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ORIGINAL ARTICLE
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Osteoradionecrosis of the jaws: A retrospective cohort study


1 Department of Dental and Prosthetic Services, Tata Memorial Hospital, TMC; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
2 Department of Dental and Prosthetic Services, Tata Memorial Hospital, TMC; Homi Bhabha National Institute (HBNI); Fellowship in Dental and Prosthetic Oncology, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Dental and Prosthetic Services, Tata Memorial Hospital, TMC; Homi Bhabha National Institute (HBNI); Fellowship in Dental and Prosthetic Oncology, Homi Bhabha National Institute University, Mumbai, Maharashtra, India
4 Homi Bhabha National Institute (HBNI); Fellowship in Dental and Prosthetic Oncology, Homi Bhabha National Institute University; Department of Dental and Prosthetic Services, Tata Memorial Centre-Advanced Centre for Treatment, Research and Education in Cancer (TMCACTREC), TMC, Mumbai, Maharashtra, India
5 Dental Department, The Sultans Special Force Medical Centre, Azaiba Garisson, Muscat, Sultanate of Oman
6 Homi Bhabha National Institute (HBNI); Professor, Department of Radiation Oncology, Tata Memorial Hospital, TMC, Mumbai, Maharashtra, India

Date of Submission29-Feb-2020
Date of Decision07-May-2020
Date of Acceptance04-Sep-2020
Date of Web Publication05-Aug-2021

Correspondence Address:
Madhura R Sharma,
Department of Dental and Prosthetic Surgery, HBB-217, Tata Memorial Hospital, Parel, Mumbai -400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_248_20

 > Abstract 


Introduction: Radiotherapy (RT) combined with chemotherapy and surgery is the indicated treatment for head and neck cancers. Even with the advent of modern technological advances in RT and improved oral hygiene awareness, osteoradionecrosis (ORN) still remains as one of the most debilitating side effects of RT.
Methodology: This is a retrospective review assessing 72 patients aged over 18 years of age reporting in the Dental Department, for treatment of ORN from April 2010 to July 2019. Each patient was clinically examined and treated according to standard protocol. The stage of ORN was noted at the diagnosis and at follow-up. The demographic data, the tumor characteristics, and the treatment of patients were evaluated using descriptive statistics.
Results: At the time of diagnosis, 84.7% of the study population was found to have Epstein Type II chronic persistent nonprogressive lesions and 11.1% of the cohort had Type III active progressive lesions. Statistically significant correlation (P = 0.00) was found for ORN grade at diagnosis and at follow-up. ORN being a chronic pathology, stabilization of the disease was observed in 72.3% of cases. The resolution of the necrotic lesion and down staging of the disease was seen only in 2.8% of patients.
Conclusion: ORN is mainly a chronic long standing pathology which is difficult to treat completely. Stabilization of symptoms and preventing further spread of the necrotic lesion should be the ultimate aim of the treatment to improve the quality of life of the patients.

Keywords: Head and neck cancers, jaw necrosis, mandible, maxilla, osteoradionecrosis, radiation therapy



How to cite this URL:
Dholam KP, Sharma MR, Gurav SV, Singh GP, Sadashiva KM, Laskar SG. Osteoradionecrosis of the jaws: A retrospective cohort study. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=323242




 > Introduction Top


Radiotherapy (RT) combined with chemotherapy and surgery is the indicated treatment for head and neck cancers (HNCs). The risk of osteoradionecrosis (ORN) increases with radiation dosages above 6000 cGy, previous cancer resection, advanced dental disease status, and postradiation dental extractions. [1,2]

Even with the advent of modern technological advances in RT like Intensity Modulated RT (IMRT) and Three-Dimensional Conformal RT (3DCRT) along with improved oral hygiene awareness, ORN still remains as one of the most debilitating side effect of RT. A systematic review by Nabil in 2012 concluded that an estimated 2.04% of the head and neck–irradiated patients are at risk of developing ORN as compared to the previous 4.74%–37.5%.[3] ORN has a significant variation in the incidence rates and clinical presentation.

In India, HNCs consist of 30% of all cancers.[4] However, there is a paucity of data on ORN from India. This is a retrospective study of details of causes, treatment and progress of 72 HNC patients with ORN.

Aims/objectives

Primary objectives of the study were

  1. To assess the demographic data, identify the tumor characteristics and the treatment of patients reporting with ORN in the dental department
  2. To evaluate the oral status, oral habits, symptomatology, stage and site of ORN in the affected patients.


Secondary objectives were

  1. To compare the stage at diagnosis and the stage at follow-up according to Epsteinclassification
  2. To co-relate factors such as gender, age distribution, type of radiation, the dose of radiation, and site of radiation to the most common stage of ORN with other stages.



 > Methodology Top


A retrospective cohort study was conducted on patients who were diagnosed with ORN in the Department of Dental and Prosthetic Surgery at Tata Memorial Hospital, Mumbai. Patients treated for ORN, from April 2010 to July 2019 were included. This study was a retrospective audit; involving no direct contact with the patient. All data were retrieved from Electronic Medical Record (EMR) and data analysis was carried out as per hospital institutional ethics committee protocol. Each patient was clinically examined and treated according to standard protocol. The stage of ORN was noted at the present stage as well as on the follow-up of three monthly intervals. A case report form was obtained for each patient with the details being recorded from the EMR, files, radiographic findings, histological examinations, photographs. The details regarding the demography, symptoms, pathology, stage, and treatment plan were also recorded.

Inclusion criteria

  • Patients with primary or recurrent head and neck tumors who received RT in definite or adjuvant setting with/without chemotherapy
  • Patients with denuded bone in the oral cavity for a period of more than 3 months.


Exclusion criteria

  • Patients with use of antiresorptive drugs before, during or after tumor therapy.


The data was evaluated for the mean age and to determine the male:female predilection for ORN. Any comorbid factors such as diabetes mellitus (DM), hypertension, cardiac ailments, hypothyroidism and/or hyperthyroidism were recorded. Habits such as alcohol, tobacco and smoking were studied to correlate any significance with the disease. General oral health was graded as good, fair or poor on clinical examination to help in further correlation with the disease and the treatment. The diagnosis and selection of treatment of ORN depends on the clinical presentation of the extent of lesion. Hence, the total population was categorized according to Epstein classification into Type I, Type II, and Type III [Table 1].[5] This classification was further divided into subgroups (a) without pathological fracture and (b) with pathological fracture. The standard treatment protocol was followed for each patient. The patients were followed up at 3 monthly intervals. The descriptive analysis of observed data was done.
Table 1: Epstein clinical classification and treatment of osteoradionecrosis[5]

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Statistical analysis

Demographic and clinical data were entered into SPSS version 25 (SPSS Inc., Chicago, IL, USA) with descriptive statistics being used to measure median and frequencies for categorical variables. Potential prognostic variables assessed by Chi-square test for significance on univariate analysis included tumor related factors, treatment-related factors and possible triggering factors influencing ORN. The analysis was also carried out to evaluate the correlation between grade at diagnosis and at follow-up; tumor laterality, site of radiation and site of ORN; median period of months since diagnosis to follow-up in months; to correlate duration of RT to extraction post RT and occurrence of ORN; correlation between grade of ORN. Further analysis was done to find correlation between most common type at diagnosis and total radiation dose received, occurrence of ORN since time period of extraction, type of radiation, with surgery, status of oral hygiene, gender, and age groups was noted.


 > Results Top


A total of 72 cases were recorded with confirmed ORN diagnosis. At the time of diagnosis, 84.7% of the study cohort was found to have Epstein type II chronic persistent non-progressive lesions while 11.1% had type I active progressive lesions.

Demographic data

Out of 72 patients, 56 (77.8%) were male and 16 (22.2%) were female patients with age range 28–84 years and the mean age was 57. The comorbidities like DM 11.2% and thyroid disorders 18.2% were present. The oral habits in the form of smoked or smokeless tobacco before and/or after the cancer treatment were noted in 52.8% of the total population. [Table 2] elaborates demographic details, other comorbidities and types of tobacco used by the study population. The oral hygiene condition was poor (multiple carious teeth and periodontal compromised teeth) in 52.8% and fair (2–3 carious teeth and mild gingival inflammation) in 47.2% of the study population.
Table 2: Demographic data

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Tumor-related factors

The most common disease site in the study population was tongue (30.6%) followed by buccal mucosa (25%). The distribution of site and types of tumors is shown in [Table 3]. Squamous cell carcinoma was the main reported histopathology 91.7%. Most predominant disease laterality in this cohort was found to be right side in 45.8% cases. Majority patients belonged to tumor staging T4 (31.9%) and T2 (30.6%). More than half of the study population had N0 (45.8%) nodal involvement.
Table 3: Tumor related factors

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Treatment-related factors

The factors like surgery, radiation and chemotherapy has the following distribution in our cohort as reported in [Table 4]. The occurrence of ORN was more common when surgery was followed by RT as was seen in 45% cases. In 51.4% cases, surgical neck dissections lead to decrease in vascularity of the region contributing to ORN. External Beam Radiation Therapy (EBRT) (81.9%) composed a major part of our cohort as compared to IMRT (2.8%) and 3DCRT (2.8%). Among the patients receiving RT, 27 (37.5%) had received radiation above 60 Gy and 33 (45.8%) received below 60 Gy. Bilateral radiation in 51.4% contributed as a risk factor for ORN. Concurrent chemotherapy having effect was noted in 31.9% of our cohort. The site of occurrence of ORN was similar to the site of the disease and hence a statistical significant correlation was found between tumor laterality and site of ORN (P = 0.000) as shown in [Table 5] and represented in [Graph 1].
Table 4: Treatment-related factors

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Table 5: Osteoradionecrosis symptoms and treatment

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Osteoradionecrosis symptomatology

In this study, most of the patients presented with multiple symptoms such as pain, pus discharge, and extra oral swelling as mentioned in [Table 6]. The most frequent complaint was pain (50.1%) and pus discharge (42.2%). The most common site of ORN was the left mandibular posterior region (37.5%). Mandible (84.8%) being more affected than maxilla (14%). The time since completion of treatment to the diagnosis of ORN was an average of 3 to 180 months with a mean of 51.15 months, i.e., approximately 4 years. Pathologic fractures were seen in 8.3% of all cases. The most common grade at the diagnosis of ORN being Type IIa (84.7%).
Table 6: Statistical analysis of site of occurrence of osteoradionecrosis and site of tumor

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Triggering factors for osteoradionecrosis

Pre-RT extraction and post RT extraction were carried out in 11 (15.3%) and 34 (47.2%) cases, respectively. Among the cohort only 30 subjects who had undergone extraction triggered ORN at the same site, in rest 42 cases the occurrence of ORN was not related to the history of extraction. The median period since extraction to the diagnosis of ORN was 1.5 months (interquartile range 0–5 months).

Factors related to treatment of osteoradionecrosis

The goal of treatment was mainly to resolve the necrotic lesion and reversion to Type I disease. Conservative ORN protocol consisting of antibiotics, Vitamin E and pentoxifylline was used as the first line of treatment for all the cases in our cohort. [Table 6] describes the treatment options provided to the patients. Local hygiene protocol consisting of betadine and hydrogen peroxide irrigations was recommended for all the patients. Spray of super oxidized water and hypochlorous acid facilitates supply of oxygen radicals in the site of ORN to help faster healing. In 11.2% of the patients, the conservative approach was not able to clinically stabilize the disease and prevent further deterioration of the condition; hence, hyperbaric oxygen therapy was used as a treatment option. Surgical intervention with removal of necrotic bone and soft-tissue reconstruction was done in 4 cases.

Follow-up findings

The median period of months since diagnosis of ORN to follow-up is 8 months (inter-quartile range = 3–18 months). A significant correlation was found between the grade at diagnosis and the grade at follow up (P = 0.000) presented in [Table 7] and depicted in [Graph 2]. There is an overall increase in trend amongst the grade at diagnosis and grade at follow-up. We could achieve stabilization of the symptoms of the disease in 72.3% of the lesions. The resolution of the necrotic lesion and down staging of the disease was seen only in 2.8% of patients.
Table 7: Statistical analysis of grade at diagnosis and grade at follow-up

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The median period of month since the last date of RT to the first report of ORN is 3 months (1–5 months). Type IIa is the most common stage at diagnosis. The median period since RT to occurrence of ORN was 30 months, i.e., 2.5 years (interquartile range 20.75–53 months).

No significant correlation was found between dose of radiation, type of radiation, surgical excision, site of ORN, oral hygiene, sex, and age group between Type IIa and other types of ORN.


 > Discussion Top


In accordance with the heterogeneous presentation of ORN, treatment regimen and its response, the Epstein classification was used to evaluate the progress of ORN in our cohort of cases. Among 72 cases, stabilization of the disease was seen in 72.3% cases, resolution of the ORN to Type I was observed in 2.8% of cases.

In this study, the predominance of males (77.8%) compared with females (22.2%) in the occurrence of ORN was noted, a finding which is in accordance with those of previous studies. The reason being males are two to four times more likely to develop oral cancer than females due to the greater use of alcohol and tobacco among male patients.[6] The median age group of the study is 57 years which was similar to the retrospective study carried out by Chornopolus 2015.[7]

In India, a major cause of oral cancer is attributed to oral habits in the form of smoked and/or smokeless tobacco. The oral habits were noted in 52.8% of the study population in the form of smoked or smokeless tobacco before and/or after the cancer treatment. Tobacco and alcohol abuse have been clearly identified as risk factors for ORN. [2, 8, 9]

Poor oral hygiene was seen in 52.8% and fair in 47.2% of the study population. Murray et al. showed a positive association between the presence of dental disease before radiation therapy and subsequent necrosis of the mandible (P = 0.09). The presence of plaque will not only cause tooth loss but also cause some of the "spontaneous" ORN cases. [10,11]

Trauma is undeniably one of the most important risk factors to the development of ORN, as in the theory of radiation, trauma, infection. [12,13] Pre-RT extraction was carried out in 15.3% cases and post RT extraction was carried out in 47.2% cases. Among the cases where post RT extraction was carried out 30 cases ended in ORN at the same site. In the 1970s and 1980s, the role of trauma as an initiating factor of ORN started to be questioned since many patients developed ORN without having any evidence of previous trauma in several studies. [5, 14, 15]

Curi and Dib reported a significantly higher incidence of ORN when the neck nodal involvement was N0.[16] These findings were found to be similar to our study findings where the most prevalent site of the tumor being carcinoma of tongue being adjacent to mandible and the most prevalent stage being T4 (31.9%) and N0 (45.8%). The most commonly affected area in our study was the left mandibular posterior region (38.9%).

Celik et al. found in their retrospective analysis that patients who underwent mandibular osteotomy for access (mandibulectomy) and marginal mandibulectomy developed ORN earlier than patients who had a segmental mandibulectomy.[17] In our cohort, a majority of the cases nearly 51% had undergone surgical neck dissection before RT, possibly correlating to being a risk factor for ORN.

Concurrent chemotherapy was used as adjuvant therapy in 40.2% of the cases. Chemotherapy is likely to weaken the local immune response by damaging the cellular immune system. This was in accordance with the findings of Sader et al.[18] and Reuther et al.[3]

The risk of ORN becomes higher as the radiation dose increases, short regimens using high doses per fraction, large field sizes, and the delivery of RT through a single homolateral field.[19] In our study, the median dose received to the study population consisted of 60 Gy. Goldwaser et al., reported patients receiving a radiation dose above 66 Gy increased the risk of developing ORN by almost 11-fold. However, in his study, some ORN patients received doses significantly lower than 66 Gy and most non-ORN patients received doses of 66 Gy or higher, it seems clear that dose by itself does not predict absolute risk.[20]

Pain (50.1%) and pus discharge (42.2%) was found to be a common complaint in our study among other complaints. A thorough clinical examination will reveal intra- or extra-oral draining fistulae, ulcerations of the mucous membrane, exposed devitalized bone, hemorrhage, cellulitis, or pathological fractures. In our cohort, after receiving the treatment, pus discharge and the disease progression were controlled although pain persisted in a few cases.

Resorption and complete healing of necrotic lesions after conservative treatment were seen in three cases of this cohort. Sequestrectomy depending on the size of the lesion was possible in 5.6% of cases though not resolving the underlying necrosis. All sequestering lesions did not resolve in the cases of Wong et al.[21] Hence, it is unreasonable to assume that sequestration alone contributes to complete recovery in all cases.

In 11.2% patients, where a conservative approach could not stabilize the disease, hyperbaric oxygen therapy as a conservative approach was advised to prevent further worsening of the condition. Marx concluded that HBO alone cannot heal ORN wounds suggesting that HBO without aggressive surgical management would not resolve the disease progress in most cases. [19, 22, 23] Progressive lesions (Type III) that did not respond to conservative management should be treated with hyperbaric oxygen and/or surgery.

Dinnoo et al. stated that the current literature does not describe the long term outcomes and particularly after the completion of the protocol. They concluded that PENTO or PENTOCLO protocol should be prescribed as a life long treatment or the outcome should be monitored at least as long as the duration of the protocol after its end. [24,25] Hence, in our study, PENTO was administered throughout. The follow up after the treatment was done after every 3 months to evaluate the outcomes of the treatment provided.

The retrospective observational design of the study introduced some limitations. The reliability of the study depended on the accuracy of EMRs or written records or individual recall (recall bias). Access to important information at times was not possible due to the retrospective nature of the study design. The radiation dosage map of each ORN site could not be evaluated due to lack of information on the details of radiation therapy.


 > Conclusion Top


The radiation changes persist for many years after RT. ORN is a chronic radiation induced late sequale of RT. The hypoxia, hypocellularity, and hypovascularity of the jaws; in addition to oral microbial infections leads to ORN which presents as a chronic long standing condition which is difficult to treat. Stabilization of symptoms and preventing further spread of the necrotic lesion should be the ultimate aim of the treatment to improve the quality of life of the patients.

Acknowledgment

We would like to thank all the members of Dental and Prosthetic Surgery Department, Tata Memorial Hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Nabil S, Samman N. Risk factors for osteoradionecrosis after head and neck radiation: A systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:54-69.  Back to cited text no. 1
    
2.
Katsura K, Sasai K, Sato K, Saito M, Hoshina H, Hayashi T. Relationship between oral health status and development of osteoradionecrosis of the mandible: A retrospective longitudinal study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:731-8.  Back to cited text no. 2
    
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Reuther T, Schuster T, Mende U, Kübler A. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients- A report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003;32:289-95.  Back to cited text no. 3
    
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Kulkarni M. Head and neck cancer burden in India. Int J Head Neck Surg 2013;4:29-35.  Back to cited text no. 4
    
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McDowell JD. An overview of epidemiology and common risk factors for oral squamous cell carcinoma. Otolaryngol Clin North Am 2006;39:277-94.  Back to cited text no. 6
    
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Chronopoulos A, Zarra T, Tröltzsch M, Mahaini S, Ehrenfeld M, Otto S. Osteoradionecrosis of the mandible: A ten year single-center retrospective study. J Craniomaxillofac Surg 2015;43:837-46.  Back to cited text no. 7
    
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Thorn JJ, Hansen HS, Specht L, Bastholt L. Osteoradionecrosis of the jaws: Clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg 2000;58:1088-93.  Back to cited text no. 8
    
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Kluth EV, Jain PR, Stuchell RN, Frich JC Jr. A study of factors contributing to the development of osteoradionecrosis of the jaws. J Prosthet Dent 1988;59:194-201.  Back to cited text no. 9
    
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Murray CG, Daly TE, Zimmerman SO. The relationship between dental disease and radiation necrosis of the mandible. Oral Surg Oral Med Oral Pathol 1980;49:99-104.  Back to cited text no. 10
    
11.
Murray CG, Herson J, Daly TE, Zimmerman S. Radiation necrosis of the mandible: A 10 year study. Part II. Dental factors; onset, duration and management of necrosis. Int J Radiat Oncol Biol Phys 1980;6:549-53.  Back to cited text no. 11
    
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Meyer I. Infectious diseases of the jaws. J Oral Surg 1970;28:17-26.  Back to cited text no. 12
    
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Watson WL, Scarborough JE. Osteoradionecrosis in intra-oral cancer. Am J Roentgen 1938;40:524-34.  Back to cited text no. 13
    
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Marx RE. Osteoradionecrosis: A new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41:283-8.  Back to cited text no. 14
    
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Bedwinek JM, Shukowsky LJ, Fletcher GH, Daley TE. Osteoradionecrosis in patients treated with definitive radiotherapy for squamous cell carcinomas of the oral cavity and naso-and oropharynx. Radiol 1976;119:665-7.  Back to cited text no. 15
    
16.
Curi MM, Dib LL. Osteoradionecrosis of the jaws: A retrospective study of the background factors and treatment in 104 cases. J Oral Maxillofac Surg 1997;55:540-4.  Back to cited text no. 16
    
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Celik NC, Wei FC, Chen HC, Cheng MH, Huang WC, Tsai FC, et al. Osteoradionecrosis of the mandible after oromandibular cancer surgery. Plast Reconstr Surg 2002;109:1875-881  Back to cited text no. 17
    
18.
Sader R, Zimmermann V, Zeilhofer HF, Deppe H, Herzog M, Auberger T, et al. The allikrein activity in saliva as a possible prognostic factor osteoradionecrosis of the lower jaw. Dtsch Z für MundKiefer Gesichtschirurg 1996;20:285-91.  Back to cited text no. 18
    
19.
Ramli R, Ngeow WC, Rahman RA, Chai WL. Managing complications of radiation therapy in head and neck cancer patients: Part IV. Management of osteoradionecrosis. Singapore Dent J 2006;28:11-5.  Back to cited text no. 19
    
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Goldwaser BR, Chuang SK, Kaban LB, August M. Risk factor assessment for the development of osteoradionecrosis. J Oral Maxillofac Surg. 2007; 65:2311-2316.  Back to cited text no. 20
    
21.
Wong JK, Wood RE, McLean M. Conservative management of osteoradionecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:16-21.  Back to cited text no. 21
    
22.
Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: A randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc 1985;111:49-54.  Back to cited text no. 22
    
23.
Thorn JJ, Kallehave F, Westergaard P, Hansen EH, Gottrup F. The effect of hyperbaric oxygen on irradiated oral tissues: Transmucosal oxygen tension measurements. J Oral Maxillofac Surg 1997;55:1103-7.  Back to cited text no. 23
    
24.
Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: A phase II trial. Head Neck 2005;27:114-23.  Back to cited text no. 24
    
25.
Dinnoo A, Bidault F, Lassau N, Elmaalou M, Moya-Plana A, Ruffier A, et al. Long-term recurrences of jaw osteoradionecrosis after apparent healing with the pentoclo protocol. J Stomatol Oral Maxillofac Surg 2019;121:286-7.  Back to cited text no. 25
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

 
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