Continuing Education Activity

Osteoradionecrosis (ORN) of the mandible is a severe iatrogenic disease of devitalized bone caused by radiation therapy of oral and oropharyngeal cancers. It is a state of injured bone tissue with inadequate healing or remodeling response of at least three to six months. The wound can result from radiotherapy combined with mechanical insult or radiotherapy exposure alone. This activity reviews the evaluation, treatment, and complications of mandibular osteoradionecrosis and underscores the importance of an interprofessional team approach to its management.

Objectives:

• Describe the etiology and pathophysiology of mandibular osteoradionecrosis.
• Review the examination process for evaluation of a patient with mandible osteoradionecrosis, including indicated diagnostic imaging.
• Summarize the preventative strategies for and treatment of mandibular osteoradionecrosis.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by osteoradionecrosis of the mandible.

Introduction

Osteoradionecrosis (ORN) of the mandible is a severe iatrogenic disease of devitalized bone caused by radiation therapy of oral and oropharyngeal cancers. It is a state of injured bone tissue with inadequate healing or remodeling response of at least three to six months. The wound can result from radiotherapy combined with mechanical insult or radiotherapy exposure alone. ORN is separate from primary bone infection or persistent/recurrent malignancy, though its clinical presentation can mimic both. While there is no universally accepted pathophysiologic description, relative tissue hypoxia and the potential effects of free radicals are commonly cited mechanisms and form the basis of most treatment strategies.[1][2][3][4]

Etiology

Radiation is a useful tool in the treatment of various cancers by damaging DNA and preventing cells from completing mitosis. Radiotherapy indiscriminately damages cells, whether they are malignant or normal, but has the most profound effects on rapidly dividing cells. As tumor cells may divide at a greater rate than non-tumor cells, they are preferentially affected; however, non-tumor cells with rapid turnover are at risk. The normal osteoclast/osteoblast activity of bone healing is undoubtedly affected and is one proposed cause of ORN. Squamous cells divide frequently and are therefore very radiosensitive, leading to the radiation-induced mucositis and dermatitis frequently observed. As there is a more robust and redundant blood supply to the skin and mucus membranes than bone and cartilage, the former tends to heal with time, while the latter may have a protracted or arrested healing course. Radiotherapy can additionally cause progressive endarteritis (damaging large- and medium-caliber vessels), as well as hindering the capillary regrowth present in normal healing. This subsequent reduction of tissue perfusion in areas exposed to radiation leads to the protracted open wounds of ORN.[5] The loss of cellularity along with impaired tissue repair mechanisms limits successful healing of the bone, leaving a chronic non-healing wound.

Epidemiology

Since the 1970s, the incidence of ORN caused by radiation hovers at approximately 3%. ORN presents, on average, two to four years after completion of radiation treatments. There is a subset of patients who will have persistent non-healing wounds at the primary tumor site (often in the mandible and larynx) that will persist immediately after radiation therapy and ultimately result in ORN or chondroradionecrosis. Most notably, the incidence is affected by radiation dose - the higher the total dose, the more likely a patient is to develop ORN. Mechanical injury anytime after radiotherapy initiation can also predispose one to ORN; in the mandible, this is commonly seen after treatment has been completed and implants are placed for dental rehabilitation. ORN can, therefore, occur years after radiotherapy, both spontaneously or induced by an insult. Mechanical insults such as dental extractions, dental implants, or poorly fitting dentures can increase the risk of developing ORN.

Pathophysiology

ORN results from a sequence of injury events beginning with radiation exposure and can be exacerbated by surgical manipulation of the affected tissue. The radiated mandible and surrounding tissues develop hyperemia, inflammation, and obliterative endarteritis. The small vessels are thrombosed, causing hypovascular-hypocellular-hypoxic tissue, which undergoes tissue breakdown. The rate of cell death and collagen lysis exceeds the homeostasis of cell replacement and collagen synthesis. The inability to repair leads to further inadequate vasculature and oxygen delivery. The overall result is a chronic, aseptic, non-healing wound. This gestalt mechanism has been proposed as a combination of earlier theories on the pathophysiology of ORN. Marx's theory proposes such acquired hypovascularity and hypoperfusion lead to the non-healing state and forms the rationale for hyperbaric oxygen (HBO) treatment. Delanian's fibroatrophic theory proposes fibroblast dysregulation and ultimately the breakdown of the healing response, leading to "fibrous atrophy," rendering tissues more prone to breakdown with minimal mechanical stressors. This forms the basis of treatments utilizing antifibrotic and antioxidant medications and is widely accepted today.[6][7][8]

Toxicokinetics

The most recent studies find ORN is rarely reported at a total radiation dose less than 6000 rads in six weeks. The next two dose ranges and their ORN incidences are 6000-7000 (1.8%) and > 7000 (9%) rads in seven weeks. As most head and neck cancers are treated to a cumulative dose of 70 Gy over six weeks, primarily oral and oropharyngeal cancer patients are at the highest risk of developing ORN.

History and Physical

The most common complaint will be a painful mouth lesion that will not heal. The patient may report an oral ulcer that persists despite treatment, odynophagia, pain-related trismus, occlusal changes, a foreign body sensation in the mouth, or the expectoration of bone chips. Occasionally halitosis or other odor-related complaints will be the presenting symptom. It is important to obtain a detailed oncologic history, including the site and stage of the primary tumor, dates of initiation and termination of radiation and/or chemotherapy, and any prior surgery. Dental history must be carefully obtained, including pre-radiation dental therapy, as well as any post-radiation dental cleanings or other procedures (implants, dentures, obturators, etc.). Oral cavity examination may reveal an obvious lesion or may reveal only granulation tissue. Flexible laryngoscopy is indicated to assess the larynx and posterior rami of the mandible and their mucosal covering, particularly in the setting of odynophagia. If the patient has teeth, a dental examination is warranted, as any loose teeth may be a harbinger of underlying ORN, as may periodontal disease. Any suspicious lesions or areas of granulation tissue must be biopsied to rule out the persistence/recurrence of cancer before any ORN treatment is begun.  A thorough neck exam is warranted to look for tumor masses or lymphadenopathy that may indicate recurrent disease.

Evaluation

The evaluation should include:

• Review radiotherapy and dental record

• Biopsy of wound

• Panographic Radiographs

• CT of mandible

• Stage the disease

Rule out recurrence/persistence of primary malignancy or new secondary malignancy by getting a biopsy of the wound.[9][10][11][8]

Imaging studies aid in the diagnosis and quantify the extent of disease.

CT findings:

• Cortical bone disruption with mixed lysis and sclerosis can be seen. Pathologic fractures can also be seen.

Panographic radiograph findings:

• Plain radiographs are useful for screening but can underestimate the extent of lesions.

• Lytic areas with ill-defined, non-sclerotic borders can be seen.

Gather record of radiotherapy and review treatment method, radiation portal, and total dose.

Marx Staging of ORN is the most common staging system in use. It is based on response to hyperbaric oxygen therapy (HBO).

• Stage 1

• Exposed alveolar bone without pathologic fracture, which responds to hyperbaric oxygen therapy and minor bony debridement

• Stage 2

• The disease does not respond to 30 daily HBO treatments with minor bony debridement, or it requires major bony debridement initially. They are then considered Stage 2 and receive more radical surgical debridement plus ten postoperative HBO treatments.

• Stage 3

• Failed treatment in stage 1 or 2 or initially present with signs below:

• Pathologic fracture

• Orocutaneous fistulae

• Evidence of lytic involvement of inferior mandibular border

• Treatment involves mandibular segmental resection of all necrotic bone and 30 preoperative and ten postoperative HBO treatments.

Treatment / Management

The prevention of ORN is extremely important. The approach to ORN treatment is separated into two phases: pre-radiotherapy prevention and ORN rehabilitation. ORN can be managed dentally, medically, surgically, and hyperbaric oxygen.[12][13][14]

The pre-radiotherapy phase of a patient who will be undergoing radiotherapy of the oral cavity includes a pretreatment dental evaluation and management by a dentist experienced with head and neck cancers. The pretreatment evaluation should include full mouth radiographs, dental and periodontal diagnosis, and extraction of teeth with poor prognosis. A tooth extraction should ideally occur at least two weeks before radiotherapy. Optimal dental health is necessary for the lowest risk of ORN. Dental prophylaxis and management should occur before, during, and after radiotherapy. Medical treatment plays a small role in the prevention and management of ORN. Maintaining adequate nutrition and saline irrigation helps to manage oral mucositis. Antibiotics are only necessary when a definitive secondary infection is also present. Pentoxifylline, an anti-inflammatory and vasodilator, has been useful for treating soft-tissue involvement and as a sialoprotective agent.

Treating diagnosed ORN requires surgical intervention. The non-viable bone will need to be removed. For planned surgery or tooth extraction in a tissue area with more than 60 Gy, HBO can be utilized prophylactically. The role of HBO is to promote angiogenesis in hypoxic tissues, thus promoting optimal reparative conditions. The standard HBO protocol includes 30 preoperative and ten postoperative treatments. The treatments occur at 2-2.5 atmospheres for 90–120 minutes, do one treatment per day, five days per week. Subsequent surgical intervention will vary with the severity of the ORN. The bone must be debrided down to healthy, bleeding bone. Depending on the location and status of surrounding tissues, local flaps can often be advanced to cover the bone. If this is unsuccessful, regional or free flaps may be required to bring in healthy, non-radiated tissue to cover and salvage the devitalized bone.[15] If these measures fail, segmental mandibulectomy with vascularized bone flap reconstruction may be required.

Differential Diagnosis

• Calcifying crown
• Odontoma
• Periapical abscess
• Periapical granuloma
• Rarefying and condensing osteitis

Pearls and Other Issues

Unavoidable post-radiotherapy extractions require careful planning and management. However, ORN risk similar to pre-radiotherapy extractions can be accomplished with HBO before and after extraction. The protocol is 20 pre-extraction treatments and ten post-extraction treatments to 2.4 atmospheres for 90 minutes, one treatment per day, five days per week.

Bisphosphate-related osteonecrosis of the jaw (BRONJ) is a separate disease sharing some similarities to ORN of the mandible. The etiology of BRONJ is due to bisphosphate usage often combined with trauma to dentoalveolar tissues. Both diseases result in a chronic, poorly healing wound of the bone. Differentiating the two relies on clinical history and imaging. ORN has a history of radiation exposure and has osteolytic lesions on CT imaging. BRONJ has a history of bisphosphate usage and is more likely to have osteosclerotic lesions on CT imaging. Differentiating the two is important as the treatment approach is distinctly oppositional. BRONJ is more likely to respond to medical treatment without the need for surgical interventions. As discussed, ORN is primarily treated surgically.

Enhancing Healthcare Team Outcomes

The diagnosis and management of ORN are best carried out with an interprofessional team that includes a dentist, surgeon, pharmacist, hyperbaric medicine specialist, and a nurse. 

The prevention of ORN is extremely important. Therefore, the approach to ORN treatment is separated into two phases: pre-radiotherapy prevention and ORN rehabilitation. ORN can be managed dentally, medically, surgically, and hyperbaric oxygen.

The pre-radiotherapy phase of a patient who will be undergoing radiotherapy of the oral cavity includes a pretreatment, dental evaluation, and management by a dentist experienced with head and neck cancers. The pretreatment evaluation should include full mouth radiographs, dental and periodontal diagnosis, and extraction of teeth with poor prognosis. Medical treatment plays a small role in the prevention and management of ORN. Maintaining adequate nutrition and saline irrigation helps to manage oral mucositis. 

Treating diagnosed ORN requires surgical intervention. First, the non-viable bone will need to be removed. For planned surgery or tooth extraction in a tissue area with more than 60 Gy, HBO should be utilized prophylactically. The role of HBO is to promote angiogenesis in hypoxic tissues, thus promoting optimal reparative conditions.

The prognosis of patients with ORN is guarded and related to the severity of the ORN, location of the affected bone, and overall medical and dental health of the patient. It is essential to rule out persistent or recurrent malignancy before treatment of any kind is initiated for suspected ORN.[16] [Level V]