,8 11 type of radiation, 8,10,12 fractionation of radiation, 8,10,11 bone invasion, 8,9,11 old age, 9,13 sex, 3,8,9 malnutrition, 4 smoking, alcohol consumption, 5,8 10 chronic renal failure under hemodialysis, 13 neck surgery, 1,9 infection, 3,4 dental extraction, 4,5,8 10,13 periodontal disease, 3,10 and type of mandibular resection. 4,5,10 However, most of the studies reporting such risk factors only included patients with ORN for final analysis. Few studies included a large population of patients with oral cancer and used a logistic regression model for risk factors analyses. Therefore, the purpose of this study was to investigate the factors associated with ORN of the mandible in a large cohort of patients with oral cancer. We also examined patients with ORN undergoing treatment and assessed their outcomes. PATIENTS AND METHODS This study protocol was approved by the Institutional Review Board of Taichung Veterans General Hospital. We retrospectively reviewed over 2000 medical records of patients with oral cancer diagnosed in our hospital 762 HEAD & NECK DOI /HED MAY 2016

2 OSTEORADIONECROSIS AND ORAL CANCER from January 2001 to December The follow-up endpoint was set as December Clinical treatments were according to the consensus guideline of the head and neck cancer team of our hospital. All patients underwent a complete dental assessment by dentists and those with poor dentition received dental extraction before radiotherapy. All patients were treated with intensitymodulated radiotherapy using conventional fractionation. Patients who were lost to follow-up, had received treatment at other institutes, had incomplete medical records, or were under oral bisphosphonates treatment for osteoporosis were excluded from this study. All patients were restaged according to the guidelines of the American Joint Committee on Cancer. Basic demographic data, including age, sex, and tumor-related features were collected. In addition, therapeutic protocols, including type of mandible resection, total radiation dose to the primary site, and re-irradiation, were also recorded. In present study, we defined ORN as loss of mucosal coverage and exposure of the mandible bone for more than 3 months. Patients with pathological proof of tumor recurrence were not regarded as having ORN. We used the Schwartz and Kagan staging system for evaluation of ORN status. 7 We used descriptive statistics for general data presentation. Comparisons of nominal or ordinal variables between subgroups were analyzed by chi-square test or Fisher s exact test, whereas continuous variables were examined by 2-tailed Student s t test. In addition, we used a receiver operating characteristic (ROC) curves to identify a proper cutoff point for the continuous variables at which to divide the patients into 2 groups. Furthermore, stepwise backward logistic regression was used to determine correlations between the presence of ORN and the variables. The logistic regression model was then adjusted for age and sex. All statistical analyses were performed using SPSS for Windows, version 12.1 (SPSS, Chicago, IL), and a p value <.05 was regarded as statistically significant. RESULTS From January 2001 to December 2011, a total of 2103 patients with oral cancer who received treatment in our institute were identified. Two hundred forty-seven patients (11.7%) received surgical intervention alone. In addition, 63 patients (3.0%) were referred from other institutes because of residual or recurrent diseases, 42 patients (2.0%) were lost to follow-up after completion of cancer therapy, 39 patients (1.9%) had incomplete medical records, and 20 patients (1.0%) were under oral bisphosphonates treatment for osteoporosis. Adequate data were obtained from the medical records of 1692 patients. The average age at diagnosis was 52.1 (611.1) years and men accounted for 93.1% (n ) of the studied population. The average follow-up period was 36.8 (616.4) months. The majority of patients had their primary in the oral cavity (n ; 86.8%) whereas 223 patients (13.2%) had their primary in the oropharynx. The detailed descriptions of primary sites are listed in Table 1. Most of the patients presented with stage IV diseases (n ; 68.2%), whereas stages I, II, and III diseases accounted for 6.1% (n 5 103), 16.8% (n 5 285), and 8.9% (n 5 150) of patients, respectively. More than half of the patients (n 5 922; 54.5%) underwent surgical intervention, whereas the remainder (n 5 770; 45.5%) received radiation therapy as their initial treatment modality. Four hundred eighty-one patients (28.4%) developed recurrent or second primary diseases during the follow-up period. Among them, 206 patients (42.8%) received salvage surgery and 328 patients (68.2%) had reirradiation. The average total dose to the primary site was Gy. The descriptive analyses are presented in Table 1. ORN was identified in 105 patients (6.2%) during the follow-up period. Based on the Schwartz and Kagan classification, over half of them were stage II (n 5 53; 50.5%), whereas 23 patients (21.9%) were stage I and 29 patients (27.6%) were stage III. The average age at diagnosis of ORN was years. The majority of patients were men (n 5 101; 96.2%). The average duration from the completion of last radiation to diagnosis of ORN was months. Most of the patients with ORN (n 5 86; 81.9%) underwent surgical intervention, whereas 19 patients (18.1%) received HBO as their first treatment. After initial treatment, 24 patients (22.9%) had persistent disease and further surgical intervention or HBO treatment session was arranged. Finally, 7 patients (6.7%) still had ORN at the end of follow-up. When stratifying patients based on the presence or absence of ORN, there were no statistically significant differences in sex, tumor stage, diabetes mellitus, hypertension, chronic renal failure under hemodialysis, bone invasion, treatment modalities, and chemotherapy between the 2 groups. However, patients with ORN tended to be younger (49.7 vs 52.3 years; p 5.021) and had higher body mass index (BMI; 24.5 vs 23.8 kg/m 2 ; p 5.017) when compared with those without. In addition, patients with ORN received higher total radiation dose to the primary site than those without (87.4 vs 64.6 Gy; p <.001). The rate of ORN was highest in patients with mouth floor cancers (11.8%) followed by those with buccal cancers (9.0%). Patients who underwent segmental mandibulectomy had a highest ORN rate (16.7%) when compared with those without mandibulectomy (3.7%) and those who received marginal (8.2%) or hemimandibulectomy (10.9%; p <.001). Detailed data are shown in Table 1. When patients with ORN were stratified according to the initial treatment modality, there were no significant differences between the 2 groups in age, sex, BMI, total radiation dose to the primary site, primary tumor site, and tumor stage. However, as the Schwartz and Kagan stage increased, the proportion of patients receiving HBO declined. Besides, a higher percentage of patients who underwent HBO had persistent disease when compared with that of patients who underwent surgical intervention as their initial treatment (63.2% vs 14.0%; p <.001). Overall, 98 patients underwent surgical intervention. Among them, 65 patients (66.3%) received simple debridement and 33 patients (33.7%) received pedicled or free flap reconstruction. Detailed data are shown in Table 2. ROC curve was used to identify a proper cutoff point for the continuous variables at which to divide the cases into 2 groups for each factor (BMI 24 kg/m 2 and HEAD & NECK DOI /HED MAY

3 CHEN ET AL. TABLE 1. Descriptive and bivariate analyses of patients with oral cancer with and without osteoradionecrosis after radiation. Variables Total no. of patients (% in column) No. of patients (%) ORN (n 5 105) Without ORN (n ) p value Age at diagnosis, y BMI, kg/m Radiation dosage to the primary site, Gy <.001 Sex.282* Female 116 (6.9) 4 (3.4%) 112 (96.6%) Male 1575 (93.1) 101 (6.4%) 1475 (93.6%) Primary tumor sites <.001 Lip 58 (3.4) 4 (6.9%) 54 (93.1%) Gingiva 136 (8.0) 11 (8.1%) 125 (91.9%) Mouth floor 51 (3.0) 6 (11.8%) 45 (88.2%) Tongue 442 (26.1) 24 (5.4%) 418 (94.6%) Buccal mucosa 589 (34.8) 53 (9.0%) 536 (91.0%) Palate 151 (8.9) 1 (0.7%) 150 (99.3%) Retromolar trigone 35 (2.1) 3 (8.6%) 32 (91.4%) Tonsil 165 (9.8) 3 (1.8%) 162 (98.2%) Tongue base 63 (3.7) 0 (0%) 63 (100%) Posterior pharyngeal wall 2 (0.1) 0 (0%) 2 (100%) Tumor stage.767 I 103 (6.1) 6 (5.8%) 97 (94.2%) II 285 (16.8) 14 (4.9%) 271 (95.1%) III 150 (8.9) 9 (6.0%) 141 (94.0%) IV 1154 (68.2) 76 (6.6%) 1078 (93.4%) Diabetes mellitus.749 No 1047 (83.2) 89 (6.3%) 1318 (93.7%) Yes 285 (16.8) 16 (5.6%) 269 (94.4%) Hypertension.571 No 1241 (73.7) 80 (6.4%) 1161 (93.6%) Yes 451 (26.7) 25 (5.5%) 426 (94.5%) Hemodialysis.385* No 1637 (96.7) 100 (6.1%) 1537 (93.9%) Yes 55 (3.3) 5 (9.1%) 50 (90.9%) Bone invasion.076 No 1289 (76.2) 72 (5.6%) 1217 (94.4%) Yes 403 (23.8) 33 (8.2%) 370 (91.8%) Treatment modalities.075 Surgery then radiation 922 (54.5) 68 (7.4%) 854 (92.6%) Radiation then surgery 206 (12.2) 8 (3.9%) 198 (96.1%) Radiation alone 564 (33.3) 29 (5.1%) 535 (94.9%) Chemotherapy.680 No 766 (45.3) 45 (5.9%) 721 (94.1%) Yes 926 (54.7) 60 (6.5%) 866 (93.5%) Mandibulectomy <.001 No 902 (53.5) 33 (3.7%) 869 (96.3%) Marginal 672 (39.7) 55 (8.2%) 617 (91.8%) Segmental 72 (4.3) 12 (16.7%) 60 (83.3%) Hemi 46 (2.7) 5 (10.9%) 41 (89.1%) Reirradiation.002 No 1364 (80.6) 72 (5.3%) 1292 (94.7%) Yes 328 (19.4) 33 (10.1%) 295 (89.9%) Edentulous status.795* No 1626 (96.1) 102 (6.3%) 1524 (93.7%) Yes 66 (3.9) 3 (4.5%) 63 (95.5%) Extraction after radiation.889 No 1561 (92.3) 96 (6.1%) 1465 (93.9%) Yes 131 (7.7) 9 (6.9%) 122 (93.1%) Abbreviations: ORN, osteoradionecrosis; BMI, body mass index. * Fisher s exact test. <24 kg/m 2, total radiation dose to the primary site 75 Gy and <75 Gy). Those curves were drawn according to the sensitivity and specificity with which the variables could discriminate the development of ORN. The longitudinal axis represents sensitivity whereas the horizontal axis represents 1 specificity (see Figure 1). The area 764 HEAD & NECK DOI /HED MAY 2016

4 OSTEORADIONECROSIS AND ORAL CANCER TABLE 2. Descriptive and bivariate analyses of patients with osteoradionecrosis stratified according to initial treatment modalities. Variables Total no. of patients (% in column) No. of patients (%) HBO (n 5 19) Surgical intervention (n 5 86) p value Age at diagnosis, y BMI, kg/m Radiation dosage to the primary site, Gy Sex.149* Female 4 (3.8) 2 (50.0%) 2 (50.0%) Male 101 (96.2) 17 (16.8%) 84 (83.2%) Primary tumor sites.453 Lip 4 (3.8) 1 (25.0%) 3 (75.0%) Gingiva 11 (12.6) 3 (27.3%) 8 (72.7%) Mouth floor 6 (5.7) 1 (16.7%) 5 (83.3%) Tongue 24 (22.9) 4 (16.7%) 20 (83.3%) Buccal mucosa 53 (50.5) 8 (15.1%) 45 (84.9%) Palate 1 (1.0) 0 (0%) 1 (100%) Retromolar trigone 3 (2.9) 0 (0%) 3 (100%) Tonsil 3 (2.9) 2 (66.7%) 1 (33.3%) Tumor stage.673 I 6 (5.7) 0 (0%) 6 (100%) II 14 (13.3) 3 (21.4%) 11 (78.6%) III 9 (8.6) 2 (22.2%) 7 (77.8%) IV 76 (72.4) 14 (18.4%) 62 (81.6%) Schwartz and Kagan classification of ORN <.001 I 23 (21.9) 14 (60.9%) 9 (39.1%) II 53 (50.5) 5 (9.4%) 48 (90.6%) III 29 (27.6) 0 (0%) 29 (100%) Persistent diseases after initial treatment <.001* No 81 (77.1) 7 (8.6%) 74 (91.4%) Yes 24 (22.9) 12 (50.0%) 12 (50.0%) Abbreviations: HBO, hyperbaric oxygen; BMI, body mass index; ORN, osteoradionecrosis. * Fisher s exact test under ROC curves for BMI and total radiation dose to the primary site were and 0.652, respectively. The sensitivity and specificity of variables were calculated and the cutoff point was chosen when the sensitivity and specificity were both as high as possible (Table 3). Then, a stepwise backward logistic regression model was applied to determine the factors associated with ORN. Table 4 shows that primary tumor site at the gum, mouth floor, buccal mucosa, or retromolar trigone (odds ratio [OR] ; 95% confidence interval [CI] ; p <.001), segmental mandibulectomy (OR ; 95% CI ; p <.001), and total radiation dose to the primary site 75 Gy (OR ; 95% CI ; p <.001) were independent factors associated with development of ORN. size, primary site of tumor, observation periods, and type of radiation delivered, the incidence of ORN varied widely in the literature. 1 A previous animal study using miniature pigs that underwent irradiation and tooth extraction found that DISCUSSION The clinical presentation of ORN varied from asymptomatic bony exposure to erythematous change, purulent discharge, and intractable pain. 3 The incidence of ORN of the mandible was reported to be as high as 56% in the past decades. 6 However, because of the advancements in the radiation techniques, the incidence of ORN has dropped to 10% or less according to recent publications. 1,5,6 In the present study, 6.2% of patients with oral cancer who underwent radiation therapy developed ORN in the mandible during the follow-up period. However, because of dissimilar populations, including the cohort FIGURE 1. Receiver operator characteristic curves for cutoff analysis of body mass index (BMI) and total radiation dose to the primary site in patients with osteoradionecrosis. The area under the curve is for BMI and for total radiation dose to the primary site. HEAD & NECK DOI /HED MAY

5 CHEN ET AL. TABLE 3. Statistical parameters associated with osteoradionecrosis calculated using different cutoff values. Statistical parameter by BMI cutoff, kg/m 2 Statistical parameter by TRD cutoff, Gy Sensitivity (%) Specificity (%) Abbreviation: BMI, body mass index; TRD, total radiation. decreased local blood flow and resultant hypovascularity may have caused an imbalance in mandible bone remodeling. 14 A study of irradiated rats indicated that hypocellularity, hypoxia, and oxidative stress were higher in the irradiated mandible than the tibia and the combination of radiation plus minor trauma promoted mandibular alveolar bone loss. 15 Bone remodeling involves a balance between osteoclast resorption and osteoblast construction. 14 Radiation promotes release of free radicals that play crucial parts in radiation-induced cell death and delayed healing by reducing production of osteoprogenitor cells while stimulating osteoclast proliferation. 15 In addition, radiation-inhibited proliferation and differentiation of existing mesenchymal stem cells and osteoprecursor cells into osteoblast cell lineages. Furthermore, the radiation effects on osteoblast differentiation were dosedependent. 14 RIF, which can cause irreversible damage after radiotherapy, was thought to play a crucial role in the pathophysiology of ORN in recent years. As the radiation doses increased, the impacts of RIF on ORN may be stronger. 4 It is therefore not surprising that higher radiation dose could render the mandible bone more vulnerable to ORN. Although reirradiation and total radiation dose to the primary were both associated with a greater risk of ORN in a bivariate analysis, we found that total radiation dose to the primary site showed the strongest association with ORN in the logistic regression model. Using ROC curves analysis, we further identified a total radiation dose to the primary site of 75 Gy was the best cutoff point to estimate the risk of ORN. To the best of our knowledge, the present study is the first study to investigate associated factors of ORN of the mandible using logistic regression analysis in a large cohort of patients with oral cancer who had undergone radiation therapy. We found total radiation dose to the primary site was the most important factor related to ORN in patients with oral cancer. Patients who received a total radiation dose of equal to or more than 75 Gy to the primary had an 8-fold increased risk of developing ORN in the mandible. Chang et al 16 found that patients who received a dose of more than 70 Gy were at a greater risk of developing ORN. Lee et al 17 indicated that a conventional dose of more than 54 Gy at 1.8 Gy per fraction was a significant factor for development of ORN in multivariate analysis. A systematic review found that extraction of mandibular teeth within the radiation field in patients who received a radiation dose of more than 60 Gy posed the highest risk for development of ORN. 18 The differences in findings TABLE 4. Factors associated with osteoradionecrosis based on logistic regression model. Variables No. of patients (N ) OR p value Lower limit 95% CI Upper limit Age, y.240 <40* Sex Female* Male BMI, kg/m 2 <24* Primary tumor site Gum, mouth floor, buccal mucosa, or retromolar trigone < Others* Mandibulectomy.001 No* Marginal Segmental < Hemi Total radiation dose to the primary site <75 Gy* Gy < Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval; BMI, body mass index. * Reference group. 766 HEAD & NECK DOI /HED MAY 2016

6 OSTEORADIONECROSIS AND ORAL CANCER between our study and abovementioned studies could be due to the diverse studied populations. These studies included a variety of patients with head and neck cancer, whereas our study included only patients with oral cancer. In addition, the radiation techniques were dissimilar. Our patients were all treated with intensity-modulated radiotherapy using conventional fractionation, whereas the abovementioned studies used Cobalt-60 and/or linear accelerator with various techniques, such as hyperfraction, brachytherapy, or accelerated fraction. The type of mandible surgery was the second most important factor related to ORN in our study. 2,4,5 Monnier et al 9 found that mandibular surgery before radiation was the only independent risk factor for developing ORN in multivariate analysis. Lee et al 17 in their study of patients with oropharyngeal cancer also indicated that mandibular surgery was the most significant risk factor for ORN. The compact nature of the mandible bone and the fact that its main blood supply is from the inferior alveolar artery makes it more vulnerable to ORN after mandibular surgery. 3 This could explain why in the current study we found that patients who received segmental mandibulectomy had a more than 4-fold increased risk of developing ORN when compared to those without mandibular surgery. Our study showed that the incidences of ORN after radiation were higher in patients with primary in mouth floor, buccal, retromolar trigone, and gum regions. A previous systemic review also indicated that patients with oral cavity cancers, especially of the tongue, floor of mouth, alveolar ridge, or retromolar trigone region, had a higher risk of developing ORN after radiation. 8 These cancer sites all included the mandible in the field of radiation. This explains why patients with primary sites at mouth floor, gum, buccal mucosa, and retromolar trigone region had a 2.5-fold increased risk of developing ORN in our study. Dental status has long been considered as a risk factor of ORN in patients receiving radiation. 1 5 Patients who need dental extractions after radiation might have delayed wound healing. Such a population was also more prone to have poor dental hygiene, thereby increasing the possibility of development of ORN. 1 However, our study failed to demonstrate such relationships between ORN and extraction after radiation or edentulous status. Careful oral and dental evaluation and systematic dental hygiene performed routinely before and after radiation might reduce the risk of developing ORN. 9 Our institute avoided dental extraction within 2 years after radiation as the average duration between radiation and dental extraction was 27.3 months (range months). A recent systematic review found the incidence of ORN after postirradiation dental extractions was low. The highest risk of developing ORN was in patients who received a radiation dose of more than 60 Gy and had teeth extracted within the radiation field. 18 In the management of ORN, no general consensusbased clinic-therapeutic protocol has been established to treat this serious condition. 2 Our study revealed a low success rate of HBO as an initial treatment (7 of 19; 36.8%), and over half of the patients needed further surgical intervention. After surgical intervention with/without HBO, the majority of patients (98 of 105; 93.3%) were free of ORN. In their review article, Jacobson et al 7 also found that high success rates were achieved by aggressive surgical intervention and microvascular reconstruction with or without HBO. However, most of the published studies represented nothing more than a particular surgeon s practice or an institutional experience. Further randomized control trials are warranted to elucidate the treatment benefits of different types of managements. Although smoking, alcohol consumption, 5,8 chemotherapy, 8 bone invasion, 9 BMI, 10 chronic renal failure under hemodialysis, 13 and tumor stage 5,8 have been reported to be related to ORN, no such association was found in our study possibly because of the difference in study populations. Dissimilar patients with head and neck cancer, different types and techniques, and diverse health and social environments make the comparisons more difficult. Some studies found that periodontitis, 8,10 malnutrition, 4 irradiated volume of the mandible, 11 and poor oral hygiene 10 were related to development of ORN. However, we did not collect relevant data so no comparisons among these factors could be made. Actually, nutritional status and oral hygiene are somewhat difficult to evaluate, and continuous assessment of these health care concerns is hard to implement. A major strength of the present study was the enrollment of a large population of patients with oral cancer in a single hospital (tertiary referral center). However, there were several limitations in our study. First, we could retrieve data on the total dose delivered to the primary site from the summary of radiation note but the note did not include the maximum/mean dose to the mandible, which might more accurately represent the radiation damage to the mandible. Second, although treatment guidelines are standardized at our institute, individual variations among surgeons likely exist. Last, the extent to which our findings can be generalized to other populations may be limited because this study was conducted at a single institute. CONCLUSIONS ORN remains a severe complication with a prevalence rate of 6.2% in patients with oral cancer who have undergone radiation. Patients with primary site at the mouth floor, buccal mucosa, retromolar trigone, or gum, received segmental or marginal mandibulectomy, or received a total radiation dose equal to or more than 75 Gy to the primary site, were at significantly greater risk of developing ORN. Recognition of associated factors can help physicians to identify those at risk. Acknowledgment The authors thank the Biostatistics Task Force of Taichung Veterans General Hospital for assistance with statistical analysis. REFERENCES 1. Tsai CJ, Hofstede TM, Sturgis EM, et al. Osteoradionecrosis and radiation dose to the mandible in patients with oropharyngeal cancer. Int J Radiat Oncol Biol Phys 2013;85: Silvestre Rangil J, Silvestre FJ. Clinico-therapeutic management of osteoradionecrosis: a literature review and update. Med Oral Patol Oral Cir Bucal 2011;16:e900 e Abughazaleh K, Kawar N. Osteonecrosis of the jaws: what the physician needs to know: practical considerations. 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