Maxillofacial osteoradionecrosis

42 Journal of Dental Research and Review ● Jan-Apr 2014 ● Vol. 1 ● Issue 1

Introduction

T he global incidence of oral cancer is 5,00,000 cases per year with mortality of 2,70,000 cases per year. The

incidence of oral cancer in India is 40% among all cancers and about 1,00,000 patients suffer from oral cancer in any year. Oral cancer is responsible for 7% of all cancer deaths in males and 3% in females.[1]

The recent protocol for management of oral cancer includes multimodal therapy, such as surgery with radiotherapy and/or chemotherapy. Radiation therapy is one of the major treatment modalities for the management of oral malignancies. Like with any treatment modality, even radiation therapy is associated with various complications. A long‑term side effect of radiotherapy that is also the most serious is osteoradionecrosis.[2,3] Literature reveals many terminologies to represent the same disease, such as radiation osteitis, radio‑osteonecrosis, radiation osteomyelitis, osteomyelitis of irradiated bone, osteonecrosis, radio‑osteomyelitis, septic osteoradionecrosis, and post‑radiotherapy osteonecrosis.[4]

This review focuses on the general information on maxillofacial osteoradionecrosis for general practitioners.

Historical perspective

In 1922, Regaud published the first report about osteoradionecrosis of jaws after radiotherapy.[4] In 1926, further description of osteoradionecrosis was given by Ewing under the name Radiation Osteitis.[5] In 1970, Meyer classified osteoradionecrosis as one special type of osteomyelitis. In 1975, Mainous advocated the use of hyperbaric oxygen therapy (HBO) for late radiation tissue injury. In 1983, Robert Marx proposed the hypoxic, hypocellular, and hypovascular theory as a new way of understanding the pathophysiology of osteoradionecrosis. In 1992, Harris introduced the use of Ultrasound as one of the modes to treat osteoradionecrosis.[6] In 1998, Marx gave the 30/10 protocol that was employed in the treatment of established osteoradionecrosis. In 2004, Delanian and Lefaix put forward a new theory named radiation‑induced fibrosis that accounts for the damage to normal tissues, including bone after radiotherapy.[7]

Definitions

In literature, osteoradionecrosis has been defined in many ways [Table 1].[8,9] However, the authors feel that the definition given by Wong, Wood, and McLean (1997)[8] is the most appropriate and complete:

“A slow‑healing radiation‑induced ischemic necrosis of bone with associated soft tissue necrosis of variable extent occurring in the absence of local primary tumour necrosis, recurrence, or metastatic disease that may or may not:i. Be superinfected (and accompanied by fistulation or cellulitis)ii. End in pathologic fractureiii. Resolve without surgery, hyperbaric oxygen therapy or both.”

Maxillofacial osteoradionecrosisAmit T. Suryawanshi, S. N. Santhosh Kumar, R. S. Dolas, Ruchi Khindria, Vivek Pawar, Manju Singh

Review Article

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How to cite this article: Suryawanshi AT, Kumar SS, Dolas RS, Khindria R, Pawar V, Singh M. Maxillofacial osteoradionecrosis. J Dent Res Rev 2014;1:42-9.

ABSTRACTOsteoradionecrosis is a severe and delayed radiation‑induced injury, characterized by bone tissue necrosis and failure to heal. Cases of osteoradionecrosis present to the clinician with features of pain, drainage, and fistulation of the mucosa or skin related to exposed bone in the previously irradiated area. The tumour size and location, radiation dose, occurrence of local trauma, dental extractions, infection, immune defects, and malnutrition are predisposing factors. A better understanding of risk factors leading to the development osteoradionecrosis and of the underlying pathophysiology may improve the ability of the clinician to prevent the occurrence and help improve the prognosis of this complication. Although the frequency of osteoradionecrosis has declined since the introduction of newer methods of radiotherapy, this review focuses on the etiology, pathophysiology, clinical features, radiological features, diagnosis, and treatment modalities including the newer modalities.

KEY WORDS: Jaws, management, osteoradionecrosis, physiopathology, risk factors

Department of Oral and Maxillofacial Surgery, DPU, Dr. D. Y. Patil Dental College and Hospital, Pimpri, Pune, Maharashtra, India

Address for correspondence: Dr. Amit Suryawanshi, E‑mail: amitsuryawanshi999 @gmail.com

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• Marx’sHypoxic,hypocellular,andhypovasculartheory[20]

• Delanian’sRadiation‑inducedfibroatrophictheory.[21]

Meyer’s radiation, trauma, and infection theory

In 1970, in an excellent monograph on infectious disease of the jaws, Meyer defined the classic triad of osteoradionecrosis as radiation, trauma, and infection [Figure 1].[19] Meyer portrayed that the trauma provided the portal for invasion by oral microbiological floraintotheunderlyingirradiatedbone.Meyer’stheorylastedfor a decade and became the foundation for the popular use of antibiotics with surgery to treat osteoradionecrosis.[19]

Marx’s hypoxic, hypocellular, and hypovascular theory

Robert E Marx in his landmark study noted that there was no injury before the onset of osteoradionecrosis in 35% of his cases. He also found that composite irradiated tissues were more hypoxic than those that had not been irradiated [Figure 2].[20] Marx concluded that “Osteoradionecrosis is not a primary infection

Table 2: Classification systems of osteoradionecrosisYear Authors Basis for classification

1983 Coffin’s classification[10] Based on the extent of involvementMinor and Major

1983 Marx classification[8] Based on time period between radiation therapy and occurrence of osteoradionecrosisType I-III

1983 Marx staging[8] Based on the treatment modalities involved along with HBO therapyStage I-III

1986 Morton and simpson’s Classification[11]

Based on the duration of occurrence of osteoradionecrosisMinor, Moderate and Major

1987 Epstein’s stages[10] Based on the progress of the diseaseStage I-III

1995 Late effects of normal tissue/ Somatic objective management analytic (SOMA) scale[12]

Based on subjective symptoms and objective signs of osteoradionecrosisGrade 1-4

1997 Clayman’s classification[13]

Based on the presence/absence of soft tissue break downType I and II

1998 Radiation therapy oncology group scoring[12]

Based on the severity of bone morbidityGrade 0-5

2000 Store and Boysen’s staging[11]

Based on the extent of involvement of soft and hard tissuesStage 0-3

2002 Kagan and Schwartz’s staging[14]

Based on the clinical assessment and physical findings of osteoradionecrosisStage I-III

2003 Notani et al’s Classification[12]

For mandibular osteoradionecrosis after clinical examination and orthopantogramClass I-III

2009 National cancer institute common terminology criteria (version-IV)[12]

Based on clinical presentation of osteoradionecrosisGrade 1-5

LENT: Late effects of normal tissue, SOMA: Somatic objective management analytic

Classification and staging systems

There have been several staging or scoring systems that have been proposed. These systems are based on response to HBO therapy, degree of bone damage, clinical–radiological findings, length of bone exposure through the overlying skin or mucosa, and treatment needed [Tables 2 and 3].[8‑15]

Risk factors

The existing articles in literature fail to give an exact etiology for osteoradionecrosis. The etiology of osteoradionecrosis is considered to be multifactorial. These factors may increase the risk of the patient for development of osteoradionecrosis. The factors are classified into four groups as shown in Table 4.[15‑18]

Pathophysiology

The pathophysiology of osteoradionecrosis is not very clear till date. However, literature reveals three theories that have been put forward since 1970, as mentioned in the following:• Meyer’sRadiation,traumaandinfectiontheory[19]

Table 1: Definitions of osteoradionecrosisYear Author(s) Definition

1983 Marx[8] An area of exposed bone greater than 1 cm in a field of irradiation that had failed to show any evidence of healing for at least 6 months

1983 BeumerIII, Harrison, Sanders and Kurrasch[9]

An exposure of bone of the maxilla or mandible within the radiation treatment volume persisting for more than 3 months or longer

1986 Morton and Simpson[9] A loss of soft tissue integrity and exposure of radiation damaged bone

1987 Marx and Johnson[9] An exposure of nonvital irradiated bone, which fails to heal without intervention

1987 Epstein, Rea, Wong, Spinelli and Stevenson-Moore[9]

An ulceration or necrosis of the mucous membrane (In the absence of recurrent or metastatic disease), with exposure of necrotic bone for more than 3 months

1989 Widmark, Sagne and Heikel[9]

A non healing mucous or cutaneous ulcer with denuded bone, lasting for more than 3 months

1990 Koka, Deo, Lusinichi, Roland and Schwaab[9]

A persistent ulceration with exposure of devitalised bone, cellulitis, fistula and a pathologic mandibular fracture. Patients tumour free at primary site

1992 Harris[9] Exposed and necrotic bone associated with ulcerated or necrotic surrounding soft tissue which persists for greater 3 months in an area that had been previously irradiated (not caused by tumor recurrence)

1993 Mirante and Urken et al.[9]

A loss of viable bone resulting from radiation therapy

1995 Van Merkesteyn, Bakker and Borgmeijer-Hoelen[9]

A bone and soft tissue necrosis of 6 months duration excluding radiation-induced periodontal breakdown

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of irradiated bone, but a complex metabolic and homeostatic deficiency of tissue that is created by radiation‑induced cellular injury; micro‑organisms play only a contaminating role in osteoradionecrosis; and trauma may or may not be an initiating factor.”[20]

Delanian’s radiation‑induced fibroatrophic theory

Radiation‑induced fibrosis is a new theory that accounts for the damage to normal tissues, including bone, after radiotherapy.

It was introduced in 2004 when recent advances in cellular and molecular biology explained the progression of microscopically observed osteoradionecrosis [Figure 3].[21] Three distinct phases are seen:• Theinitialprefibroticphaseinwhichchangesinendothelial

cells predominate together with the acute inflammatory response

• The constitutive organised phase in which abnormalfibroblastic activity predominates, and there is disorganisation of the extracellular matrix

Table 3: Classification of osteoradionecrosisYear Classification Stages/

gradesDescription Management

2002 Kagan and Schwartz’s staging[15]

Stage I Minimal soft tissue ulceration and limited exposed cortical bone

Conservative management

Stage II Localized involvement of the mandibular cortex and underlying medullary bone

Conservative management or minor surgical procedures

Stage II a Minimal soft tissue ulcerationStage II b Presence of an oro-cutaneous fistula and mild soft tissue

necrosisStage III Full thickness involvement of the bone, including the

inferior border. Pathological fracture may also be presentSurgical intervention, including bone and/or soft-tissue replacement

2009 Bone toxicity according to the National Cancer Institute Common Terminology Criteria[12]

Grade 1 Asymptomatic Clinical or diagnostic observations only; intervention not indicated

Grade 2 Symptomatic Medical intervention indicated (e.g., topical agents); limiting instrumental ADL

Grade 3 Severe symptoms Limiting self-care ADL; elective operative intervention indicated

Grade 4 Life-threatening consequences Urgent intervention indicatedGrade 5 Death

ADL: Activities of daily living

Table 4: Risk factors of osteoradionecrosisType of risk factors Risk factors Description of risk factors

Patient related factors

Gender[15] Male predominance (male:female=1.6:1)Age[16] Common in elderly patientsRace[15] Common in whites (74%)

Tumour-related factors

Site[15] The oral cavity and oropharynx comprised the vast majority of primary tumors leading to osteoradionecrosis of the jaws

Histopathology[17] Squamous cell carcinoma is more prone to lead to the occurrence of osteoradionecrosisStage[18] As the stage of carcinoma increases the risk for development of osteoradionecrosis increasesSize[16,17] Larger tumours were associated with higher incidence of osteoradionecrosis

Treatment-related factors

Radiotherapy setting[15,18] Patients undergoing adjuvant radiotherapy had more risk for developing osteoradionecrosisRadiotherapy modality[15,17] 3D-CRT or IMRT, have reduced the risk of developing osteoradionecrosisRadiotherapy dose[17,18] Risk of developing osteoradionecrosis increases with higher RT dosesChemotherapy[16,17] Increases acute toxicity especially mucositis, but its effect on late toxicity is less clearSurgery[17,18] Ablative surgical procedures increased risk of developing osteoradionecrosis after radiation

Miscellaneous factors[15-18]

Active smoking[15-18] Tobacco smoking as a risk factor for osteoradionecrosisAlcohol[16] Alcohol consumption during and after radiotherapy is one of the risk factors for developing

osteoradionecrosisInadequate oral hygiene[17] Poor oral hygiene increases the risk for development of osteoradionecrosisSteroids and anticoagulants[15]

Steroid and anticoagulants use before or after radiation reduced the risk of osteoradionecrosis

Dental diseases[15] Positive association between presence of dental disease pre-radiation therapy and osteoradionecrosis

Body-mass index[16] For every one point increase in BMI, osteoradionecrosis risk decreased by 27%Secondary infection[17] Secondary infection in post-radiotherapy phase correlated with severe mandibular

osteoradionecrosisDental extraction[18] Dentoalveolar surgery in post-radiotherapy phase is an established predisposing factor for

the development of osteoradionecrosisNutritional status[15] Poor nutritional status increases the risk of osteoradionecrosis

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Figure 3: Delanian’s radiation-induced fibroatrophic theory

Figure 1: Meyer’s radiation, trauma and infection theory Figure 2: Marx’s hypoxic-hypocellular-hypovascular theory

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• The late fibroatrophic phase, when attempted tissueremodelling occurs with the formation of fragile healed tissues that carry a serious inherent risk of late reactivated inflammation in the event of local injury.[10]

Microbiology

Osteoradionecrosis was earlier attributed to secondary infection in the traumatized irradiated tissue following the nonhealing wounds and exposed bone. However, this was challenged by Robert Marx in 1983.[20] The detailed description of various microorganisms detected in osteoradionecrosis is given in Table 5.[8,22‑27] Further studies on bacterial flora associated with osteoradionecrosis are required, which may contribute to a more precise use of antibiotics.

Clinical features

The incidence of osteoradionecrosis varies from 0.95% to 35% as shown in Table 6.[28‑36] The patient is usually asymptomatic. Pain and evidence of exposed bone are the most common chief complaints. Trismus, fetor oris, and elevated body temperature are usually present during the initial period although acute infection is usually not present. Other clinical features of osteoradionecrosis are swelling, nonresolving painful mucosal ulcer, dysgeusia, dysguesia, xerostomia, food impaction, malocclusion, telangiectasia, orocutaneous fistula, and missing hair follicles. The tissues surrounding the bone may be indurated. Surface texture changes such as cutaneous flaking and keratinisation may be present. Surface colour changes may also be seen. Pathologic fracture of the jaws may be evident in severe cases. Rarely, Deep cellulitis of face and neck may be present.[28]

Radiological features

The presence of osteoradionecrosis cannot always be diagnosed radiographically and often clinically obvious signs of exposed necrotic may not be accompanied by significant radiologic changes.

Plain radiography shows an ill‑defined cortical destruction without sequestration. The periphery may be ill‑defined as in osteomyelitis. Bone pattern can be granular. Scattered regions of radiolucency may be seen, with or without central sequestra. The most common effect on surrounding bone is stimulation of sclerosis.

Computed tomography plays an important role in diagnosis of osteoradionecrosis since it is hard tissue lesion. Anterior–posterior and supero–inferior extent of the osteolytic lesion is best judged with CT scans comparatively. Hence, from diagnostic purpose to the surgical intervention, CT is recommended as far as osteoradionecrosis is concerned.[29]

MRI reveals development of new heterogeneous signal within the marrow of an irradiated area (intermediate or low T1 signal, intermediate or high T2 signal). Adjacent muscles may appear oedematous and show intense enhancement, which can be

difficult to differentiate from recurrent tumour if bone changes are not visible on CT.[28]

PET scan is helpful to differentiate between osteoradionecrosis and recurrent tumour.[28]

Radionuclide bone scanning with technetium methylene diphosphonate (99mTc‑MDP) can identify pathophysiologic

Table 5: Microbiology of osteoradionecrosisYear Author(s) Microorganisms isolated

1983 Marx[8] Surface contaminants2005 Store and

Olsen[22]

Polymicrobial bacterial infection-rods, spirochetes and cocci. Rods were the predominant

2005 Støre, Eribe and Olsen[22]

Porphyromonas gingivalisActinomyces species

2006 Hansen, Wagner, Kirkpatrick and Kunkel[23]

Actinomyces species

2007 Nason and Chole[24]

50% of the oral and 80% of the intestinal indigenous bacterial flora consist of uncultured phylotypes

2005 Aas, Paster, Stokes, Olsen and Dewhirst[25]

FirmicutesActinobacteriaProteobacteriaFusobacteria-Fusobacterium nucleatumSpirochaetesBacteroidetesCampylobacter gracilisStreptococcus intermediusPeptostreptococcus sp. oral clone FG014Uncultured bacterium clone RL178Prevotella spp

1988 Calhoun, Shapiro, Stiernberg, Calhoun and Mader[26]

Streptococcus sp.Bacteroides sp.Lactobacillus sp.Eubacterium sp.Klebsiella sp.Actinomyces

2006 Kjetil Pedersen[27]

Treponema sppPorphyromonas gingivalis

Table 6: Incidence of osteoradionecrosisYear Author(s) Incidence (%)

1972 Carl, Schaaf, Chen, and Tak Yee[28] 41972 Daley, Drane, and Mc Comb[29] 221974 Wang[30] 171976 Bedwinck[31] 141980 Murray, Herson, Daly, and

Zimmerman[32]

19

1995 Constantino, Friedman and Steinberg[33]

5 to 15

1997 Epstein and van der Meij et al.[34] 5 to 151997 Clayman[35] Before 1968-11.8

After 1968-5.42000 Thorn, Sand Hansen, Specht and

Bastholt[36]

5 to 15

2003 Vissink, Jansma, Spijkervet, Burlage and Coppes[37]

2.6 to 22

2004 Reuther, Schuster, Mende, and Kübler[38]

1 to 37.5

2006 Wahl[39] 3 to 3.5

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Table 7: Preventive management of osteoradionecrosisMeasures to be taken

Preradiation protocolA thorough clinical and radiographic examination is recommended for patient scheduled for radiotherapyTeeth with poor prognosis should be removedOral hygiene regimen should be started as soon as possible. This includes.

Teeth brushing with soft brush with the frequency of four times dailyWarm saline (NaCl and NaHC03) mouth wash daily especially after brushingFluoride treatment either 0.4% stannous fluoride gel, 1% sodium fluoride or 1% acidulated fluorophosphate gel in a custom tray for 15 min twice daily

Intraradiation protocolWeekly prophylaxis with fluoridated polishing pasteAnalgesics, dietary supplements, antifungal and antibiotics prescription

Postradiation protocolPatients who have completed radiotherapy should not wear dentures for at least a year to maximize tissue healingFluoride treatment and oral hygiene care should be continued. Artificial saliva may have to be prescribedLife-long follow-up

Table 8: Precautions to be taken for dental extractions in osteoradionecrosisPrecautions to be taken

Preradiotherapy dental extractionsThe policy followed in most institutions is to remove unrestorable teeth prior to radiotherapyThe mandibular teeth in the bone to be radiated above 6,000 cGy are indicated for extractionThe extractions should be carried out in a nontraumatic manner with minimal damaged to the surrounding tissues. Planned preradiotherapy extractions include alveoloplasty and primary closure with minimal periosteal elevationAntibiotic therapy is usually prescribed for 1 to 4 weeksThe interval period between extraction and radiotherapy is extremely crucialBeumer III and Curtis and Maxymiw, Wood & Liu stated that at least two weeks interval is required in order not to delay the radiation therapyMarx and Johnson recommended an interval of three weeks before commencing radiotherapy, based on experimental studies that show osteoid takes 3 weeks to formTeeth with questionable prognosis should be carefully discussed with the patient

Post-radiotherapy dental extractionsExtractions should be limited to one or two teeth at a timeThe techniques should be as Atraumatic and aseptic as possibleFlaps should be raised conservatively to minimize displacement of mucoperiosteumSharp projections of bone require· re-contouring or minor alveoloplasty followed by primary closureHyperbaric oxygen therapy can be considered as prophylaxis against ORNThe prophylactic use of ultrasound as an alternative to hyperbaric oxygen is recommended by Reher and HarrisProphylactic antibiotics for extractions are required

ORN: Osteoradionecrosis

changes in bone earlier than conventional radiography because scan changes reflect osteoblastic activity and good blood flow.[28]

Infrared spectroscopy is a noninvasive method. This shows a reduction of the amount of deoxygenated haemoglobin

at sites of osteoradionecrosis, confirming that it is a hypovascular and hypoxic tissue with decreased metabolic rate.[28]

Histologic features

The histological findings noted by Marx showed endothelial death, hyalinisation, and thrombosis of vessels with a fibrotic periosteum.[25]

Diagnostic criteria

In 1997, Wong, Wood, and McLean have given diagnostic criteria for osteoradionecrosis that seem to be agreed by the majority of the authors:• Theaffectedsiteshouldhavebeenpreviouslyirradiated• Thereshouldbeabsenceofrecurrenttumourontheaffected

site• Mucosalbreakdownorfailuretohealshouldoccur,resulting

in bone exposure• Theoverlyingboneshouldbe‘dead’,usuallyduetoahypoxic

necrosis• Cellulitis, fistulation, orpathologic fractureneednotbe

present to be considered as osteoradionecrosis.[30]

Osteoradionecrosis usually develops after 3‑6 months having bone exposure at least for 3 months.[30]

Management

The management of osteoradionecrosis is divided into two methods.1. Preventive management2. Therapeutic management.

Preventive management

The prevention of osteoradionecrosis begins as early as the head and neck malignancy is diagnosed. The patient should be reviewed by the multidisciplinary team consisting of

Table 9: Therapeutic management of osteoradionecrosisMethods

Nonsurgical managementPharmacological

Antibiotic therapyAnalgesicsAntifungal therapyAntiviral therapyNewer agents: Pentoxyphilline, tocopherol, clodronate and combination therapy

NonpharmacologicalLocal wound careHyperbaric oxygen therapyUltrasound therapyElectrotherapyOzone therapy

Surgical managementSequestrectomyResection with continuity defectReconstructionRehabilitation

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a dentist/oral and maxillofacial surgeon. The measures taken toprevent osteoradionecrosis, as perDonoff’s protocol, arementioned in Table 7.[37] The precautions that are to be taken during dental extraction are summarized in Table 8.[38]

Therapeutic management

The nonsurgical and surgical management with a note on recent medications are summarized in Table 9.[39]

Conclusion

Osteoradionecrosis can be a cruel blow to patients and their families who have been enduring radiotherapy for the treatment of cancer. Prevention of osteoradionecrosis by regular follow‑up and early diagnosis should be the goal of every health care professional managing head and neck cancer patients. Improved radiotherapy protocols, multidisciplinary preventive care and reconstructive surgery can help to improve the quality of life of patients suffering from osteoradionecrosis.

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Source of Support: Nil, Conflict of Interest: None declared.

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