This systematic review aims to identify and review the best available evidence to answer the clinical question ‘What are the incidence and the factors influencing the development of osteoradionecrosis after tooth extraction in irradiated patients?’. A systematic review of published articles on post-irradiation extraction was performed via electronic search of the Medline, Ovid, Embase and Cochrane Library databases. Additional studies were identified by manual reference list search. Evaluation and critical appraisal were done in 3 stages by two independent reviewers and any disagreement was resolved by discussion with a third party. 19 articles were selected for the final analysis. The total incidence of osteoradionecrosis after tooth extraction in irradiated patients was 7%. When extractions were performed in conjunction with prophylactic hyperbaric oxygen, the incidence was 4% while extraction in conjunction with antibiotics gave an incidence of 6%. This systematic review found that while the incidence of osteoradionecrosis after post-irradiation tooth extractions is low, the extraction of mandibular teeth within the radiation field in patients who received a radiation dose higher than 60 Gy represents the highest risk of developing osteoradionecrosis. Based on weak evidence, prophylactic hyperbaric oxygen is effective in reducing the risk of developing osteoradionecrosis after post-radiation extractions.
Radiotherapy is an established treatment modality in the management of malignant disease of the head and neck. Radiotherapy targets all cells with a high turnover rate, whether malignant or normal host tissue. A balance of tumour eradication and normal tissue preservation must be reached to achieve cure without further debilitating the patient. This adverse effect on normal tissue limits the dose and dose delivery rate of radiation therapy. Certain adverse effects of therapy may have to be accepted in exchange for cure of this lethal disease. Bone is radio-resistant compared with other tissues but, due to compromise in its blood supply and reparative ability, it remains a problem when irradiated.
Osteoradionecrosis (ORN) is recognized as one of the most severe complications of radiation therapy. ORN is difficult to treat and often leads to poor outcome and deformity. ORN is defined as an area of exposed devitalized irradiated bone that fails to heal over a period of 3–6 months in the absence of local neoplastic disease . ORN can occur spontaneously, due to periodontal and apical disease and possibly after trauma induced by dentures, or after surgery or tooth extraction . Extraction before or after irradiation is said to be the most common initiating factor in the development of ORN in irradiated jaws . Incidence of ORN after tooth extraction in irradiated patients is estimated to be around 2–18% .
To prevent this complication after post-irradiation extraction, several methods have been tried. Antibiotic prophylaxis before the extraction procedure is the most common initiative to prevent ORN . This is probably because it is easy to administer and widely available. Others have suggested using hyperbaric oxygen (HBO) before extraction . The high oxygen level with HBO is thought to induce fibroplasia and angiogenesis in the hypoxic, hypocellular and hypovascular tissue, thus preventing the occurrence of ORN after tooth extraction . Scarce availability possibly limits the routine use of HBO in the irradiated population needing tooth extraction. Recent suggestions include the use of pentoxifylline and tocopherol some weeks before extraction .
Intra-operatively, measures such as alveoloplasty, primary closure and limited periosteal trauma during extraction are said to be critical steps in avoiding ORN . Limiting the number of teeth to be extracted in a single session and using low-adrenaline local anesthesia or avoiding certain local anesthetic (LA) agents are also used . These suggestions are based on years of clinical experience with the disease.
The exact incidence of ORN after post-irradiation extraction is unknown. The effectiveness of the methods used to reduce the incidence of ORN is also unknown. Given the increase in the head and neck irradiated population and the devastating morbidity of ORN, a systematic review to determine the exact incidence of ORN post-extraction and identify the best prevention methods available appears timely.
Materials and methods
A systematic review of the best evidence available in the literature was performed to answer the following clinical question: ‘What are the incidence and the factors influencing the development of ORN of the jaw bones after tooth extraction in irradiated head and neck cancer patients?’
An initial electronic search was performed using MEDLINE (1950 to April 2010) via Pubmed and Ovid. Further search was performed through Embase and The Cochrane Library database. A broad search strategy was undertaken using the following keywords: Osteoradionecrosis AND (Hyperbaric oxygen OR Extraction OR Prevention OR Antibiotics). The title and abstract (when available) of the articles retrieved using the described strategy were then screened by 2 reviewers. For studies appearing to be relevant, and for those with insufficient data in the title and abstract to make a clear decision, the full article was obtained. The reference lists from the selected articles were also screened and the full text of any relevant citation was retrieved to be included in the study selection phase.
The full text of all articles retrieved from the first round of search and the articles retrieved from the manual reference list search were evaluated independently by 2 reviewers. Articles reporting data regarding extraction of teeth in human adults after irradiation of the oral and maxillofacial region were accepted. Single case reports were excluded at this stage. Articles selected after the full text assessment were submitted to final eligibility assessment for inclusion in the review. The criteria described below were used to determine eligibility. Articles excluded from this phase and the reasons for exclusion were also reported.
All types of study with data assessing ORN occurrence after tooth extraction in patients who had radiation in the head and neck region with a minimum sample size of 5 patients were considered. No restriction on language, publication date or publication status was imposed. In order to avoid selection bias, studies had to include a consecutive group of patients who had radiation to the head and neck and underwent post-irradiation extraction.
Subjects who had teeth extracted after radiotherapy for treatment of a neoplasm of the head and neck region were eligible. Subjects could be treated by radiotherapy alone, chemoradiotherapy or as adjunct therapy with surgery. Subjects with irradiation of the head and neck region that did not include the maxilla or mandible were considered ineligible and were excluded. Subjects with ORN present before tooth extractions were also excluded.
Studies with or without intervention to prevent the occurrence of ORN after extractions in post-irradiated patients were accepted. Those without any intervention to prevent ORN were accepted as controls. The intervention, if any, had to be clearly described.
The primary outcome measure is the occurrence of ORN at the extraction socket. Diagnosis of ORN had to be made by a clinician after clinical examination. ORN for the purpose of this review was defined as an area of exposed devitalized irradiated bone that failed to heal over 3 months with no evidence of recurrence of local neoplastic disease. Abiding by this definition, unhealed sockets of individual subjects had to be followed-up for at least 3 months post-extraction. Articles reporting follow-up in a group of patients had to have a median/mean follow-up period of at least 6 months post-extraction to be included in this review. Other outcomes were: ORN incidence under different prevention/intervention methods; and analysis of risk factors (relation of interval between extraction and RT treatment, extractions in mandible/maxilla, radiation dose and radiation field) in the development of ORN after extraction in irradiated patients.
The data were collected in a Microsoft Excel table by the first reviewer. The second reviewer checked the extracted data to avoid any omissions or inaccuracies in the data extracted. Any differences were discussed by the 2 reviewers and disagreement managed by consultation with a third party.
The electronic database search last updated on 30 April 2010 yielded 518 hits from Pubmed, 384 hits from Ovid, 167 hits from Embase and 2 from the Cochrane Library. 121 articles were considered relevant to the topic after title and/or abstract screening. A manual reference list search of the 121 selected articles yielded a further 23 articles. Full texts of these 144 articles were evaluated for the reporting of clinical data on tooth extraction in irradiated jaws. 47 articles were selected and entered for eligibility assessment, using the eligibility criteria in Table 1 .
|Eligibility criteria for inclusion in the final review|
|Minimum sample size of 5 patients|
|Radiotherapy in head & neck region affecting mandible, maxilla or both|
|No previous ORN at the extraction site|
|Consecutive group of patients undergoing extraction after RT|
|Diagnosis of ORN made after clinical examination by clinician|
|ORN occurred at site of extraction|
|For individual subjects with unhealed sockets follow-up must be at least 3 months and for group of subjects median/mean follow-up must be more than 6 months after extraction|
Of these 47 articles, 28 articles that did not meet one or more of the eligibility criteria were excluded; the reasons for exclusion are listed in Table 2 . 19 articles were accepted for the final review ( Table 3 ). They underwent a critical evaluation process to obtain the best available valid data for this review. A flow chart of the selection and evaluation process is presented in Fig. 1 .
|Year||Author||Title||Study type||Reason for exclusion||ORN/patient||%|
|2009||K aur et al.||Retrospective audit of the use of the Marx Protocol for prophylactic hyperbaric oxygen therapy in managing patients requiring dental extraction following radiotherapy to the head and neck||Retrospective||ORN was not diagnosed by clinician/clinical exam||1/26||3.8%|
|2007||C hang et al.||Do pre-radiation dental extractions reduce the risk of osteoradionecrosis of the mandible?||Retrospective||Inadequate description of the ORN site||12/51||23.5%|
|2006||W ahl||Osteoradionecrosis prevention myths||Review||No new data||–||–|
|2005||B ennet et al.||Hyperbaric oxygen therapy for late radiation tissue injury||Systematic review||No new data||–||–|
|2004||O h et al.||Risk of osteoradionecrosis after extraction of impacted third molars in irradiated head and neck cancer patients||Retrospective||Less than 5 patients||1/4||25%|
|2004||F eldmeier||Hyperbaric oxygen for delayed radiation injuries||Review||No new data||–||–|
|2003||A fanasyev et al.||Removal of teeth in patients with malignant maxillofacial tumours during different periods of radiotherapy||Unclear||Inadequate description of the ORN site; Inadequate description/duration of follow up period||0/5||0%|
|2002||F eldmeier and H ampson||A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: an evidence based approach||Systematic review||No new data||–||–|
|1999||V udiniabola et al.||Hyperbaric oxygen in the prevention of osteoradionecrosis of the jaws||Prospective||Non-consecutive patient undergoing post-irradiation extraction (Data presented as any oral surgery procedure—unable to extract data on post-radiation extraction)||–||–|
|1998||T oljanic et al.||Osteoradionecrosis of the jaws as a risk factor in radiotherapy: a report of an 8-year retrospective review||Retrospective||Less than 5 patients||0/4||0%|
|1997||C layman||Management of dental extraction in irradiated jaws: a protocol without hyperbaric oxygen therapy||Review||No new data||–||–|
|1995||H enrich et al.||Untersuchungen zur problematik einer chirurgischen zahnsanierung im zusammenhang mit der bestrahlung maligner tumoren||Retrospective||Inadequate description/duration of follow up period||0/167||0%|
|1989||W idmark et al.||Osteoradionecrosis of the jaws||Retrospective||Non-consecutive patients undergoing post-irradiation extraction||–||–|
|1986||M arciani and O wnby||Osteoradionecrosis of the jaws||Retrospective||Inadequate description/duration of follow up period||0/17||0%|
|1985||K raut||Prophylactic hyperbaric oxygen to avoid osteoradionecrosis when extractions follow radiation therapy||Case report||Less than 5 patients; non-consecutive patients undergoing post-irradiation extraction||0/3||0%|
|1983||H oriot et al.||Dental preservation in patients irradiated for head and neck tumours: A 10-year experience with topical fluoride and a randomized trial between two fluoridation methods||Prospective||Inadequate description/duration of follow up period||4/29||13.8%|
|1981||H oriot et al.||Systematic dental management in head and neck irradiation||Prospective||Inadequate description/duration of follow up period; duplicate data||–||–|
|1980||M urray et al.||Radiation necrosis of the mandible: a 10 year study. Part II. Dental factors; onset, duration and management of necrosis||Retrospective||Inadequate description/duration of follow up period||7/8||87.5%|
|1979||B eumer et al.||Radiation therapy of the oral cavity: sequelae and management, part 2||Review||Duplicate data||–||–|
|1976||R egezi et al.||Dental management of patients irradiated for oral cancer||Retrospective||Inadequate description/duration of follow up period||0/9||0%|
|1976||B edwinek et al.||Osteonecrosis in patients treated with definitive radiotherapy for squamous cell carcinomas of the oral cavity and naso- and oropharynx||Retrospective||Non-consecutive patients undergoing post-irradiation extraction (Data presented as combination of pre and post-radiation extraction-unable to extract data on post-radiation extraction)||–||–|
|1973||C arl et al.||Oral surgery and the patient who has had radiation therapy for head and neck cancer||Retrospective||Non-consecutive patients undergoing post-irradiation extraction (data presented as combination of pre and post-radiation extraction—unable to extract data on post-radiation extraction); inadequate description/duration of follow up period||–||–|
|1972||B eumer et al.||Hard and soft tissue necroses following radiation therapy for oral cancer||Retrospective||Inadequate description/duration of follow up period||1/23||4.3%|
|1972||C arl et al.||Oral care of patients irradiated for cancer of the head and neck||Retrospective||Duplicated data; Inadequate description/duration of follow up period||–||–|
|1972||D aly and D rane||Osteoradionecrosis of the Jaws||Retrospective||Less than 5 patients; inadequate description/duration of follow up period||3/3||100|
|1969||H offmeister et al.||Radiation in dentistry–surgical comments||Retrospective||Inadequate description/duration of follow up period||14/24||58.3%|
|1968||S olomon et al.||Extraction of teeth after cancericidal doses of radiotherapy to the head and neck||Prospective||Inadequate description/duration of follow up period||0/31||0%|
|1966||G rant and F letcher||Analysis of complications following megavoltage therapy for squamous cell carcinomas of the tonsillar area||Retrospective||Inadequate description/duration of follow up period||7/16||43.8%|
|Year||Author||Title||Study type||Number of patients||Intervention||Follow-up||ORN||Percentage|
|2008||K oga et al.||Dental extraction related to head and neck radiotherapy: ten-year experience of a single institute||Retrospective||57||86% used antibiotics, 17.5% used HBO||Median 42.8 month||1||1.75%|
|2007||B en -D avid 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||Retrospective||13||2 undergone HBO, others not mentioned clearly||Median 26 month||0||0%|
|2007||L ye et al.||The effect of prior radiation therapy for treatment of nasopharyngeal cancer on wound healing following extractions: incidence of complications and risk factors||Prospective||40||Antibiotics; Chlorhexidine 0.2% mouthwash; LA without adrenaline; suturing||3 month||3||8%|
|2004||C haux -B odard et al.||Extractions dentaires en territoire irradie||Prospective||107||Antibiotics; Alveoloplasty and primary closure; Chlorhexidine 0.2% mouthwash; Low-adrenaline anaesthesia||3 month||1||0.93%|
|2003||S ulaiman et al.||Dental extractions in the irradiated head and neck patient: a retrospective analysis of Memorial Sloan-kettering Cancer Centre protocols, criteria and end results||Retrospective||107||7 received HBO; 65% did not receive antibiotic; 35% received antibiotic, suturing, Post-radiation extraction in multiple visits||mean 22m||2||1.87%|
|2001||D avid et al.||Hyperbaric oxygen therapy and mandibular osteoradionecrosis: a retrospective study and analysis of treatment outcome||Retrospective||24||HBO||6 month||0||0%|
|2001||C haves and A dkinson||Adjunctive hyperbaric oxygen in irradiated patients requiring dental extractions: outcomes and complications||Prospective||40||HBO||12 month||4||10%|
|1999||T ong et al.||Incidence of complicated healing and osteoradionecrosis following tooth extraction in patients receiving radiotherapy for the treatment of nasopharyngeal carcinoma||Retrospective||43||Antibiotics; Chlorhexidine 0.2% mouthwash; suturing +/− alveoloplasty in muktiple extraction||6 month||2||4.65%|
|1998||C arl and I kner||Dental extractions after radiation therapy in the head and neck area and hard tissue replacement (HTR) therapy: a prelimenary study||Prospective||8||Alveoloplasty and primary closure; hard tissue replacement; antibiotics||Minimum 7 month||0||0%|
|1997||L ambert et al.||Management of dental extractions in irradiated jaws: a protocol with hyperbaric oxygen therapy||Retrospective||46||HBO; alveoloplasty and primary closure||Minimum 2 1/2 month||0||0%|
|1991||M axymiw et al.||Postradiation dental extractions without hyperbaric oxygen||Prospective||72||Antibiotics; low-adrenaline and non-lidocaine anaesthesia; less then 2 teeth persession||Minimum 2 1/2 month||0||0%|
|1987||M akkonen et al.||Dental extractions in relation to radiation therapy of 224 patients||Retrospective||25||6 received antibiotics, 6 did not received antibiotics; 13 unclear||1–8 years||0||0%|
|1987||E pstein et al.||Osteonecrosis: study of the relationship of dental extractions in patients receiving radiotherapy||Retrospective||42||Antibiotic; primary closure +/− alveoloplasty||3 month||3||7.14%|
|1987||S chweiger||Oral complications following radiation therapy: a five-year retrospective report||Retrospective||24||Antibiotics||1 month||2||8.33%|
|1985||M arx et al.||Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin||RCT||74||HBO versus antibiotic||6 month||13||17.57%|
|1983||B eumer et al.||Postradiation dental extractions: A review of the literature and a report of 72 episodes||Retrospective||72||Alveoloplasty and primary closure for multiple tooth extraction, HBO in 4||3 month||16||22.22%|
|1981||M orrish et al.||Osteonecrosis in patients irradiated for head and neck carcinoma||Retrospective||18||Not clear||3 month||9||50%|
|1976||B eumer et al.||Radiation complications in edentulous patients||Prospective||11||Not clear||6 month||1||9%|
|1953||W ildermuth and C antril||Radiation necrosis of the mandible||Retrospective||5||Antibiotics in 4, none in 1||Minimum 1 month||0||0%|
Among the 47 selected articles, there were two systematic reviews (SR), one randomized controlled trial (RCT) and 10 prospective studies reporting data on tooth extraction in irradiated jaws. The remaining articles were 28 retrospective studies, 4 reviews, 1 case report and 1 not clearly described. 19 articles were included in the final review. For the prevention of ORN, 8 reported the use of HBO, 12 used antibiotics and 2 failed to describe clearly the intervention used. There were also articles reporting alveoloplasty, primary closure, local anesthesia with low adrenaline and limiting the number of extractions per session combined with the measures described above.
11 articles reported clearly the relation of ORN occurrence to the number of teeth removed with 8 studies specifying the site of extraction as the maxilla or mandible. In 7 studies, mention was made of whether the tooth extracted was in the field of radiation or outside it. The radiotherapy dose received by the patient was clearly described in 9 studies.
There were 57 ORN cases after post-radiation extraction in 828 patients. This gives a total incidence of 7% ( Table 3 ). 11 of the 19 articles described the number of teeth extracted. There were 2766 tooth extractions and 54 of the extraction sockets later developed ORN ( Table 4 ).
|L ye et al.||155||3||1.94%|
|C haux -B odard et al.||287||1||0.35%|
|S ulaiman et al.||647||2||0.31%|
|D avid et al.||54||0||0%|
|C haves and A dkinson||371||6||1.62%|
|T ong et al.||237||4||1.69%|
|C arl and I kner||44||0||0%|
|M axymiw et al.||449||0||0%|
|M akkonen et al.||94||0||0%|
|E pstein et al.||137||3||2.19%|
|M arx et al.||291||35||12.03%|
In the 8 articles reporting the use of HBO, 7 articles reported its relation with the occurrence of ORN in which the total incidence was 4%. HBO was described as breathing 100% oxygen at 2.4 ATM for 90 min. The protocol was 20 sessions pre-extraction and 10 sessions post-extraction as suggested by M arx et al. . Extraction of 595 teeth with ORN occurring in 10 of the sockets (an incidence of 2% per tooth) was reported after using HBO. On the use of antibiotics, 9 of the 12 articles reporting the use of antibiotics clearly described the incidence of ORN in relation to its use. The overall incidence of ORN with the use of antibiotics was 6%. 1444 teeth were extracted in this group and ORN occurred in 42 of the sockets (incidence 3% per tooth) ( Table 5 ). In these studies, the antibiotic regimens used were variable. The antibiotics most widely used were penicillin and clindamycin ( Table 6 ).
|K oga et al.||10 a||n.a.||49 a||n.a.||n.a.||n.a.||n.a.||n.a.|
|B en D avid et al.||2||0||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.|
|L ye et al.||0||0||40||2||0||0||155||3|
|C haux -B odard et al.||0||0||107||1||0||0||287||1|
|S ulaiman et al.||7||0||n.a.||n.a.||14||0||n.a.||n.a.|
|D avid et al.||24||0||0||0||54||0||0||0|
|C haves and A dkinson||40||4||0||0||371||6||0||0|
|T ong et al.||0||0||43||2||0||0||237||4|
|C arl and I kner||0||0||8||0||0||0||44||0|
|L ambert et al.||46||0||0||0||n.a.||n.a.||n.a.||n.a.|
|M axymiw et al.||0||0||72||0||0||0||449||0|
|M akkonen et al.||0||0||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.|
|E pstein et al.||0||0||42||3||0||0||137||3|
|M arx et al.||37||2||37||11||156||4||135||31|
|B eumer et al.||4||0||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.|
|M orrish et al.||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.|
|B eumer et al.||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.||n.a.|
|W ildermuth and C antril||0||0||4||0||n.a.||n.a.||n.a.||n.a.|
|2008||K oga et al.||Yes||Not clear|
|2007||B en -D avid et al.||Not clear||–|
|2006||L ye et al.||Yes||Preoperatively Pen V 2 g/clindamycin 600 mg and postoperatively Pen V/clindamycin with metronidazole for 1 week|
|2004||C haux -B odard et al.||Yes||Postoperative amoxycillin for 8 days|
|2003||S ulaiman et al.||Yes||Not clear|
|2001||D avid et al.||No||–|
|2001||C haves and A dkinson||No||–|
|1999||T ong et al.||Yes||Postoperative penicillin 250 mg qid for 1 week|
|1998||C arl and I kner||Yes||Postoperative clindamycin bid for 4 days|
|1997||L ambert et al.||No||–|
|1991||M axymiw et al.||Yes||Preoperative Penicillin V 2 g and postoperatively 600 mg qid for 1 week|
|1987||M akkonen et al.||Yes||Not clear|
|1987||E pstein et al.||Yes||Not clear|
|1987||S chweiger||Yes||Not clear|
|1985||M arx et al.||Yes (one arm)||Preoperative 1mu IV Penicillin G and postoperative Penicillin V 500 mg qid for 10 days|
|1983||B eumer et al.||Not clear||–|
|1981||M orrish et al.||Not clear||–|
|1976||B eumer et al.||Not clear||–|
|1953||W ildermuth and C antril||Yes||Penicillin|
The most common intra-operative measures performed with the intention to prevent ORN were alveoloplasty/alveolotomy and suturing, performed separately or in combination. Eight articles reported the use of alveoloplasty and/or suturing. One article did not use the procedure, while the remaining authors failed to mention clearly whether they used the procedure or not. Three articles reported the use of low adrenaline or non-adrenaline vasoconstrictor in the local anesthesia solution before performing the extraction. Limiting the number of extractions per-session in an effort to avoid ORN was reported in two studies ( Table 7 ).
|Alveoloplasty and/or suturing||Performed||9, 12, 16, 28, 46, 50, 58, 81|
|Not clear||4, 8, 17, 22, 44, 54, 60, 73, 78, 87|
|LA with no/low adrenaline||Performed||16, 50, 59|
|Not clear||4, 8, 9, 12, 17, 22, 28, 44, 46, 54, 60, 73, 78, 81, 87|
|Limited extractions per-session||Performed||59, 78|
|Not clear||4, 8, 9, 12, 17, 22, 28, 44, 46, 50, 54, 58, 60, 73, 81, 87|
When extraction was performed in the maxilla, only 1% of the sockets developed ORN. The risk is 3 times higher in the mandible as 38 of 1136 sockets (3%) developed ORN post-extraction ( Table 8 ).
|Author||Extraction in mandible||ORN at mandible||Percentage||Extraction in maxilla||ORN at maxilla||Percentage|
|L ye et al.||89||2||2.25%||66||1||1.51|
|D avid et al.||54||0||0%||0||0||0%|
|C haux -B odard et al.||231||1||0.43%||56||0||0%|
|T ong et al.||121||0||0%||116||4||3.45%|
|C arl and I kner||32||0||0%||12||0||0%|
|M axymiw et al.||252||0||0%||197||0||0%|
|M akkonen et al.||66||0||0%||28||0||0%|
|M arx et al.||291||35||12.03%||0||0||0%|