Download Osteoradionecrosis - a review of prevention and man

Journal of Disability and Oral Health (2010) 11/1 03/09
Osteoradionecrosis - a review of prevention and management
M Burke BDS FDS RCS(Eng)1 and M Fenlon MA PhD BDentSc MGDS FDS RCS(Ed)2
Guy’s and St Thomas’ NHS Foundation Trust, 2King’s College London
1
Abstract
It has long been recognised that patients who receive radiotherapy for cancer of the head and neck area are at
risk of developing osteoradionecrosis (ORN) of the jaws. Guidelines to reduce risk have been written, based
upon the evidence of many studies which have looked at the incidence of ORN in different groups. Much of the
research was carried out over 20 years ago and more recent analysis of data and consideration of the changes
in radiotherapy raises the question as to whether modifications to the guidance is now needed. There is a wide
variation in recommendations and a simpler, more unified approach to prevention of ORN could be developed
as well as research on recent management techniques.
Clinical relevance: ORN is a serious condition which can adversely affect quality of life and treatment outcome of patients who have already suffered the trauma of oral cancer. Features include chronic exposed bone
which fails to heal, pain, fractures and fistulae. The incidence is decreasing, probably as a result of improved
radiotherapy techniques. The general dental practitioner may play the greatest role in prevention with regular
oral health care.
Key words: Radiotherapy, osteoradionecrosis
Introduction
First described by Regaud in Paris in 1920, osteoradionecrosis is non-healing exposed bone in an area previously
irradiated. Although defined as exposed bone present for
over three months, realistically, exposed bone of just a few
weeks duration gives an early sign (Kanatas et al., 2002).
In the jaws it can occur in dentate and edentulous patients,
spontaneously or following trauma, for example, after tooth
extraction (Figures 1 and 2). It may be symptomless or the
patient may complain of sharp bony edges or of pain. Sometimes the area of exposed necrotic bone enlarges and considerable areas are exposed, there may be surrounding redness or a discharging sinus either intra- or extra-orally and
development of a pathological fracture. When severe it can
be very debilitating and require surgical resection.
Figure 1 Osteoradionecrosis following dental extraction
before radiotherapy on the lower left (a) and after radiotherapy on the right (b)
04 Journal of Disability and Oral Health (2010) 11/1
Figure 2 Radiological appearance of patient in Figure 1
Figure 3 Bone resection and grafting for management of
osteoradionecrosis after failure of conservative treatment,
same patient as in Figure 1
Incidence
Studies in the literature of varying population groups report
the incidence of ORN to range from 0.95 to 35% (Reuther
et al., 2003). The wide range may be a result of differences
in the study populations or length of observation. Clayman
(1997) reviewed the incidence of ORN reported in the literature for all patients who had received radiotherapy, whether
they had extractions or not, dividing it pre- and post-1968,
by which time most units had megavoltage machines. The
incidence was 11.8% and 5.4% respectively. Reviewing literature post-1968, of patients only undergoing extractions,
the rate was 5.8% for extractions post radiotherapy, and
there was little difference between this and rate for extractions pre radiotherapy (4.4%) . Wahl (2006), reviewed cases
since 1986 and found 3.0-3.2% and 3.1-3.5% incidence of
ORN when extractions were undertaken, pre- and post-radiotherapy, respectively. Since 1997, the incidence was
even lower, 3.0% for all cases, not limited to patients who
had extractions (Whal, 2006).
Risk Factors
The risk of ORN is related to the dose of radiation, the higher
the dose, the greater the risk; below 50 Gray it is uncommon,
above 60 Gray it is more frequent (Curi and Lauria, 1997).
In a study by Thorn et al. (2000) 93% of patients with ORN
had doses in excess of 64 Gray. Combined chemotherapy
and radiotherapy led to earlier development of ORN than
radiotherapy alone (Reuther et al., 2003). Careful planning
of fields using IMRT may reduce risk of ORN even when in
combination with chemotherapy (Huang et al., 2008). Other
factors implicated include high Body Mass Index and use of
steroids in patients receiving more than 66Gy (Goldwaser
et al., 2007).
Osteoradionecrosis is more likely to develop in the mandibular molar area when this is in the field of radiation, believed to be a result of less blood supply in the mandible
(Curi and Lauria, 1997).
The greatest risk factor is considered to be dental extractions, either pre- or post-radiation (Thorn et al., 2000)
and a recent review suggests little difference between these
(Whal, 2006). A retrospective study over 30 years by Reuther et al, (2003) found tooth extractions were responsible
for 50% of cases. Careful, atraumatic extraction technique
is important in reducing the risk (Maxymiw et al., 1991).
Other factors are denture trauma, in particular ORN may develop over the mylohyoid ridge, implant placement, biopsy
and periodontal surgery. Osteoradionecrosis is more common with increasing age of the patient and in men (Reuther
et al., 2003; Lye et al., 2007). Some studies have shown
increase with use of alcohol and tobacco (Glanzmann and
Gratz, 1995; Reuther et al., 2003) but others have not found
this to be a risk factor (Thorn et al., 2000). Katsura et al.,
(2008) did not find pre treatment oral health to be a predictor
of ORN but oral health one year after the end of treatment,
periodontal status, radiographic evidence of advanced bone
loss and pocketing greater than 5mm, were predictors of
ORN. Other studies have also shown poor dental status is a
risk factor (Niewald et al., 1996). The risk of ORN remains
years after radiotherapy (Epstein et al., 1997) and probably
for ever (Lambert et al., 1997). Some studies have found the
risk decreases with time (Brown et al., 1998) although others believe it may increase (Chavez and Adkinson, 2001).
There are approximately 5,000 new cases of cancer of the
mouth and oropharynx in the UK each year, the number increasing especially in younger people. Approximately 90%
are squamous cell carcinomas. Worldwide, it is estimated
about 400,000 new cases of oral cancer are diagnosed each
year and account for 3% of all cancers, but this proportion
is considerably higher in the Indian sub-continent, parts of
France and in Hungary (International Agency for Research
on Cancer, 2003). Surgery and radiotherapy are equally effective for treatment of early stage disease (Worrell, 2005).
In late stage disease, surgery followed by radiotherapy gives
best survival times (Roberson et al., 1998). Radiotherapy is
also given to the neck if nodal resection shows two or more
lymph nodes are affected or extracapsular spread has occurred (Franceshi et al., 1993). In situations where surgery
Burke and Fenlon: Osteoradionecrosis 05
is not possible or would be very debilitating, radiotherapy is
given, often combined with chemotherapy which has been
shown to reduce local recurrence (Munro, 1995). Radiotherapy with curative intent is used either alone or as a component of treatment in about 60% of patients with cancer of
the head and neck area. A short course of radiotherapy is
sometimes used in palliative care for symptom control.
Radiotherapy is usually given as an external beam to the
tumour site and affected tissues. Interstitial brachytherapy
(placement of radioactive needles within the tumour) may
be used in small tumours on the lateral border of the tongue
(Henk, 1992).
There have been considerable advances in radiotherapy
(Harari, 2005). Since 1968 megavoltage machines have been
used which can give a high dose to deep seated tumours, as
occur in the oropharynx, with less skin damage. Over the
last 20 years three-dimensional conformal radiotherapy has
been developed: CT simulators are used in planning to determine the tumour volume and shape. The beam is shaped
to this by a multi-leafed collimator to give improved accuracy. The dose is usually 50-70 Gray given in fractions of five
daily doses each week over 4-6 weeks (Robinson, 2008). A
more recent development of conformal planning is intensity
modulated radiotherapy (IMRT), in which a varying radiation dose can be delivered to different parts at the same time.
This allows increased dose to the tumour and less to surrounding structures, for example the salivary glands. Oral
health related quality of life was preserved in patients in a
study utilising IMRT (Parliament et al., 2004). There is also
evidence that increasing the dose and shortening the treatment time can improve tumour control (Horiot et al., 1990).
This is called hyperfractionation. In continuous hyperfractionated accelerated radiotherapy (CHART) treatment is
given three times a day for just 12 days.
The Calman Report emphasised that care should concentrate on quality of life as well as longevity (Calman and
Hine, 1994). Appropriate assessment, preventive regimes
and oral care before and after cancer treatment can minimise
complications and improve quality of life (Sulaiman et al.,
2003). Patients should be informed about the importance of
oral care, with written information about the side effects of
treatment (Shaw et al., 1999).
Pathology of osteoradionecrosis
When first described, ORN was believed to be the result of
radiation delivered above a critical dose, local trauma and
infection. Marx (1983) proposed a hypothesis of radiationinduced hypoxic, hypovascular and hypocellular bone, so
there was inadequate repair of bone. If the overlying soft
tissue was damaged, the bone became exposed and infected. In addition, radiotherapy reduces the proliferation of
bone marrow, periosteal and endothelium cells and collagen production (Store and Boyson, 2000). Suppression of
bone turnover has been proposed as the primary aetiological
factor (Al-Nawas et al., 2004). Others have proposed that
ORN is caused by a fibro-necrotic process, which is relevant
to new drug treatments (Delanian et al., 2005). There is a
broad spectrum of micro-organisms in osteonecrotic bone,
but it is not believed to be an infectious process and microorganisms are probably opportunistic (Kanatas et al., 2002;
Store et al., 2005).
Prevention
Dental assessment
A multi-disciplinary approach to care is recommended and
every patient should have a dental assessment prior to radiotherapy for the best outcome following cancer treatment
(Shaw et al., 1999; Sulaiman et al., 2003). An analysis of
patients on a strict preventive regime together with IMRT
found no cases of ORN (Ben-David et al., 2007). It is recommended that a dentist is attached to the head and neck
team (NICE, 2004) or it may be the general dental practitioner who sees the patient. Either way, there should be a clear
pathway of care and in order not to delay cancer treatment it
is important the patient is seen urgently (Shaw et al., 1999).
The purpose is twofold, to carry out treatment and to instigate a preventive programme during and after radiotherapy.
Dental extractions
Because dental extractions are a major risk factor in the development of ORN, in the past, extraction of all teeth before
radiotherapy has been recommended. This is no longer the
treatment of choice and has many disadvantages. Osteoradionecrosis occurs almost as frequently after pre-radiation
extractions as post-radiation extractions (Chang et al., 2007).
Clearly, any teeth causing pain or with infection should be
extracted. Removal of all teeth of poor prognosis, generally
considered less than five years, is recommended (Shaw et
al., 1999), and planning should take into account the likely
future problems with oral care, for example if severe trismus develops. The patient’s wishes must also be taken into
account. Extractions are planned with the view to avoiding
extractions in the future. Some have advocated removal of
all mandibular molars in fields over 60 Gray, unless the patient has excellent oral hygiene (Johnson, 1997). An aggressive approach to extractions may not always be desirable,
keeping teeth plays a significant role in maintaining chewing and swallowing function as well as quality of life in patients with cancer of the head and neck area (Allison et al.,
1999). Consideration should also be give to the difficulty of
wearing dentures after radiotherapy on account of trismus
and xerostomia, and that denture trauma can cause ORN.
Certain teeth may be essential for successful provision of
a prosthesis to replace a surgical defect. Instead, a rigorous
preventive programme is crucial for patients where teeth are
retained.
Teeth requiring extraction should be removed as soon as
possible to permit maximum healing before radiotherapy.
06 Journal of Disability and Oral Health (2009) 11/1
Generally a minimum of ten days is recommended before
commencement of radiotherapy (Clayman, 1997; Shaw et
al., 1999), although some have recommended a minimum
14- 21 days (Sulaiman et al., 2003). However, it is undesirable to delay cancer treatment and since there is little difference between the risk of ORN whether extractions are
pre- or post-radiation, and neither is it entirely preventable,
radiotherapy should not be delayed. The extraction technique and experience of the operator has been debated as a
factor in development of ORN. It is always recommended
trauma is minimised (Sulaiman et al., 2003).
Preventive regime
Excellent tooth brushing is encouraged, if the mouth becomes too sore during radiotherapy a soft brush may be necessary for a time, supplemented with chlorhexidine mouthwash, which may be diluted with equal volume of water if
too sore on the mucosa (Shaw et al., 1999). In addition a
fluoride regime, either high fluoride toothpaste (Duraphat
5000), fluoride gel (Gel Kam) in splints for 10 minutes each
day or alcohol free fluoride mouthrinse (Sulaiman et al.,
2003). The regime needs to be tailored to the patient’s oral
condition, for example, some patients are unable to open
sufficiently for fluoride trays or to access the back of the
mouth or there may be post surgical anaesthesia making
brushing difficult. Altered taste and mucosal ulceration may
mean some toothpastes or rinses are too strong for a time but
the patient should return to the best regime as soon as possible. Motivation is very important and ideally the patient
should see a dental hygienist who can monitor the patient
during and after radiotherapy. Patients may be given several
oral preparations to help with a sore or dry mouth and it is
important the patient understands their function and avoids
preparations which could harm the teeth. Saliva substitutes
should be pH neutral. Some patients require frequent oral
food supplements because of chewing and swallowing difficulties; these are very cariogenic.
After radiotherapy
Patients remain vulnerable to radiation caries and periodontal disease, especially if they have severe xerostomia or access for brushing is difficult. Restorative and periodontal
treatment should be carried out where necessary, endodontic treatment is preferable to extraction, although this may
be difficult or impossible where there is trismus. Unrestorable teeth may be decoronated. Dentures should be regularly checked for pressure areas and adjusted but it may be
preferable to avoid dentures if the patient can manage with
a shortened dental arch (Finlay et al., 1992).
Extractions after radiotherapy
Although undesirable, it may become necessary to extract
teeth from the irradiated jaw. Kanatas et al. (2002) give a
practical guide for extractions. The risk of ORN developing
should be assessed, depending on the radiation dose, site
and ease of extraction. Patients should be informed of the
risk and be observant for early signs of ORN.
Summary of recommendations:
• 0.2% chlorhexidine mouthwash prior to extractions
• Antibiotics 3g orally 1 hour pre extraction (or if allergic
600mg clindamycin)
• Postoperative amoxicillin 250mg tds or metronidazole
200mg tds for 3-5 days
• Minimal trauma, simple extraction of mobile teeth
• Primary closure for firm teeth, by a minimal periosteal
flap and alveolectomy
• An experienced operator
• Possibly pre-operative hyperbaric oxygen for mandibular molars in areas of high radiation
• Review after 5 days, weekly review until healing is
complete
These recommendations are followed in most centres, although there is controversy about the best antibiotic regime
and use of hyperbaric oxygen.
Antibiotics
Most studies on ORN have recommended antibiotic prophylaxis for extractions in post-radiation patients. A survey
of British maxillofacial surgeons in 2002 found 86% recommended pre-surgical prophylaxis and 89% post-operative antibiotics for extraction of a mandibular molar in the
radiotherapy field, although there was no consensus on the
choice of antibiotic, timing and duration of course (Kanatas
et al., 2002).
Wahl (2006) found the incidence of ORN post-extraction
after 1986 was 3.6% in cases using antibiotics and 2.6-3.4%
in cases not reporting the use of antibiotics, indicating antibiotics appear to give no improvement in the rate of ORN.
Antibiotics can have adverse side effects including gastrointestinal upset and risk of allergy for the patient. There is
also a move to reduce the use of antibiotics to counter the
development of resistant organisms. Antibiotic prescribing
to prevent infection is increasingly controversial and some
no longer recommend their use to prevent ORN (StevensonMoore and Epstein, 1993).
Hyperbaric oxygen
Hyperbaric oxygen (HBO) stimulates vascualisation and
increased tissue oxygenation, encourages collagen and cell
formation with improved healing (Kanaras et al., 2002).
Since some studies indicated this may be effective in treating ORN consideration was given to its use in prevention.
Marx et al. (1985) reported 5.4% ORN in patients who received HBO and antibiotics compared to 29.9% in patients
who had antibiotics alone, for post-radiation dental extractions. A study in 1999 also showed favourable results with
HBO (Vudiniabola et al., 1999), however, both these studies
have a very high rate of ORN and small patient numbers.
Burke and Fenlon: Osteoradionecrosis 07
Studies since 1986 have shown far lower rates of ORN, even
without HBO (3.1-3.5%) and even a slightly higher rate for
HBO patients (4.0%) (Whal, 2006). Some recommend the
prophylactic use of HBO (David et al., 2001; Kanatas et al.,
2002) and a Cochrane review suggested there was evidence
for some reduction in ORN (Bennett et al., 2005) although
others believe there is insufficient evidence to support its
use for prophylaxis of ORN (Clayman, 1997). A survey of
British maxillofacial surgeons found most recommended it
as part of management but protocols varied (Kanatas et al.,
2005). There are considerable difficulties with provision of
HBO. The typical treatment regime is 20 dives before surgery and 10 afterwards, 90 minutes each, breathing 100%
oxygen at high pressure in a chamber, so it is very time
consuming. A course of treatment costs several thousand
pounds and only a few centres are able to provide it. There
are serious risks to the patient, including fits and ear damage
as well as claustrophobia.
Implant placement
Patients who have had radiotherapy, especially if they have
had additional extensive surgery, may have difficulty wearing a conventional denture. Implants are very useful in these
situations. Hyperbaric oxygen has been recommended prior
to implant placement to improve the success (Shaw et al.,
1999; Kanatas et al., 2005) but a recent Cochrane review
found no evidence for or against the use of HBO in this situation (Coultard et al., 2006).
Treatment of osteoradionecrosis
The course of ORN is variable. Sometimes ORN is symptomless and dental practitioners should therefore be observant for areas of exposed bone developing and take a careful history. Osteoradionecrosis can become very severe and
debilitating but early intervention can lead to a good result.
Patients should be managed in a maxillofacial unit. Conservative treatment for ORN usually involves smoothing sharp
edges of necrotic bone and prolonged course of broad spectrum antibiotics (Kanatas et al., 2002; Reuther et al., 2003),
either orally or intravenously. In one study antibiotic therapy and surgery led to complete healing in 40% of cases, the
others continued as either a chronic or an aggressive form of
ORN (Reuther et al., 2003). Surgery included local debridement and excision of necrotic bone with primary wound
closure. In severe cases a block resection (with preservation
of the lower border of the mandible) or a segmental resection with reconstruction with bone and skin grafts may be
needed (Figure 3), (Yanagiya et al., 1993; Buchbinder and
St Hilaire, 2006). It is important to be aware that recurrent
disease can masquerade as ORN. In one study, seven of 33
cases initially diagnosed as ORN involved recurrent disease
(Hao et al., 1999).
Hyperbaric oxygen
Hyperbaric oxygen therapy has been recommended in severe cases of ORN (Marx and Ames, 1982), often in combination with surgery. However, its effectiveness is uncertain.
A randomised, double-blind trial in 2004 showed no benefit
(Annane et al., 2004).
Ultrasound
Ultrasound stimulates the blood supply and bone metabolism and there has been some interest to assist healing of
ORN. It has been applied to the mandible for ten minutes
daily for 50 days with good results, although in a limited
number of cases (Reher, 1997).
Pentoxifylline and vitamin E
Pentoxifylline (PTX) and vitamin E have been used to treat
advanced cases of ORN, with promising results. These
drugs are believed to promote healing, PTX lowers blood
viscosity, increases tissue oxygen level, reduces fibroblast
proliferation and increases collagenase activity; it is used to
treat intermittent claudication. Vitamin E is an antioxidant.
Pentoxifylline alone improved healing of radiation-induced
mucosal injury (Futran et al., 1997) and one case of severe
ORN of the sternum was completely healed with a combination of PTX, vitamin E and clodronate, which inhibits
osteoclast activity (Delanian and Lefaix, 2002). A trial of 18
patients with severe ORN and oro-cutaneous fistulae was
carried out in Paris 1995-2002 (Delanian et al., 2005). All
these patients had failed to respond to conservative treatment, with or without HBO and surgery. The radiation dose
was 55-75 Gray. Patients were given daily doses of 800mg
PTX and 1000 IU vitamin E for at least six months The last
eight patients treated also had 1600mg clodronate. Patient
tolerance was very good. Quantitative regression of exposed
bone was seen in 100% of patients by six months, and 89%
had complete healing with mucosal coverage, most by six
months. Qualitatively, assessment showed rapid pain relief, trismus reduction and closure of fistulae. These results,
which are for patients for whom other treatments had failed,
are promising. The drugs used were well tolerated and inexpensive (about £2 per day). Further clinical trials are necessary to assess the regime, including possible use as an early
intervention measure or prophylactically and to study any
long term side effects.
Summary
It is time to reconsider recommendation for prevention and
management of ORN. Radiotherapy has improved and the
incidence of ORN has reduced. Analysis of evidence for traditional preventive regimes of antibiotics or HBO does not
consistently show any advantage, both have disadvantages
and can no longer be wholeheartedly recommended. Similarly, in the management of established osteoradionecrosis,
08 Journal of Disability and Oral Health (2009) 11/1
HBO is of questionable benefit. Antibiotics with surgery if
necessary lead to healing in some cases. Pentoxifylline and
vitamin E may be a promising alternative conservative treatment and further studies are needed to evaluate them. Thorough pre-radiotherapy assessment, removal of teeth with
poor prognosis and commencement of a preventive regime
will reduce the need for dental extractions in the irradiated
jaw. Patients are at high risk of oral disease following radiotherapy and should have frequent reviews and early intervention although the sequelae of surgery and radiotherapy
can impose a challenge for the dentist. The continuation of
preventive therapy is extremely important and the general
dental practitioner has a vital role to play in the care pathway. For more complex cases, there is a place for development of specialist head and neck cancer care teams, including a dentist and dental hygienist.
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Address for correspondence:
Dr Mary Burke
Department of Sedation and Special Care Dentistry
King’s College London Dental Institute
Floor 26, Tower Wing
Great Maze Pond, London,
SE1 9RT, UK
[email protected]