Osteoradionecrosis (ORN) is a serious complication of radiation therapy in cancer treatment where radiated bone becomes necrotic and exposed. ORN occurs most commonly in the mouth during the treatment of head and neck cancer, and can arise over 5 years after radiation. Common signs and symptoms include pain, difficulty chewing, trismus, mouth-to-skin fistulas and non-healing ulcers.
The pathophysiology of ORN is fairly complex and involves drastic changes to bone tissue as a result of DNA damage and cell death caused by radiation treatment. Radiation therapy targeting tumor cells can affect normal cells as well, which can result in the death of bone tissue. Advances in radiation therapy have decreased the incidence of ORN, estimated at around 2%. Certain risk factors including the size and location of tumor, history of smoking or diabetes, and presence of dental disease can affect the chances of developing ORN.
Osteoradionecrosis is difficult to prevent and treat. Current prevention strategies are aimed at avoiding excess doses of radiation as well as maintaining excellent dental hygiene. Treatments are variable depending on the provider and disease severity, and can range from medical treatment with antibiotics to hyperbaric oxygen therapy (HBO) to surgical debridement or reconstruction.
Clinical findings There are not many specific clinical signs of ORN. It may be first seen as an area of exposed bone which is not healing, or the non-specific signs may become evident prior to this. Symptoms vary depending on the degree of ORN that has occurred. Early indicators may be numbness or paresthesias within the mouth or jaw. Other signs and symptoms include:
Pain Swelling Non-healing sore or ulcer in the mouth Trismus An extra-oral fistula (from jaw to skin) Infection in gums/teeth Extra-oral draining sinuses Lymphadenopathy Malocclusion Jaw fracture Sequestrum (most commonly found below the mandible)
If symptoms are evident, these should be reported to the patient's doctor or healthcare team as soon as possible.
Epidemiology and etiology
Epidemiology The epidemiology of osteoradionecrosis has proven difficult to estimate, with previous studies reporting incidence of disease between 4.74-37.5%. More recent reports have estimated the incidence to 2%, which is likely attributable to improvements in radiation therapy.
Pathophysiology Radiation therapy destroys cancer primarily by causing DNA damage that promotes cell death. Tumor cells within a cancer are especially susceptible to damage by radiation as they frequently develop mutations in the DNA repair mechanisms that allow normal, healthy cells to recover from radiation damage. However, excessive radiation doses can cause even normal cells to be overwhelmed by DNA damage and lead to local tissue changes and necrosis. Scientists have been conducting investigations into the exact mechanisms of these changes to help create treatments since osteoradionecrosis (ORN) was first described by Regaud in 1922. Several competing theories have emerged over the years with resultant changes to accepted treatments. Initially, it was believed that ORN arose from a combination of radiation, trauma and infection. According to this belief, radiation damage to the bone caused the bone to weaken, making it susceptible to microfractures caused by trauma and allowing bacteria to invade. This theory placed ORN on a spectrum of disease with osteomyelitis, so it was primarily treated with antibiotics. In 1983, Robert E. Marx, a prominent oral and maxillofacial surgeon, refuted the notion that trauma and infection were requirements in the development of ORN. Marx proposed that ORN was the result of cumulative tissue damage caused by radiation, creating disturbances in cell metabolism and homeostasis that resulted in cell death and hypocellular tissues. In addition, radiation causes injury to the endothelial cells of local vasculature, creating a hypovascular environment which leads to decreased oxygen delivery resulting in hypoxic tissues. The decrease of vasculature helps explain why the mandible is more commonly affected than maxilla, as the mandible is served primarily by the inferior alveolar artery, whereas the maxilla is served by various arteries and has a more robust blood supply. In sum, Marx believed that ORN was essentially hypocellular-hypovascular-hypoxic tissues behaved much like chronic non-healing wounds. Initial reports by Marx and others showing that treatment with hyperbaric oxygen (HBO) prevented ORN helped support this theory. However, later studies began to raise doubts about the effectiveness of HBO therapy and question whether Marx's theory was comprehensive enough to guide treatment.
Current understanding is guided primarily by the work of Delanian and Lefaix, who proposed the radiation-induced fibroatrophic (RIF) process. Advances in lab techniques allowed scientists to perform more detailed studies of ORN specimens. Analysis of samples showed that tissues undergoing ORN underwent three phases of disease: 1) prefibrotic, 2) constitutive organized and 3) late fibroatrophic phases. During the prefibrotic phase, injury to endothelial cells secondary to radiation causes destruction of local vasculature, and recruitment of inflammatory cells and fibroblasts via pro-inflammatory cytokines like TNF-α, FGF-β and TGF-β1. In addition, osteoblasts within the bone are damaged and destroyed, leading to decreased production of normal bone tissue. In the constitutive organized phase, fibroblasts persist and are converted to myofibroblasts by these same cytokines, that begin to fibrous extracellular matrix (ECM) within the affected bone. Consequently, the increased production of ECM by myofibroblasts coupled with decreased production of osteoid by osteoblasts results in weakened bony tissue. Finally, during the late fibroatrophic phase, the affected bone becomes hypocellular as myofibroblasts begin to die and leave behind weak, fibrotic tissue. Ultimately, these tissues are fragile and susceptible to damage by trauma or infection with little ability to repair or defend themselves due to the lack of vasculature caused during the pre-fibrotic phase. Given this understanding of the pathophysiology of ORN, current treatments are targeted at decreasing inflammatory cytokines and reducing free radical damage to DNA.
Risk factors Risk factors for osteoradionecrosis include:
Size and location of tumor; the risk of developing ORN increases with larger tumors, since they require higher doses of radiation to achieve cure, subsequently exposing nearby tissues to higher doses. While radiation therapy has become more targeted and precise, patients with tumors located closer to the mandible (e.g. oral cavity) or maxilla (e.g. nasopharynx) will more commonly develop ORN since the bone is more likely fall within the radiation field. Dose and delivery of radiation; generally speaking, higher doses of radiation are more likely to result in ORN, especially when doses exceed 65 Gy. While minimizing radiation doses and avoiding excess radiation to bone can reduce ORN, there does not appear to much evidence that different radiation strategies (i.e. conventional radiotherapy, IMRT, brachytherapy) reduce risk. Smoking; tobacco use is associated with significant increases in risk of developing ORN. This increased risk is attributed to the vasoconstrictive properties of nicotine, which coupled with damage to endothelium by radiation, exacerbate the decreased perfusion of affected tissues. Diabetes mellitus; diabetes is a known cause of microvascular disease, which similar to smoking, can worsen the blood supply and perfusion to tissues affected by radiation. Dental disease and extractions; patients with poor oral hygiene and dental disease prior to radiation, including edentulous patients and those with dentures, are more susceptible to developing ORN. Diseased teeth near the radiation field may need to be extracted, and should be evaluated prior to radiation treatment.
Staging The staging system can be useful as a baseline reference for management after a definitive diagnosis of ORN has been established. Stage Presentation Duration Plain radiographsSigns & Symptoms 0Exposed mandibular bone < 1 monthNo significant change No Pain
No Sinus/ fistulas IA
(Asymptomatic)Exposed mandibular bone ≥ 1 month No significant change No Pain
No Sinus/ fistulas IB
(Symptomatic)Exposed mandibular bone ≥ 1 month No significant change Pain
Sinus/ fistulas IIA
(Asymptomatic)Exposed mandibular bone ≥ 1 month Significant change
Lower border of mandible is not involved No Pain
No Sinus/ fistulas IIB
(Symptomatic)Exposed mandibular bone ≥ 1 month Significant change
Lower border of mandible is not involved Pain
Sinus/ fistulas IIIExposed mandibular bone ≥ 1 month Significant change
Lower border of mandible is involved Irrespective other signs of symptoms
Prevention and management There is currently no universally accepted prevention and management of ORN and in many cases depends on how severe the condition presents. Currently, there are many preventive approaches for ORN proposed, but yet to be justified by high quality evidence. Studies have been conducted to measure effectiveness of current interventions. However, there lacks evidence to conclude that one approach is more effective than others. This leads to uncertainty for clinicians and patients on deciding the best treatment that can be provided.
There are a number of classifications of ORN stages present with different basis of staging and most updated one being the Notani classification. The Notani classification of stages is based on the radiographic and clinical findings, with studies describing low grade ORN being treated conservatively and advanced ORN including pathological fractures, and oro-cutaneous fistula treated surgically.
Prevention
Prior to radiotherapy
Dental assessment It is recommended to have a multi-disciplinary approach to care and dental assessment before the patient undergoes radiotherapy. It has been reported, that analysis of patients who have a strict preventive regime paired with IMRT resulted in no cases of ORN.
Dental extractions As dental extractions are a major risk factor in ORN development, it was recommended to extract all teeth prior to radiotherapy. However, this is now discouraged as a treatment of choice and has many disadvantages. According to one study, the frequency of ORN pre-radiotherapy extractions and post-radiotherapy extractions are almost the same. Extractions of teeth of poor prognosis, usually less than five years is recommended and planning should take into account the likely future problems with oral care, for example if severe trismus develops and if dentures were to be prescribed, denture trauma may cause ORN. The patient's wishes must also be taken into account.
If teeth are required to be extracted, they should ideally be completed as soon as possible to maximise healing prior to radiotherapy. One study recommended a minimum of 14–21 days prior to radiotherapy. However, commencement of radiotherapy should not be delayed as there is little difference in frequency of ORN in pre- and post-radiotherapy extractions and it is recommended that trauma should be kept to a minimum during extractions.
Preventive regime It is important to ensure that tooth brushing technique and habit is kept to a high standard. Patients undergoing head and neck radiotherapy may experience a sore mouth, therefore a soft bristle toothbrush may be preferred. Chlorhexidine mouthwash can also be used in conjunction with tooth brushing, and if too sore on the mucosa, can be diluted with equal amounts of water.