Advances and Controversies in the Management of Osteoradionecrosis After Head and Neck Cancer Treatment: A Narrative Review

Abstract

Osteoradionecrosis (ORN) is a painful and debilitating serious late complication following treatment for head and neck cancer (HNC) often requiring surgical resection of the jaw and complex multidisciplinary management. An important aggravating factor for mandibular ORN is surgical trauma, commonly dental extractions or implant placement following head and neck radiotherapy. The evidence on the treatment protocols ranges from conservative management to more radical surgical strategies including the use of hyperbaric oxygen therapy. The available evidence on the preventive approaches for ORN includes prophylactic dental care prior to radiotherapy, the use of hyperbaric oxygen (HBO) treatment and prophylactic antibiotics for post-radiotherapy extractions. However, the efficacy of hyperbaric oxygen therapy has been questioned recently signifying poor understanding of the pathophysiology of the condition and therapies targeting the fibroatrophic process have become a focus of ORN treatment. Implementing recent IMRT radiation techniques has also shown evidence to reduce the incidence of ORN. This review provides an insight into the variations in definition and classification of the ORN, the controversies in its pathophysiology and the advances in the prevention and management.

Introduction

Radiotherapy alone or in conjunction with chemotherapy or as an adjuvant treatment after surgery is often the treatment for head and neck cancer (HNC) [1]. The acute side effects of HNC treatment involving radiotherapy are commonly oral mucositis, dermatitis, salivary changes and taste alterations, whereas the late toxicities in particular are osteoradionecrosis, hypo-salivation and xerostomia, trismus, radiation caries [2]. Among them, osteoradionecrosis (ORN) is a challenging clinical problem. ORN is most common in patients treated with over 60 Grays (Gy) of radiation, patients of advanced age, smokers, those currently using alcohol, and those with poor nutritional status [3]. Medical comorbidities such as diabetes mellitus, hypertension and collagen vascular diseases have also been found to increase the risk of developing ORN [4]. Dental patient risk factors include active periodontal disease and extractions [5]. Evidence regarding the incidence and prevalence of ORN varies, due to the non-uniformity in its definition, inconsistencies in the length of follow-up between studies and the scarce data available from prospective studies [6]. The incidence of ORN in the mandible is between 2 and 22% of cases, and it most often affects the body [7]. The management of ORN has been controversial and highly varying from conservative management including prescribing mouthwash, analgesics and antibiotics to radical surgical strategies due to lack in evidence-based standard protocol [8]. The purpose of this paper is to review the recent evidence regarding ORN and to discuss the controversies in the diagnosis and management of the condition.

Definition of ORN

There exists controversies in the literature regarding the definition of ORN [9]. ORN is described as a necrotic process of the bone that results from high-dose radiation therapy that persists for 3 months or longer, slowly progresses and does not heal spontaneously. Importantly, it must be unrelated to tumour occurrence [10]. Based on the above common clinical presentation, ORN can be defined as occurring when irradiated bone becomes devitalised and exposed through the overlying skin or mucosa without healing for 3 months, without recurrence of a tumour’ [11]. However, the timing of the bone exposure, and the definition of ‘devitalised’ bone varies in the literature contributing to the lack of clarity in defining this post-radiotherapy complication. Regarding the timing of the exposed bone after radiation therapy, when few authors do not rely on the time of exposure of bone as a predictive factor, others recommend a 2 month period post-RT before diagnosing ORN or even 3–6 months [11, 12]. ORN usually develops during the first 6–12 months after radiotherapy; however, the risk remains for life [13]. Interestingly, the findings of the study by Berger and Symington et al. reported two late presentations in their study, one after 45 years of placement of radium implant, and the other case 38 years after the last exposure to external beam radiation therapy [14]. Also, with respect to the role of devitalised bone in defining ORN, clinical findings confirm the existence of underlying bony changes although it presents with full mucosal coverage, misleading the diagnosis clinically [15].

Staging of ORN

Regardless of several staging and classification systems described in the literature, the first classification introduced by Marx et al. in [16] is perhaps the most widely applied and is based on response to treatment with hyper baric oxygen therapy (HBOT). The mechanisms of action for HBOT are thought to increase oxygen supply in hypoxic tissues which in turn stimulates the proliferation of fibroblasts, angiogenesis and collagen formation. HBOT can have bactericidal as well as bacteriostatic effects. Table 1 summarises the different staging systems proposed and the basis of it.

Table 1.

Classification systems of Osteoradionecrosis

Author, Year	Based on	Classification
Marx, 1983	Response to hyperbaric oxygen therapy (HBOT)	Stage I: exposed alveolar bone without pathological fracture which responds to HBOT Stage II: disease does not respond to HBOT, and requires sequestrectomy and saucerization Stage III: pathologic fracture, orocutaneous fistula, radiographic evidence of resorption to inferior border and requires resection and reconstruction with free tissue
Epstein, 1987	Imaging and clinical findings (sub-category A) pathologic fracture B) no pathologic fracture)	Stage I: resolved or healed orn Stage II: chronic (> 3 months), persistent, non-progressive ORN Stage III: progressive, active ORN
Kagan and Schwartz, 2002	Imaging and clinical findings	Stage I: superficial involvement of the mandible only Stage II: localised involvement of the mandible Stage III: diffuse involvement of the mandible
Notani, 2003	Imaging and clinical findings	Stage I: ORN confined to alveolar bone Stage II: ORN limited to alveolar bone and/or the mandible above level of mandibular canal Stage III: ORN extended to mandible under level of mandibular canal with skin fistula or pathological fracture
Lyons, 2014	Extent of the condition and its management	Stage I. < 2.5 cm length of bone affected (damaged or exposed); asymptomatic. Medical Treatment only Stage II. > 2.5 cm length of bone; asymptomatic, including pathological fracture or involvement of inferior dental nerve or both. Medical treatment only unless there is dental sepsis or obviously loose, necrotic bone Stage III. > 2.5 cm length of bone; symptomatic, but with no other features despite medical treatment. Consider debridement of loose or necrotic bone, and local pedicled flap Stage IV. 2.5 cm length of bone; pathological fracture, involvement of inferior dental nerve, or orocutaneous fistula, or a combination. Reconstruction with free flap if patient’s overall condition allows

Pathophysiology of ORN

The pathophysiology of ORN has not been fully understood since its first reported occurrence in the early 1920s. Watson and Scarborough later reported that the exposure to radiotherapy above a critical dose; local injury; and infection as the three crucial factors in the development of ORN based on their clinical observations in the year 1939. However, the initial experimental models of ORN to find out the pathophysiology showed evidence of bacteria in tissues affected by ORN and documented microscopic tissue changes, namely thickening of arterial and arteriolar walls, loss of osteocytes and osteoblasts and the filling of bony cavities with inflammatory cells [17]. Meyer’s theory published in 1971 proposed the radiation, trauma and infection theory. His theory suggested that injury led to the invasion of oral microbiological flora into the underlying irradiated bone and became the foundation for the popular use of antibiotics with surgery to treat ORN [18]. The pathophysiological sequelae of ORN, according to the hypoxic–hypocellular–hypovascular theory proposed by Marx in the year 1983, stated the initial formation of hypoxic hypocellular–hypovascular tissue following irradiation results in cellular death and breakdown of collagen that exceeds cellular replication leading to a chronic non-healing wound. These explanations of his landmark study formed the cornerstone for the use of hyperbaric oxygen (HBO) in the treatment of ORN.

Radiation-Induced Fibro-Atrophic Theory

Delanian et al. in 2004 suggested that ORN may not actually be the result of hypoxia and hypovascularity, but rather due to a radiation-induced fibro-atrophic process secondary to altered bone turnover rate in the jaws. The pathologic sequence is initiated by injury to the endothelial cells following radiotherapy, either due to direct damage by radiation and/or from indirect damage from radiation generated reactive oxygen species or free radicals produce chemotactic cytokines such as, tumour necrosis factor α (TNF-α), platelet-derived growth factor, fibroblast growth factor β, interleukins 1, 4 and 6, transforming growth factor β1 (TGF-β1), and connective tissue growth factor. These TNFs trigger an acute inflammatory response and results in further release of reactive oxygen species from polymorphs and other phagocytes. The following events lead to the destruction of endothelial cells, along with vascular thrombosis, leading to microvascular necrosis and local ischaemia. This loss of the natural endothelial cell barrier allows uninterrupted passage of various cytokines that cause transformation of fibroblasts to myofibroblasts. These characteristic myofibroblasts have high rates of proliferation, secretes abnormal extracellular matrix products and possess a reduced ability to degrade such unusual cellular components. This imbalance between synthesis and degradation of fibroblasts in irradiated tissue is obvious in bone structures too. The combination of destruction of osteoblasts after irradiation coupled with excessive proliferation of myofibroblasts results in a reduction in bony matrix and its replacement with fibrous tissues. Micro-radiographic analysis of bone in ORN suggests four possible mechanisms of bony destruction: progressive resorption of osteoclasts mediated by macrophages that are unaccompanied by osteogenesis; increased rate of periosteocytic lysis, extensive demineralisation that is secondary to external stimuli such as salivary secretion and bacterial products; and accelerated bony ageing. Ultimately, the myofibroblasts undergo apoptosis. Remarkably, even decades after radiotherapy, the bone remains paucicellular, poorly vascularised, and fibrosed. To condense, the theory of radiation-induced fibrosis proposed the activation and dysregulation of fibroblastic activity that leads to atrophic tissue within a previously irradiated area that leads to ORN [19].

In 2004, Assael et al. proposed that ORN also occurs by the same mechanism as other types of osteonecrosis (e.g. bisphosphonate-related osteonecrosis) and results from decreased osteoclastic bone resorption [20]. It has always appeared unusual that technetium, gallium and indium scans nearly showed sharply increased uptake in osteoradionecrosis, suggestive of an increased (not decreased) bone turnover rate, inflammation, and infection. Another striking clinical finding is the increased subperiosteal bone deposition resulting in increased thickness of the jaw in the radiated zone indicating altered remodelling suggestive of increased bone turnover rate. Also, sequestrum formation is severely delayed in ORN and only occurs when very dense surrounding new bone appears to cut off the central core vascular supply. Therefore, bone grafting of the affected site with a vascularised free flap, seems to do well when the soft tissue bed. Hence, in addition to the concept of hypovascularity, hypocellularity, and hypoxia theory of Marx et al., the selective suppression of osteoclasts in radiated bone is also a detrimental event in osteoradionecrosis. Radiation dose, portals, voltage, host immune response, concomitant therapy, cardiovascular disease, diabetes, atherosclerotic heart disease, cytotoxic drugs, cancer stage, surgical method, bisphosphonates, nutrition, endocrine response, or other yet unknown alterations of bone physiology may all play a part in the development of osteoradionecrosis.

Clinical and Radiological Findings of ORN

ORN most often affects the mandible, particularly the posterior mandible, than maxilla or any other bones of head and neck region due to its compact and dense nature. It presents clinically as painful and denuded bone with purulent drainage and/or possible fistula formation [10, 21]. The majority of cases occur in the first years after treatment for Head and Neck Cancer, with increasing yearly incidence for several years after treatment [22, 23]. An Orthopantomogram x-ray (OPG) is the most frequently used imaging method for the diagnosis of ORN and is usually supplemented with other extra-oral or intraoral radiographs. In an OPG, ORN is depicted as an undefined radiolucency, without sclerotic demarcation, which surrounds necrotic zone. However, radiopaque areas can also be identified when bone sequestra are formed. To be visible in an OPT, a substantial alteration in mineral content and extensive involvement of bone is required and this only occurs in later stages of ORN [6]. Ardran et al. noted that a 30% loss of bone mineral content is necessary before any radiographic change can be seen [24]. Computer tomography (CT) image shows bony abnormalities, such as focal lytic areas, cortical interruptions and loss of the spongiosa trabeculation, resulting in soft tissue thickening on the symptomatic side, clinically. These changes may be misinterpreted as a recurrent tumour [25]. In MRI with gadolinium administration, an abnormal marrow signal, cortical destruction and slight-to-mild irregular enhancement are also confirmed [26]. MRI has the advantage of excellent tissue contrast and high spatial resolution [27].

Treatment modalities of ORN

The management of ORN has been controversial and highly variable between centres ranging from local debridement and sequestrectomy may be offered for grade II ORN, and resection is usually reserved for late-stage grade III ORN [7].

Efficacy of Hyperbaric Oxygen Therapy (HBOT)

The use of hyperbaric oxygen (HBO) in damaged irradiated tissue improves vascularity and fibroblastic cellular density, thus limiting the amount of nonviable tissue to be removed surgically, thereby enhancing wound healing. The therapeutic value of HBO was observed firstly in controlled in vivo experiments on burns in which daily increases in the oxygen tensions in hypoxic tissues were found to encourage capillary angiogenesis, proliferation of fibroblasts, and synthesis of collagen [28], whereas the findings of the recent papers suggest that cellular radiogenic effects in bone occur earlier than the already known vascular alterations. This hypothesis challenges the well-accepted “three-H concept” (hypoxia, hypocellularity, hypovascularity) of Marx et al. [29].

In 1983, Marx’s presented the field-defining, Wilford Hall protocol for HBO in the management of refractory ORN in a retrospective series of 58 cases. Those retrospective cases included in the study had persistent ORN, and conservative or surgical management, or both, had failed. The observations of these retrospective series noted the clinical success as being pain free, having mandibular continuity, mucosal healing, and the ability to wear dental prostheses and function normally. Later reports by Myers and Marx detailed the successful treatment of 268 patients, and others have also found similar success with the above-mentioned protocol [30]. However, due to the logistic and financial limitations of using so many hours of HBO, many centres preferred a simplified protocol of 30 dives before and 10 dives after the surgery [31]. Later, Marx reported a further 104 patients who required mandibular reconstruction in tissue beds exposed to ≥ 64 Gy radiotherapy using mesh trays with free bone grafts and the intervention comprised of 20 preoperative and 10 post-operative HBO sessions. The results showed established bony continuity in 48 out of 52 patients for those with HBO compared with 34 of 52 without HBO. The largely outdated method of oromandibular reconstruction, and the lacunae in the information concerning the methodology of the trial makes the data hard to evaluate.

The aforementioned “Wilfred-Hall Protocol” by Marx consists of the three stages.

Stage I Thirty consecutive treatments. If the wound showed no definitive clinical improvement, a further ten exposures are indicated, to a full course of 40 exposures. If there is failure to heal after 3 months, the condition is advanced to the next stage.

Stage II The exposed bone is removed by alveolar sequestrectomy and further 20 HBO treatments have to be given to the affected patients, to a total of 60 exposures. If wound dehiscence or failure to heal occurs, the patient is advanced to the next stage.

Stage III The criteria for this category are failure of Stage II, pathological fracture, orocutaneous fistula, or radiographic evidence of resorption to the inferior border of the mandible.

The need for evidence from randomised trials is essential due to the uncertainty of treatment outcome in many affected patients. The optimum therapeutic use of HBO remains poorly understood, and this is evident in the lack of standardisation of HBO protocols used by both UK and European chambers [8]. The protocols often deviate from the “consensus” Marx protocol of 30 sessions before and 10 sessions after operation at 2.4 atmospheres for 90-min sessions. Most British Hyperbaric Association (BHA) registered chambers only deviate from the Marx protocol in the pressures used, for example a reduction to 2.2 atmospheres, because of anecdotal evidence of fewer complications (transient myopia) at this pressure [32].

Shaw et.al in 2019 conducted the HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis) trial as the evidence for using hyperbaric oxygen continued to be poor. The purpose of this clinical trial was to assess the benefit of hyperbaric oxygen in the prevention of osteoradionecrosis during surgery on the irradiated mandible. The phase III, multi-centre, randomised controlled HOPON trial employed an unblinded design, wherein the diagnosis of osteoradionecrosis was assessed on anonymised clinical photographs and radiographs by a blinded expert panel. The included patients were randomised 1:1 to hyperbaric oxygen arm (Marx protocol) the control arm; however, both the groups received antibiotics and chlorhexidine mouthwash. The primary objective was to assess the occurrence of osteoradionecrosis at 6 months following surgery and secondary objective assessed the time of onset of ORN, acute symptoms and pain, quality of life, the position of implants placed, their successful retention [8]. A total of 144 patients were randomised, and data from 100 patients were analysed. The incidence of ORN at 6 months was 6.4% and 5.7% for the HBO and control groups, respectively. Patients in the hyperbaric arm had fewer acute symptoms but no significant differences in late pain or quality of life. The authors concluded that the incidence of ORN was low, making the recommendations for HBO in dental extractions or implant placement in the irradiated mandible unnecessary. The results of the study were in contrast with a recently published Cochrane review and previous trials and further reinforces the prevention of unnecessary indication of HBO for dental extractions or implant placement according to their results.

Hyperbaric Oxygen Therapy Versus Perioperative Antibiotic Prophylaxis

Marx et al. found that there was a reduction in the incidence of ORN while employing hyperbaric oxygen therapy compared to the intervention with perioperative antibiotic prophylaxis, with follow-up at six months although the radiation doses for the included patients were not mentioned in the study. Whereas, the results of the study by Schoen et al. in 2007 suggested that there was no reduction in the incidence of ORN in the intervention arm employing combined hyperbaric oxygen therapy and perioperative antibiotics as compared to antibiotics alone, with a follow-up period of one year from the time of prosthesis delivery [33]. Additionally, the authors reported the results of multiple quality of life questionnaires and clinical parameters with respect to oral status, functioning and other satisfaction measures at pre-operative, as well as at the end of six weeks, and 12 months following new denture placement. Though the authors found emotional functioning and pain to be significantly higher at the end of six weeks in the hyperbaric oxygen therapy group, there were no significant differences between the two groups at the end of 12 months.

Platelet-Rich Plasma (PRP)

It is an autologous blood product created by spinning whole blood in a centrifuge to isolate a platelet-rich gel. Platelets contain growth factors namely the platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGFβ). The use of PRP gel has been already indicated for improving the survival of bone grafts, in dental implantology, cosmetic surgery and orthopaedic procedures. According to a case report published by Scala et al. in 2010, an autologous PRP gel was introduced into the ORN necrotic defect of a 44-year-old patient previously treated for squamous cell carcinoma of the tongue. They reported that post-operative two-year follow-up demonstrated by panoramic X-ray showed regain of the mandibular bone continuity with a complete repair of the necrotic defects. This case illustrated an incident of successful regeneration of ORN critical-sized defect of the mandible by autologous PRP gel [34]. Whereas Batstone et al. in 2012 found that there was no reduction in the incidence of ORN despite the application of PRP gel [35].

Pharmacological Management

The results of few earlier studies showed that advanced full thickness ORN (Notani grade III), especially in the setting of a pathological fracture or an orocutaneous fistula, has traditionally been treated with surgical resection and vascularized free flap reconstruction [36]. However, due to concerns regarding operating within an irradiated field, many patients can be unsuitable for resective and reconstructive therapy, so conservative management and supportive care remain a commonly adopted treatment for ORN. In addition, many patients refuse further surgery. Pentoxifylline and tocopherol were first used in the management of early ORN as the two agents directly counteracted the proposed fibro-atrophic pathogenesis of ORN [19]. Initial studies have shown good results with no significant adverse effects from the medications. The role of pentoxifylline and tocopherol in advanced ORN, where patients are unsuitable for resection, has been reported by Delanian et al. in 2004.

Pentoxifylline is a methylxanthine derivative that has been found to act against some inflammatory mediators including TNF-alpha, increases erythrocyte flexibility, dilates blood vessels, inhibits inflammatory reactions in vivo, and increases collagenase activity in vitro. It is given in combination with tocopherol, a vitamin E analogue, which scavenges the reactive oxygen species that were generated during oxidative stress by protecting cell membranes against peroxidation of lipids, partial inhibition of TGF-1 and expression of procollagen genes, in turn reducing fibrosis³⁷. Then, a first-generation non-nitrogenous bisphosphonate, clodronate, was also added in non-responsive cases to promote osteogenesis and osteoblast differentiation. The use of pentoxifylline, tocopherol and clodronate together (PENTOCLO) in the management of ORN was first proposed by Delanian and Lefaix. The benefits of PENTOCLO were first described in a case of sternal ORN in a female patient who had previously underwent radiation therapy for the management of breast cancer [38]. As a result, PENTOCLO was then successfully used in 16 of 18 patients with mandibular ORN of the jaws, not responding to conservative therapy. Among the observed patients, four had stage III ORN with pathological fractures. Although the paper did not discuss these more advanced patients in significant detail, it appears that all the patients had pathological fractures without ‘shifting’ or without displacement [39]. A subsequent study by the same author in 2011 evaluated the role of the PENTOCLO protocol in the management of 54 patients [40]. Among them, 36 patients were classified as having advanced ORN (Epstein III with fistula, fracture, or osteitis). However, it was unclear how many patients had fractures, and in the conclusions, the authors advised that surgical management should still be considered in patients with fractures without displacement.

Surgical Management of ORN

In advanced ORN cases, surgical management is generally considered the therapy of choice [41]. However, in several severe ORN patients with extensive bone and soft tissue defects, functional and aesthetic reconstruction represents a huge challenge with an increased risk of post-operative wound healing complications. Even by using a free flap with bone segments and large soft tissue parts, the risk of post-operative complications, including wound dehiscences, necrotic tissue and functional and aesthetic limitations, is more prevalent. Furthermore, restoration of the three-dimensional anatomical boundaries cannot be ensured.

Outcome of Microvascular Free Flap Reconstruction

Microvascular free flaps (MVFF) are the current standard of care for reconstruction of oral ablative defects [42]. Microvascular free flaps are commonly used for mandibular reconstruction in ORN. When MVFF reconstructions are contraindicated, regional pedicle flaps combined with rigid fixation and autologous bone grafts are commonly reported options that can provide satisfactory functional and aesthetic outcomes [43]. Hirsch et al. in 2008 compared 305 consecutive patients who underwent MVFF reconstruction for a variety of cancer-related therapies. Among them, 21 patients who underwent surgery for Marx stage III ORN involving the mandible were identified and for purposes of comparison, patients who received preoperative radiation therapy and underwent microvascular reconstruction but did not have ORN were identified and included in the test group. Similarly, matched patients who never received preoperative radiotherapy served as controls. Overall MVFF survival and complication rates among patients with ORN versus control groups were the same. Free tissue transfer is another viable option for the management of advanced mandibular ORN [36].

Prevention of ORN

Prophylactic Dental Care

Preventive measures must be evaluated to reduce the severity of ORN. Poor maintenance of oral hygiene has been shown to increase the risk of osteoradionecrosis. The fluoride gel application and use of high content fluoride toothpaste reduced the incidence of ORN according to the study by Hariot et al.[44]. Before commencement of radiation therapy, a thorough dental examination is indicated. The Marx protocol of 20 dives at 2.4 atmospheres for 90 min per dive before extraction and ten dives after extraction has become the de facto The results of the systematic review by Nabil et al. in 2011 suggested that a total ORN incidence of 7%, which was reduced to 6% in conjunction with antibiotics, and 4% with prophylactic HBO therapy. They concluded that prophylactic HBO therapy was effective in reducing the risk of developing ORN after post-radiation extractions. These conclusions were drawn from a total of seven articles reporting on a combined 160 patients and 595 extractions.

The results of the review published by Peterson et al. in 2010 identified three studies that evaluated the use of HBO therapy to a comparison group in those requiring dental extractions, two retrospective cohort studies demonstrated a similar prevalence of ORN in HBO versus non-HBO groups, whereas the prospective trial by Marx et al. in 1985, the landmark study, showed a markedly elevated complication rate in the non-HBO plus antibiotic versus HBO groups. These findings led the authors to conclude that only level III evidence supported the use of prophylactic HBO therapy prior to post-radiotherapy dental extraction. Limited prevention studies regarding hard tissue replacement in extraction sockets, post-operative antibiotics, and pre-radiation extraction of impacted third molars were also reported; however, it was concluded that additional studies were required to evaluate these preventive options. Medical treatment including pentoxifylline, tocopherol and clodronate has also been reported before and after extraction.

Owosho et al. conducted a study in 2016, to determine the prevalence and correlation of various risk factors [radiation dose, periodontal status, alcohol, and smoking] to the development of ORN. The medical records of 1023 patients treated with IMRT for oral cavity cancer (OCC) and oropharyngeal (OPC) were retrospectively reviewed to identify risk factors among patients who developed ORN. The result of their study suggested that higher radiation dose, poor periodontal status and alcohol use are significantly related to the risk of developing ORN [5].

Role of Intensity-Modulated Radiotherapy (IMRT)

The risk of osteoradionecrosis increases with higher total radiation doses, short regimens using high doses per fraction, large field sizes, and the delivery of radiotherapy through a single field (15, 16). Recent advances in the delivery of photon radiotherapy such as 3D conformal radiotherapy (3D CRT) or intensity-modulated radiotherapy (IMRT) have reduced the risk of osteoradionecrosis^45,46 compared to the previous conventional two-dimensional (2D) radiotherapy that documented 5% to 20% higher risk of incidence [47].

As mentioned earlier, with the advances in the delivery of radiation therapy, such as intensity-modulated radiation therapy (IMRT), there is a fall in the incidence of osteoradionecrosis as it uses increasing the conformality of the high dose prescription to spare larger volumes of mandible by improved conformality of the high prescription dose and improved dose homogeneity. Thus, to date the best outcomes with IMRT with regard to ORN appear to be when the dose to organs at risk (mandible, oral cavity and parotid) are constrained, conventional fractionation is utilised, and meticulous dental hygiene is applied[48]. The use of more advanced, intensity-modulated proton therapy (IMPT) theoretically allows delivery of highly conformal and homogeneous dose deliveries to the target while simultaneously sparing adjacent organs at risk to a greater degree than is possible with IMRT. Proton therapy allows energy to be contained at a specific depth within tissues, with rapid energy fall off beyond that point (the Bragg peak). The use of IMPT minimised excess irradiation of the mandible and consequently reduced the risk of osteoradionecrosis as compared with IMRT for oropharyngeal cancer[49]. However, further prospective studies with larger number of patients incorporating mandibular dose-volume histogram analysis should be undertaken to clarify the influence of radiation technique (IMRT or IMPT) on the prevalence of and severity of osteoradionecrosis. According to Clayman et al., the application of megavoltage therapy resulted in a significant reduction in the overall prevalence of ORN from 11.8% before 1968 to 5.4% after this time [13]. Wahl et al. also described similar results and noted a prevalence of ORN of 3% during the period 1997 to 2006 [44]. Lee et al. found that the frequency of ORN was 6.6% among 198 patients with either oral cavity or OPCs treated with radiation between 1990 and 2000[50].

Conclusion

Effective management of any disease process initially requires a timely diagnosis. Although there exists no gold standard treatment or consensus, a combination of therapeutic strategies shall be considered, taking into account the severity of disease and individual patient characteristics. The available evidence shows clinical success with conservative management of early stage ORN with antibiotics and meticulous oral hygiene, and any sign of progression requires early surgical intervention with debridement and local mucosal flaps to cover exposed bone. Extensive surgical resection with fibular free flap may be considered for patients with advanced disease who have persistent symptoms refractory to conservative treatments. A better understanding of underlying pathophysiology and risk factors will help to improve the prognosis for those being treated for ORN. The role of HBOT and medical management (antifibrotics, antioxidants, steroids) is yet to be understood better.

Availability of Data and Materials

This is a review article, and hence, no data were collected.

Declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical Approval

Being a literature review, no formal ethical approval needed.