From Volume 49, Issue 1, January 2022 | Pages 64-67
Osteoradionecrosis (ORN) is a late complication of radiotherapy treatment for head and neck cancer. In the past two decades there have been significant changes in the mode by which radiation is delivered and it was assumed this would lead to a reduction, or even elimination, of this complication. Paradoxically, ORN rates may have risen. This article provides a summary of the current understanding and approach to ORN.
Osteoradionecrosis (ORN) was first reported almost a century ago.1 To date, numerous approaches have been taken to prevent it from occurring or to treat it once established. This includes improvements in radiotherapy (RT) delivery, pre-treatment dental assessment and continuing dental care. However, ORN continues to occur, in part due to a change in the profile of head and neck cancer (HNC) patients. This article highlights some of the key changes occurring in the modern era that impact on the development of ORN.
Although ORN is a well-recognized condition, no international agreed definition exists. In the UK, the most commonly accepted ORN description is ‘an area of exposed bone present for longer than 2 months in a previously irradiated field, in the absence of recurrent tumour’ (Figure 1).2 The definition is incomplete in that it ignores both maxillary ORN and non-exposed ORN. A commonly used and simple classification is one proposed by Notani et al3 (Table 1 and Figure 2).
| Grade I | ORN confined to the alveolar bone |
| Grade II | ORN limited to the alveolar bone and/or the mandible above the level of the mandibular alveolar canal |
| Grade III | ORN that extends to the mandible under the level of the mandibular alveolar canal, and ORN with a skin fistula and/or a pathological fracture |
Understanding the pathophysiology of a disease is the key to developing effective treatment strategies. Unfortunately, there is still debate about the processes underlying the development of ORN. In the UK, until recently, ORN was thought to occur via the 3H theory (hypoxia, hypocellularity and hypovascularity) proposed by Marx.4 This theory suggested the depletion of oxygen, cellular content of the bone and vascular supply all combined over time to produce non-vital patches of bone as a result of the inability to metabolize and repair the osseous structure. More recently, this explanation has been superseded by a newer theory termed ‘radiation-induced fibrosis’ (RIF). Here, tissues that have received radiation essentially develop fibrous scar-like tissue. This extends to the blood vessels walls and inevitably the lumen becomes narrower. This process progresses over time and leads to a reducing blood supply to the tissues, leading eventually to atrophy and tissue necrosis. At present, the latter explanation has primacy as drug medication to reduce fibrosis has a positive impact on ORN.
Several factors have been found to increase the risk for developing ORN.5 These risk factors can be divided into three broad categories, namely radiation, dental and patient factors.
Intensity modulated radiation treatment (IMRT) is a novel delivery system ideally suited to HNC owing to its ability to target tumours, considering the complex anatomy of this region. RT beams are divided into many small beamlets with varying intensity. These are spun around the patient with careful precision so that interacting beams deposit the energy at high density only at the tumour site. The surrounding tissues are also irradiated, but to a lesser degree. Owing to its precision, it was anticipated that the introduction of IMRT would lead to a reduction, or even an elimination of serious RT-induced complications. Unfortunately, this has not been the case because it is apparent that the multi-beam IMRT actually incorporates more of the jaws than traditional techniques.6
The dose of radiation received by the bone is also important. There is no absolute threshold dose after which ORN will develop. However, it is generally accepted the risk commences above 40 Gray (Gy).7 Established areas of ORN have consistently received >50Gy8,9,10,11 even using the new radiation delivery systems.
What has changed in the past two decades is the realization that combining chemotherapy with radiation provides a substantial increase in survival,13 but it comes at the cost of an increased risk of complications in general, including ORN.5,12 This combination is used in advanced disease, and extensively in oropharyngeal cancer (OPC). This may be one of the reasons why those in this tumour group have seen a rise in ORN. The relevance of this association is that OPC is numerically the fastest growing cancer in head and neck specifically due to human papilloma virus (HPV) and is projected to be responsible for 35–50% of head and neck cancers within the next decade.13,14
The dentition in irradiated HNC patients is considered the main risk factor for developing ORN as teeth are a natural portal for oral bacteria to access the underlying bone. Historically, HNC patients have been stereotyped as having detrimental lifestyle habits, such as excess smoking and alcohol drinking, together with irregular dental attendance and a neglected dentition. The situation is compounded after RT by an oral environment parched by xerostomia, with limited access due to trismus and, because of difficulty in swallowing, to eat frequently (as often as 4 hourly) using high calorific liquid food supplements. The combination fosters dental decay, notably root decay, commonly termed radiation caries. This perfect storm of events has led to the mandatory requirement for all HNC patients to have a dental assessment prior to radiation treatment.15,16,17 However, there is no agreement on what constitutes ‘dental fitness’. The pre-treatment screening has reduced the risk of ORN, but it has not eliminated it. As mentioned previously, the rise of HPV-related OPC has provided a new clinical challenge. These patients do not have the typical lifestyle factors associated with oral cancer, nor have the typical dental status.18,19 They are an upwardly mobile and younger population with a much better dentition and can afford complex dental restorations.18,19
In the era preceding IMRT, a systematic review suggested the incidence of ORN after tooth extraction in irradiated patients to be 7%.20 By taking prophylactic antibiotics or hyperbaric oxygen therapy (HBOT) there was a suggestion that ORN rates fell to 4–6%.20 This has been eclipsed by a recent prospective randomized trial that showed no advantage for HBOT or antibiotics.21 In contrast, results from drugs that reduce fibrosis (pentoxifylline and tocopherol) point towards an ORN rate of only 1.2% or 0.26% per dental extraction.22
Some HNC sub-sites that are in close proximity to the mandible are inevitably associated with ORN. This applies to the oral cavity and the oropharynx,9 whereas for nasopharyngeal or sinonasal cancers, the beam of radiation falls on the maxilla.23 Unfortunately, the risk of ORN is not limited to these two sites, as occasionally, unusual areas fall victim to this disease. A recent mini-case series reported ORN in the hyoid and temporal bones, even with the use of IMRT.24
A substantial change that has become evident has been the dynamic shift towards the increased number of young male patients with HPV-associated OPC. In addition, ORN tends to affect the male population by a factor of 3:1,25 and at a relatively early age of 55 ± 10.1 years.26 Once again, these factors may be influencing the skewed trend seen regarding ORN and OPC. Another risk factor is smoking.27 Patients who continued to smoke during radiation treatment had a 32% increased risk of developing ORN.28 The association of alcohol to ORN is a little more indistinct, but excessive consumption may increase risk by 3.22 times.9
The morbidity associated with ORN can be significant, and there appears to be an international consensus regarding prevention and good practice.15 In contrast, agreement on the management of established ORN remains as fractious as the pathogenesis of the disease, and remains undecided. To date, no treatment regimens have been able to guarantee a cure, although each has claimed continual success in the absence of incisive large patient cohort prospective randomized studies.
Antibiotics are commonly used, but on their own are not deemed to be an option for cure. The disease progresses unrelentingly. No one antibiotic carries advantage. The empirical protocol that has been adopted involves a broad-spectrum antimicrobial in the acute phase, switching to low-dose long-term antibiotic in the tetracycline group to tackle chronic infection.
Mainous et al proposed the use of HBOT,29 but it was Marx's endorsement that led to its routine use in the 1980 to date.4 In isolation, the results are poor, and the recommendation is to use it as an adjunct to surgery. The objective is to prime and optimize the compromised surgical site for healing. The principle of its use is to oxygenate the hypoxic tissue by placing the patient in a high oxygen pressure chamber prior to the operation. Each visit, often referred to as a ‘dive’, can last up to 90 minutes. In preparation for surgery, a patient would be expected to undergo 30 consecutive daily dives, followed by a further 10 after surgery. Understandably this is impractical for the majority of patients as HBOT facilities are few, and patients have to relocate for periods of treatment. HBOT has fallen out of favour in the UK, although it is still used in the USA. The lack of effect in a recent prospective randomized trial seems to have invalidated it use.21
Surgery is still a viable management option in the right circumstances and varies from minimal procedures, such as sequestrectomy, saucerization and debridement to jaw resection and repair with microvascular flaps. Successful major reconstructive procedures open the possibility for comprehensive dental rehabilitation that may involve dental implants, but is seldom achieved. The route is strewn with complications that may compromise the expected treatment plan.
The RIF theory of ORN has allowed for a novel pharmacological solution to ORN.30 A combination of three medications; pentoxifylline, tocopherol (vitamin E) and clodronate have shown promising results in managing ORN.31,32,33 When all three are used in conjunction, they are often referred to as PENTOCLO (PENtoxifylline, TOcopherol, CLOdronate).
Pentoxifylline was originally licensed for treatment of peripheral vascular disease. Consequently, the aims are to encourage improved blood flow at the irradiated site. The addition of clodronate, a bisphosphonate, seems nonsensical considering this group of drugs have been implicated in osteonecrosis of the jaw. However, when combined with PENTO, it improves efficacy, leading to exfoliation of sequestrum and new bone formation.31 Evidence continues to grow regarding the value of this approach. A recent systematic review concluded that the combination of PENTO with or without clodronate is effective for the treatment of mandibular ORN.34 This drug combination is not a panacea for ORN, and cases of gross ORN remain a problem. Currently, most early (Notani I) and moderate (Notani II) cases of ORN will heal with this regimen. Notani III cases are much more challenging, but can respond to this regimen, but over a protracted period of time (>12months).31,35 Treatment via PENTOCLO needs very careful and individual management. Simply prescribing the drugs will not produce a satisfactory outcome. Treatment has to be tailored to the individual and there are limitations. Pentoxifylline is only available in tablet form and some patients are tube fed (nasogatric or percutaneous endoscopic gastrotomy). Crushing the tablet can increase side effects, such as gastric irritation, and although a liquid preparation has been developed, its efficacy in this formulation is yet to be validated.36
The success of PENTO37 has led to its use being extended to a prophylactic role when extracting teeth for previously irradiated patients. The results are promising.22 A trial is in preparation to test whether the drug combination taken prophylactically at the time of RT will help avoid ORN, trismus and dysphagia.
Numerous other management strategies have been employed such as piezosurgery to debride limited areas of necrotic bone,38 platelet rich plasma,39 ultrasound therapy40 and laser treatment.41 They have not been incorporated into routine or regular use for the management of ORN.
The dental profession needs to appreciate that, hidden in their patient group, there will be an increasing number of patients who have been successfully treated for HNC and, in particular, OPC. This group have a good prospect of long-term survival. They are usually treated exclusively by RT or chemo-RT and their precarious dental situation may not be immediately apparent to the dentist. The pool of ‘at risk’ patients is slowly building in the community. The time will take its natural toll on the dentition, inevitably accentuated by the effects of the radiation. This population will seek access to complex dental restorations, including crowns, bridgework and dental implants. It is unclear where the line should be drawn as to what is safe in terms of inducing late complications of RT. It may be prudent, for the general dental practitioner when treatment planning these cases to look two decades in advance to prevent complex problems evolving. Mass extractions prior to RT is not the solution and personal experience shows it is deeply resented42 by the patient and impacts on their quality of life.43 A concerted effort is required by both patient and dentist to maintain the dentition. The burden of responsibility will inevitably fall upon the primary care practitioner who will be expected to meet the patient's routine dental needs. It is this care that will help avoid ORN. It is recognized that there is limited information, training, support and funding provided to the primary care practitioner to fulfil the needs of these patients and this requires addressing by the administrative arm of the dental fraternity.
