Osteoradionecrosis of the Mandible

Frequency

ORN is rare in patients who receive less than 60 gray (Gy) radiation therapy. Patients with ORN who receive less than 60 Gy and more than 50 Gy have been reported, but these cases are extremely rare. The overall incidence of ORN has decreased since the latter part of the 20th century. In general, studies from prior to the 1970s showed an ORN incidence from 5.4-11.8%. Studies in the early years of the 21st century, however, placed the incidence closer to 3.0%.[2] The true frequency of ORN is impossible to determine because no mechanism exists for reporting the disease. Incidence is increased in patients who receive combined chemotherapy-radiation. The Radiation Therapy Oncology Group (RTOG) requires their members to report radiation toxicity including ORN; however, the disease is probably under-reported.

More valuable than an understanding of frequency is an appreciation for the decrease in reparative capacity in tissue exposed to more than 60 Gy of radiation.

ORN can be either spontaneous or the result of an insult. Spontaneous ORN occurs when, in the process of otherwise normal turnover of bone, the degradative function exceeds new bone production. ORN develops following injury when the reparative capacity of bone within an irradiated field is insufficient to overcome an insult. Bone injury can occur through direct trauma (eg, tooth extraction [84%], related cancer surgery or biopsy [12%], denture irritation [1%]) or by exposure of the irradiated bone to the hostile environment of the oral cavity secondary to overlying soft tissue necrosis.[3] The cumulative progressive endarteritis caused by radiotherapy results in insufficient blood supply (tissue oxygen delivery) to effect normal wound healing.

A study by Chronopoulos et al indicated that risk factors for grade III osteoradionecrosis include active smoking, excessive alcohol use, diabetes mellitus, and dental treatment and/or local pathologic conditions. The study involved 115 patients (153 lesions).[4]

A study by Huang et al found that in head and neck cancer patients, the presence of sialadenitis was associated with a 2.55-fold increase in the risk for osteonecrosis of the jaw (ONJ), with the likelihood of ONJ development being particularly high in oral cancer patients with both sialadenitis and radiation exposure (odds ratio = 15.9).[5]

The images below depict a patient who developed ORN following tooth extractions.

This patient developed ORN following tooth extractions. Sequential debridement was attempted prior to patient referral.

The patient seen in the image above developed a pathologic fracture at the mandibular angle. He underwent resection of the area of the fracture. At the time of surgery, surgeons thought the patient had bleeding bone, but further ORN is evident.

A retrospective study by Kubota et al indicated that in patients with head and neck squamous cell carcinoma, independent risk factors for ORN of the jaw include oropharyngeal or oral cancer, as well as administration of 60 Gy of radiation to more than 14% of the jaw’s volume (V60 >14%). The investigators found the 3-year cumulative incidence rate of jaw ORN to be 8.6% in patients with V60 of greater than 14%, compared with 2.5% in those with V60 of 14% or less. In addition, patients with a primary oropharyngeal or oral cancer site had a 3-year cumulative incidence rate of 9.3%, compared with 1.4% in those with other cancers.[6]

In a retrospective study of ORN development in association with postoperative radiation therapy in patients with oral cavity cancer, Möring et al found that for active smokers at diagnosis who received 60 Gy or more to a volume of over 40%, the 1-year incidence of ORN was 29%. This was in contrast to an estimated cumulative 1-year incidence of 8.4% for the entire cohort. Forty one of the 46 cases of ORN in the study were in the mandible.[7]

A study by Caparrotti et al found ORN of the mandible to be relatively uncommon in patients with squamous cell carcinoma of the oropharynx who underwent curative-intent treatment with intensity-modulated radiotherapy (IMRT). Even so, it was reported that ORN continued to develop more than 5 years posttreatment in these patients. The study also found that the ORN rate may be reduced by minimizing the mandibular volumes receiving more than 50 Gy or over 60 Gy during treatment. In addition, the data indicated that smoking and bisphosphonate use are modifiable risk factors for ORN.[8]

ORN was first described by Marx in 1983 as hypovascularity, hypocellularity, and local tissue hypoxia.[9, 10] Prior to this, many other theories existed regarding the etiology of ORN. The report by Marx, clinical experience, and subsequent research support this now widely accepted theory.

The irradiated mandible, periosteum, and overlying soft tissue undergo hyperemia, inflammation, and endarteritis. These conditions ultimately lead to thrombosis, cellular death, progressive hypovascularity, and fibrosis. The radiated bed is hypocellular and devoid of fibroblasts, osteoblasts, and undifferentiated osteocompetent cells.

Mandibular ORN develops most commonly after local trauma, such as dental extractions, biopsies, related cancer surgery, and periodontal procedures, but it may also occur spontaneously.

Clinical signs and symptoms include the following:

• Pain

• Swelling

• Trismus

• Exposed bone

• Pathologic fracture

• Malocclusion

• Oral cutaneous fistula formation

On physical examination, missing hair follicles, surface texture changes, and color changes are common findings that assist clinicians in assessment of the area of radiation injury.

In a histologic study of irradiated osteoradionecrotic mandibles, several characteristic changes were noted. The inferior alveolar artery (the predominant arterial blood supply to the body of the mandible) and periosteal arteries had significant intimal fibrosis and thrombosis. Normal marrow was replaced by dense fibrous tissue with loss of osteocytes. Finally, the study noted buccal cortical necrosis with sequestrum formation and periosteal fibrosis with a tendency to detach from the cortex.[11] In the elderly, the inferior alveolar artery’s flow to the mandible diminishes and the periosteum and muscle attachments predominate as the primary blood supply. The thrombosis of the inferior alveolar artery and surgical disruption of this soft tissue blood supply may contribute to the development of osteoradionecrosis (ORN).

Rule out recurrence or second primary malignancy through biopsy where indicated. Obtain the radiation oncology treatment summary to determine the method of treatment, total dose, and radiation portal.

Radiography

Plain radiography of the mandible, or Panorex, depicts areas of local decalcification, osteolysis (see the images below) or sclerosis.

An absence of healing is evident in this radiograph following extraction of a tooth within a field of radiation therapy.

Osteoradionecrosis developed in the patient seen in the image above. Osteolysis is clearly evident.

Pathologic fracture has developed in this case of osteoradionecrosis (ORN). This constitutes, by definition, stage III disease. This is the same patient seen in the 2 images above.

CT scanning and MRI 

CT scanning and MRI may allow early diagnosis of osteoradionecrosis (ORN) and better delineate the extent of disease.

MRI depicts ORN with reduced bone marrow signal intensity on T1-weighted images and increased signal intensity on T2-weighted images.

Absence of marrow signal on MRI can be used to identify significant radiation injury in the mandible. This abnormal bone must be excised in the definitive treatment.

Panoramic radiography and CT scan images can be used to determine sites of significant bone injury. Alteration in trabeculation, cortical thinning, and sclerosis are common findings in sites of injury.

A retrospective study by Akashi et al found that CT scanning demonstrated periosteal reaction in patients with medication-related osteonecrosis of the jaw but not in those with ORN.[12]

SPECT scanning

Single-photon emission computed tomography (SPECT) imaging may have a role in the future as more experience is gained with this modality.

Two specific intervals exist in which prudent clinical practice can diminish the incidence of osteoradionecrosis (ORN). These are in the pretreatment phase and in the rehabilitation phase.

All patients diagnosed with head and neck cancer (HNC) who may need radiotherapy to the oral cavity in the course of their cancer treatment should undergo a thorough pretreatment dental evaluation. The dentist who completes the evaluation must have experience with the management of patients with HNC. Such an individual is usually a part of the multidisciplinary cancer therapy team at large institutions but must be sought when treatment occurs elsewhere.

Prior to beginning radiation therapy, all patients should undergo a thorough dental evaluation, including full mouth radiographs, dental and periodontal diagnosis, and prognosis for each tooth. Outline a complete treatment plan, taking into account the patient's motivation and compliance based upon discussions with the patient and his or her family. Patient education regarding the need for meticulous oral hygiene and frequent follow-up must be stressed.

The dentist should perform prophylaxis, periodontal scaling, caries control, and fabrication of fluoride trays.

Teeth that cannot be salvaged with conservative endodontic therapy should be extracted. Ideally, extractions should be performed 3 weeks prior to beginning radiation therapy. Extraction of teeth during radiation therapy should be discouraged and delayed until the completion of treatment with resolution of the oral mucositis.

To prevent radiation caries, patients should begin daily fluoride treatment with 1% neutral sodium fluoride gel in prefabricated trays for 5 minutes each day. This practice should continue for life.

Medical therapy in treatment of ORN is primarily supportive, involving nutritional support along with superficial debridement and oral saline irrigation for local wounds. Antibiotics are indicated only for definite secondary infection. Pentoxifylline has been used for the treatment of radiation-related soft tissue injury with some success. Its use in the treatment of mandibular ORN is unknown, however.

A study by Rogers et al indicated that the health-related quality of life is relatively poor in patients with severe ORN of the mandible who undergo composite resection. The investigators, whose study involved 71 patients with ORN of differing severity levels, suggested that it may be appropriate to use nonsurgical management of osteonecrosis for as long as possible, delaying resection and reconstruction until the patient experiences a significant reduction in quality of life and pain control becomes difficult.[13]

Hyperbaric oxygen (HBO) therapy is outlined below.

Treatment of mandibular ORN is controversial. In 1983, Marx demonstrated successful resolution of mandibular ORN in 58 patients using a staged protocol with HBO and surgery.[10] HBO transiently elevates tissue oxygen tension and stimulates fibroblastic proliferation and oxygen-dependent collagen synthesis. This allows for angiogenesis in the radiated bed. This does not totally resolve the radiation injury, however, and some degree of tissue hypoxia persists.

Current protocol for treatment of mandibular ORN, according to Marx

Stage I: Perform 30 HBO dives (1 dive per day, Monday-Friday) to 2.4 atmospheres for 90 minutes. Reassess the patient to evaluate decreased bone exposure, granulation tissue that covers exposed bone, resorption of nonviable bone, and absence of inflammation. For patients who respond favorably, continue treatment to a total of 40 dives. For patients who are not responsive, advance to stage II.

Stage II: Perform transoral sequestrectomy with primary wound closure followed by continued HBO to a total of 40 dives. If wound dehiscence occurs, advance patients to stage III. Patients who present with orocutaneous fistula, pathologic fracture, or resorption to the inferior border of the mandible advance to stage III immediately after the initial 30 dives.

Stage III: Perform transcutaneous mandibular resection, wound closure, and mandibular fixation with an external fixator or maxillomandibular fixation, followed by an additional 10 postoperative HBO dives.

Stage IIIR: Perform mandibular reconstruction 10 weeks after successful resolution of mandibular ORN. Marx advocates the use of autogenous cancellous bone within a freeze-dried allogeneic bone carrier. Complete 10 additional postoperative HBO dives.

The use and efficacy of HBO prior to tooth extraction has been debated in the literature. Those who argue against the use of HBO prior to tooth extraction state that the overall risk of developing ORN with preradiation or postradiation extractions is quite low, that HBO therapy is expensive, and that it is time consuming.[14, 15] HBO has not definitely been shown to prevent the development of ORN, and it does not reverse established ORN. However, several studies have shown some benefit in using HBO in the management of Stage I and II ORN.[16, 17] Most reconstructive surgeons currently use vascularized free tissue transfers instead of HBO therapy in the management of stage III ORN.

Microvascular reconstruction

Microvascular free tissue transfer offers the clinician and patient a 1-stage procedure to correct mandibular ORN. Significant experience and documentation of the use of immediate reconstruction of the mandible using free bone flaps has been reported in the literature. Microvascular free tissue transfer is considered the standard of care for stage III ORN management. Particular care must be exercised in delineating the margins of resection when a primary bone flap is planned. Preoperative planning must also address the availability of suitable recipient vessels within the neck for microvascular anastomosis.

After resection of nonviable bone, vascular free tissue transfer offers immediate reconstruction and restoration of mandibular continuity. Free tissue transfers offer patients a shorter treatment course, often without the need for HBO.

Early criticism of microvascular reconstruction of the mandible included inadequate bone stock for prosthetic dental reconstruction, prolonged ICU stay and hospitalization, and increased donor site morbidity. Experience with microvascular reconstruction has lessened these concerns.

The literature in fact shows that dental rehabilitation can reliably be successfully completed on patients who receive fibula or iliac free bone flaps.[18] Documented cases also exist of implant-supported dental rehabilitation in patients who underwent scapula and radial bone flaps, although these certainly are exceptions to the norm.[19, 20, 21, 22, 23] The total treatment cost is decreased when primary mandibular reconstruction is completed with free tissue transfer.

Prudent clinical practice can diminish the incidence of ORN at 2 specific intervals. These are in the pretreatment phase and in the rehabilitation phase.

The risk of developing ORN is clearly cumulative in relation to radiation dose, and risk continues throughout the patient's life. In fact, the risk of ORN in patients who must undergo procedures that involve the mandible following radiation treatment increases with time from radiation therapy. Before dental rehabilitation, perform a careful assessment of risk of ORN. Prior to dental extraction or dental implant placement, radiation fields and doses must be ascertained. The clinician must then determine the patient’s potential benefit from HBO therapy on a case-by-case basis.[24]

The use of HBO therapy prior to implant placement has also been debated. The use of HBO may decrease morbidity and increase the success of dental implant therapy. Recent studies have shown an increase in long-term dental implant failure in patients who did not receive HBO with implant placement.[25] The placement of dental implants in irradiated jaws carry the same risk for developing ORN as those seen with tooth extractions in a similar clinical setting.

Prior to dental extraction/implant placement, consider HBO if surgery will occur in a field of radiation that is known to have received 60 Gy. Follow the standard HBO regimen of 20 preoperative treatments and 10 postoperative treatments. Perform surgery in as atraumatic a fashion as possible. When placing dental implants, allow for a marked decrease in integration rates (65-80% vs 95%).

Data available are insufficient to assist clinicians faced with the management of osteoradionecrosis (ORN) in counseling patients as to the anticipated outcome of therapy. Additional documentation regarding the costs and successful outcomes for primary versus secondary reconstruction are needed. Patient satisfaction for each available therapy must be further investigated. A significant problem exists when consulting with patients who received previous radiation therapy prior to dental extraction. The costs of prophylactic hyperbaric oxygen (HBO) are a major consideration because inadequate outcome data often result in failure to receive insurance authorization for prophylactic HBO.

The increased use of radiation therapy concurrently with chemotherapy warrants attention to incidence rates for development of osteoradionecrosis (ORN). The potential for increased tissue sensitivity in the setting of such therapy has not been well studied. Development of late complications of therapy is seldom considered in short-term studies of multimodality therapy. Efforts should be made to monitor patients who have been enrolled in such treatment protocols for long periods of time to evaluate the quality of life and late complications of therapy.

Modalities and treatments for mandibular ORN are numerous and controversial. Although some authors recommend a combination of hyperbaric oxygen (HBO), sequestrectomy, resection, and free bone grafts, others recommend vascularized free tissue transfer without HBO. Definite advantages and disadvantages of each method exist. Several important facts are known, including the following:

• HBO reduces radiation-induced hypoxia, hypovascularity, and hypocellularity and improves wound healing.

• Dead necrotic bone requires resection.

• Vascularized free tissue transfer provides an immediate reconstruction option with a shortened treatment course.