Introduction

Osteoradionecrosis (ORN) is a severe complication of external beam radiotherapy (RT) for malignancies affecting the head and neck (1,2). It is defined as ‘A potentially severe, delayed radiation-induced injury, characterized by bone tissue necrosis, failure to heal, and exposed bone for at least three months’ (3). The incidence of ORN in the head and neck region varies from 2% to 22% in subjects with a history of radiotherapy (3).

Various mechanisms have been proposed to explain the occurrence of ORN. These include the most commonly accepted hypoxic-hypocellular-hypovascular concept where radiation causes hypoxia of the bone, death of bone cells and long term damage to vascular supply as a result of endothelial cell damage ultimately leading to bone death (4). Another theory suggests that radiotherapy results in decreased soft tissue matrix which gets replaced with fibrous tissue, thereby increasing the tendency to develop ORN (5). Another suggested cause is the suppression of osteoclast related bone turnover. Some authors have proposed that radiation leads to a local inflammatory process which causes osteoblastic cell death, thereby preventing the repopulation of cells (6). The most recent theory of ORN is the fibroatrophic theory. According to this theory, vascular changes in the bone lead to endothelial changes along with an inflammatory response. This is followed by abnormal fibroblastic activity and altered bone healing which is more susceptible to infection (6).

Among the various classifications, the one given by Notani et al. (7), which is based on the amount of bone involvement, is simple and preferred by many authors (8). ORN is a progressive condition which is difficult to treat. Various management strategies include sequestrectomy, resection, segmental mandibulectomy, and hyperbaric oxygen (HBO) therapy with varied results. Recent methods include the use of Pentoxifylline, Tocopherol and Clodronate, “PENTOCLO” (8).

The present report reviewed the current literature of the demographic characters, clinical features, and latest management techniques employed in the treatment of ORN.

A “PubMed” database search was done to identify case reports on ORN, published using the keywords “osteoradionecrosis”, “jaw”, “mandible”, and “maxilla”. Data on ORN published within the past 10 years from 2008 to 2018 were collected and analyzed. Only those case reports for which full text was available were considered in the review. Demographic characters, clinical features, and management were tabulated. Descriptive statistics were calculated using means and percentages.

A total of 23 full text articles reporting 27 cases of ORN were identified. The age range of the subjects was from 18 years to 84 years with a mean of 49 years. Males constituted 84% of the cases while females accounted for 16%. In 96% of the cases, the mandible was affected while 4% involved both the maxilla and mandible. The right and left mandible were equally affected in 34.6% of cases; and ORN was present bilaterally in 26.9% of cases. The posterior mandible was the most common site in 53.8% of cases.

ORN occurred three months -13 years later following radiotherapy, with an average time of 3.87 years. Associated malignancies varied with maximum cases having received radiotherapy for tonsillar carcinoma (Figure 1).

Radiotherapy was the primary treatment given in 25.9% of cases; surgery and radiotherapy were given in 40.7% of cases; subjects received adjuvant chemotherapy in 25.9% of cases while a combination of surgery, chemotherapy and radiotherapy was given in 7.4% of cases (Figure 2).

The amount of radiation received ranged from 50 Gy to 77 Gy.

The presenting features of ORN included pain and discharge in 25.9% of cases, pathological fracture in 14.8% of cases, dysphagia and swelling in 7.4% of cases and anesthesia of the inferior alveolar nerve in 7.4% of cases.

Risk factors for ORN were tooth extraction, tobacco and alcohol abuse, and underlying medical conditions.

Management included surgical resection with fibular graft in 37% of cases, HBO therapy in 29.6% of cases, and segmental resection in 18.5% of cases. Other methods of ORN management included the use of leukocyte platelet-rich plasma (PRP), sequestrectomy, surgical debridement with Integra skin regeneration system and vacuum-assisted closure (VAC) system.

Recurrence of ORN was reported in 22% of cases, which ranged from three weeks to one year later. Table 1 (6,9-27) summarizes the details of subjects with ORN as reported by the various authors.

Discussion

Regaud first described post radiation ORN of the jaw in 1922 (13). Ewing, in 1926, reported the bone changes after radiotherapy as radiation osteitis (11).

Early bone changes after radiotherapy includes hyperemia, endarteritis, and cell death, while late changes include thrombosis, hypovascularization, and fibrosis (5).

ORN is a late effect of radiotherapy. RT for cancer in the head and neck has an increased chance of causing mandibular ORN. Recent reports suggest that the incidence of ORN has decreased from 20% to around 4-8%. This decrease is related to the elimination of all risk factors prior to radiotherapy and recent advances in radiotherapy such as intensity modulated radiotherapy (IMRT) (28). The incidence of occurrence of ORN in the mandible is between 2% and 22% with most cases occurring in the mandibular body (9). This is in accordance with the present report where the mandible was the most affected, predominantly the posterior mandible. This increased predilection for the mandible is due to the richer vascularity in the maxilla and also because the mandible is irradiated more often. Also, since the mandibular bone is denser, the amount of radiation absorbed by the bone is more (6,29).

Around 70-90% of ORN cases are reported to occur within the first three years after radiotherapy. In the present report, ORN occurred from three months to 13 years following radiotherapy. However, the majority of cases occurred within the first five years. This variability could be because of the size and nature of the tumor, the type of radiotherapy used or individual patient risk factors (28).

The amount of radiation received ranged from 50 Gy to 77 Gy. The risk of developing ORN is medium at a radiation dosage of 40-60 Gy and high at a dose above 60 Gy (23). This is in conformity with our results.

The subjects may be asymptomatic in the initial stages. The main diagnostic feature is the presence of exposed bone in the mucosa or skin which can get secondarily infected. Other features include pain, dysesthesia, halitosis, and dysgeusia. Severe cases may lead to fistula formation from the oral mucosa or skin and pathological fractures (9). Diagnosis of ORN is made on the basis of patient history and the presence of exposed bone for more than three months. Radiological investigations such as panoramic radiographs and computed tomography are used to assess the extent of bone changes (17,23,30). This is similar to the clinical features reported by ORN cases in the present review.

Chemoradiotherapy (CRT) is linked to better locoregional control and overall survival and eradicates micrometastases. Although CRT is associated with an increase in early toxicity such as mucositis, the role of CRT in late toxicity is not clear. Recent studies have concluded that CRT does not increase the risk of ORN. In the present review, 25.9% of the cases received CRT. However, previous studies show difference in the incidence of ORN after RT and CRT (31).

Conventional management of ORN includes surgical debridement, sequestrectomy, oral hygiene maintenance with oral antiseptics, and the use of medications such as analgesics, antibiotics and corticosteroids (11). Segmental mandibulectomy is the next option followed by a complex reconstruction. In accordance with the fibro atrophic theory, a recent regimen for ORN recommends the use of vascular directed therapy using alpha – tocopherol (Vitamin E) and pentoxifylline (PENTO). Addition of clodronate to PENTO was found to be beneficial but carried the risk of bisphosphonate induced osteonecrosis (9,26). Delanian et al. (30,32) reported that PENTOCLO resulted in spontaneous sequestrectomy within the first six months of therapy leading to bone healing. PENTOCLO is not recommended in patients with recurrent or residual tumor. HBO therapy has been used along with surgery due to its ability to promote vascularity. HBO therapy includes the use of 100% oxygen for 90 mins at 2.4 atm pressure (24). However, recent trials have failed to demonstrate definite benefits. HBO is advised as an adjunct when resection or reconstruction surgery is needed (26). In the present report, HBO therapy was used in 29.6% of cases, usually in association with surgical debridement and resection with good results.

ORN can be of two types-spontaneously occurring and trauma induced (5). Spontaneously occurring ORN depends on the radiation dose that is received while ORN after dental treatments is categorized as trauma-induced ORN (5,27). Around 5% of cases occur following dental extraction (8). This is reflected in the present results where only two cases of ORN were reported after tooth extraction.

Spontaneous ORN commonly occurs between 6 months and 2 years after radiotherapy while the possibility of trauma-induced ORN is for long term. Thus, the risk of trauma induced ORN is higher in the dentate subjects due to extraction or dental and periodontal infection (9). Other factors include the grade and site of tumor, amount of radiation, immune deficiencies and any comorbidities (14). Moon et al. (28) found that pre-radiotherapy extractions were an independent risk factor for ORN but mentioned that it might be a reflection of the poor oral hygiene of the subjects. The use of IMRT has decreased the incidence of ORN especially in combination with good oral hygiene measures and decreased radiation to the mandible and parotid salivary glands (8). Contributing factors noted in the present review included tobacco and alcohol abuse and underlying medical conditions.

Marx’s staging of ORN as stage 1, stage 2 and stage 3 is still widely followed (21). Stage 3 ORN requires surgical intervention (23). Kraeima et al. (23) used a novel method of combining the chemotherapy with the radiotherapy isodose curves in order to accurately predict the areas of ORN risk, and plan exact resection of affected bone and screw locations for reconstruction plates which are outside high dose areas.

Management of ORN in the present review was done using various methods. Most management strategies involved surgical treatment with the debridement of non-viable tissue and subsequent reconstruction. Successful management strategies included the use of allogeneic platelet gel (1) and skin regeneration systems for the repair of minor to moderate intraoral defects (3). Schepers et al. (10) described successful prosthetic rehabilitation with fibular graft using virtual implant planning. PRP was used to regain mandibular integrity and continuity of bone following ORN (14). The most commonly reported treatment in large defects involved mandibular resection followed by free fibular graft and implant supported prosthesis (15). Tursun and Green (20) reported the use of processed allogeneic nerve allograft during surgical treatment for regaining neurosensory function in patients with ORN. Iliac marrow aspirate was used successfully for bone regeneration in one case (16). Kakarala et al. (21) used VAC dressing over free flap muscle to assist the closure of cutaneous defects in ORN. Horta et al. (22) reported a case where the failure of fibular graft was managed using chimeric anterolateral thigh flap and a dural substitute membrane with acceptable results.

Based on the fibroatrophic theory of ORN, a combination of pentoxifylline, tocopherol and clodronate is being tried as medical management in ORN cases refractory to surgery and HBO therapy. This protocol included antibiotic and corticosteroid treatment for one month to control infection followed by pentoxifylline, tocopherol and clodronate for at least six months. The authors reported a resolution rate of around 89% (33,34). In the present review, Garg et al. (6) was able to achieve good results with a combination of PENTOCLO therapy and sequestrectomy. An additional finding in the study was the incidence of ORN recurrence. As much as 22% of cases reported the recurrence ranging from three weeks to one year later; thus highlighting the recalcitrant nature of ORN.

The present review has certain limitations. In the reviewed case reports, data regarding newer methods of surgical management are highlighted. Pharmacologic management using pentoxifylline, tocopherol, and clodronate “PENTOCLO” has shown promise in treating patients with ORN. However, none of the reviewed case reports had data regarding the pharmacologic management of ORN. The incidence of ORN can be decreased through the use of new RT protocols such as 3D conformational radiotherapy and IMRT, which are able to deliver maximum radiation to the affected area while sparing the normal surrounding tissue as far as possible. However, data regarding the use of these methods were not available in the reviewed articles.

Conclusion

ORN is an important late complication of RT for head and neck cancer. The present review highlights the predilection of ORN to occur in the posterior mandible in subjects who have received radiation doses greater than 60 Gy. Tooth extraction, tobacco and alcohol use, and patient comorbidities are the risk factors for the development of ORN. All patients should undergo prophylactic oral care before, during and after the completion of radiotherapy.

Ethics

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: V.A., S.H., Design: V.A., S.H., Data Collection or Processing: V.A., Analysis or Interpretation: V.A., S.H., Literature Search: V.A., Writing: V.A., S.H.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.