The management of osteoradionecrosis of the jaws – A review

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

Available online at www.sciencedirect.com

ScienceDirect The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net

Review

The management of osteoradionecrosis of the jaws e A review Niamh Rice a,*, Ioannis Polyzois b, Kumara Ekanayake a, Osama Omer b, Leo F.A. Stassen a a

Department of Oral and Maxillofacial Surgery, Oral Medicine, Oral Pathology, Dublin Dental University Hospital, Lincoln Place, Dublin 2, Ireland b Department of Restorative Dentistry and Periodontology, Dublin Dental University Hospital, Lincoln Place, Dublin 2, Ireland

article info

abstract

Article history:

Purpose: To review the conservative and surgical management options of osteoradionec-

Received 16 March 2014

rosis, in particular, highlighting the recent the use of anti-radiation fibrosis drugs (pen-

Received in revised form

toxifylline, tocopherol and clodronate).

2 July 2014

Material and methods: We performed a literature review. The management options were

Accepted 4 July 2014

divided into two groups, conservative and surgical management.

Available online xxx

Results: Over the years several treatment options have been proposed including; conservative management (antibiotics, analgesics, oral hygiene), ultrasound therapy, hyperbaric

Keywords:

oxygen therapy, surgical resection with reconstruction and more recently the use of anti-

Osteoradionecrosis

radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). Early or low grade ORN

Radiation induced fibroatrophic

can be managed conservatively using a combination of treatment options. In advanced or

process

refractory cases of ORN (pathological fracture, orocutaneous fistula) surgical treatment, at

Pathological fracture

present, remains the only treatment option available. A new understanding of the path-

Mandibular reconstruction

ophysiology of ORN (radiation induced fibroatrophic process) has lead to the development of new therapeutic management regimes. Conclusion: In advanced or refractory cases of ORN surgical treatment, including microvascular reconstructive techniques for bone and soft tissue, remains the only option available. © 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ353 877644060. E-mail address: [email protected] (N. Rice). http://dx.doi.org/10.1016/j.surge.2014.07.003 1479-666X/© 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

2

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

Introduction Radiation therapy has an important part to play in the management of oral cancer. It is most commonly used as supportive treatment for more advanced cases but can also be used as the primary treatment for smaller soft tissue oral cancers.1,2 Osteoradionecrosis (ORN) of the jaws is one of the most severe and debilitating complications following radiation therapy for head and neck cancer patients. It is a radiationinduced ischaemic necrosis of bone with associated soft tissue necrosis occurring in the absence of primary tumour, recurrence, or metastatic disease.3 The incidence of ORN ranges from 5 to 15% and is most frequently noted (>70%) in the first three years after completion of treatment.4,5 Mandibular ORN is more prevalent when compared to the maxilla due to the relatively poor vascularisation and to the dense structure of mandibular bone.4,6e9 Several risk factors have been implicated including tumour stage, tumour infiltration of adjacent bone, pre-radiation mandibular surgery, radiation modality, tooth extractions, and poor oral health.4,8 ORN can also develop spontaneously.4,8,10 Controversy exists over the management of ORN. Conservative measures include antiseptic mouthwashes, antibiotics, sequestrectomy, ultrasound therapy and hyperbaric oxygen therapy. Surgical management includes more radical procedures with or without the use of conservative measures. An overview of the management of ORN, pre- and postradiation, is outlined in the algorithm (Fig. 1).

Several theories have been proposed regarding the pathophysiology of ORN. The most recent theory, radiation-induced fibrosis, has led to the development of new therapeutic management regimes including the use of a drug that exerts an anti-tumour necrosis factor-a effect and a drug that scavenges reactive oxygen species.11 Tumour necrosis factor-a mediates the body's response to infection and promotes inflammation. The new drug regime inhibits this effect.

Literature review Conservative management No universally accepted treatment exists for ORN and, in many cases, depends on the severity of the condition. Several staging systems have been proposed (Table 1). Marx's classification system, introduced in 1983, has three stages and is based on the response to hyperbaric oxygen therapy.12 This classification has been updated, resulting in more recent classifications based on clinical and radiologic findings.13 Studies have described early ORN (lower grades) being managed conservatively and more advanced disease, including pathologic fracture, and oro-cutaneous fistula, being managed surgically (Figs. 2e5).14e21 Conservative treatment includes non-operative (improvement in oral hygiene, antibiotics and analgesics) and surgical management (debridement, sequestrectomy, excision and reconstruction) as well as hyperbaric oxygen therapy.18,21 Conservative

Patient undergoing Radiation Therapy

Pre-Radiation Dental assessment

Dentulous

Edentulous

Post-Radiation treatment

Asymptomatic (No bone exposure)

Dental Care -Regular oral health monitoring

Symptomatic (Exposed bone 17± 8mm)

Not-infected

Ultrasound Hyperbaric Hyp y erbaric oxygen Combination drug dru r g regime (pentoxify f lline, (pentoxifylline, tocopherol, clodronate)

Infected

Antibiotics Chlorhexidine mouthwash

Does not settle

Surgery

Small

Big

Monitor Debrideme & Debridement local cov cover

Excision & reconstruction with vascularised tissue

Monitor

Fig. 1 e Algorithm for patient undergoing radiation therapy.

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

3

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

Table 1 e Classification of stages of ORN. Reference

Stages

Basis of stage

Marx 198312

IeIII

Epstein et al. 19875

IeIII

Kagan & Schwartz 200213

IeIII

Notani et al. 200341 (Figs. 2e5)

IeIII

Based on response to hyperbaric oxygen therapy I: 60 dives- full mucosal coverage II: Sequestrectomy & 60 dives- full mucosal coverage III: Pathologic fracture, Orocutaneous fistula, radiographic evidence of resorption to inferior border. 30 dives & resection Based on imaging and clinical findings I: Resolved or healed ORN II: Chronic (>3 months), persistent, non-progressive ORN III: Progressive, active ORN Based on imaging and clinical findings I: Superficial involvement of the mandible only II: Localised involvement of the mandible III: Diffuse involvement of the mandible Based on imaging and clinical findings I: ORN confined to alveolar bone II: ORN limited to alveolar bone and/or the mandible above level of mandibular canal III: ORN extended to mandible under level of mandibular canal with ORN skin fistula or pathological fracture

management of ORN with antibiotics, local wound care and/or hyperbaric oxygen has been shown to be effective in 25%e44% of cases.3,5,6,22 Small sample sizes, diminished the power of these results. Conservative approaches, when ineffective, have been described as having a built-in cost in human and financial resources. It can involve an unacceptable amount of clinical time and patient effort as well as the potential for causing patient drug addiction.12 Marx associated the poor results of conservative therapy to the fact that the basic pathology of the disease was not being addressed.10,12 Oh et al. in 2009 reported that 65% of patients, who had received more than 60Gy of radiation had a poor response to conservative treatment.18 These results are in agreement with Beumer et al. (1984) who reported that ORN occurring after exposure to dosages in excess of 65Gy did not respond favourably to conservative treatment. For these cases a 44% mandibular resection rate was reported.22 The radiation modality has an effect on the severity and incidence of ORN. Intensity-modulated radiotherapy (IMRT) is used to deliver precise radiation doses to the tumour and

Fig. 2 e Notani Classification I.

areas within the tumour, as a result, minimizing the dose delivered to surrounding normal tissues. IMRT has resulted in a decrease in incidence and severity of ORN, compared to the use of conventional radiotherapy.23 As the cases of ORN are less severe, the use of conservative management may increase. Maxillary ORN usually demonstrates a more benign clinical course due to anatomic factors, small bone size and good aeration (Fig. 6). For this reason conservative management and localised sequestrectomy is generally sufficient, even for advanced maxillary cases.24 The management of acutely infected ORN includes the use of mouth-rinses including 0.02% aqueous chlorhexidine and saline rinses.25 Analgesics and anti-inflammatory drugs are prescribed as necessary. To eliminate infection in the area tetracyclines have been recommended, because of their selective uptake by bone. Because of superficial contamination with oral bacteria, penicillin antibiotics can also be used.26

Ultrasound therapy Harris, in 1992, introduced ultrasound (US) as a treatment modality for ORN.27 US is the term applied to sound waves with a frequency greater than the upper limit of the human hearing range, which is approximately 20 kHz. Ultrasound therapy induces angiogenesis, improves blood flow to muscles, and healing of ischaemic varicose ulcers.28e30 Harris demonstrated that US is an important means of revascularisation in mandibular ORN.27 US was applied for 15 min a day to the skin overlying the ORN area of mandible for 40e100 applications with a mean of 55 applications in 21 cases. In this study, 48% of cases showed healing, when treated with debridement and ultrasound alone. For the patients that satisfactory healing was not observed further treatment was provided in the form of debridement and cover of the affected area with a local flap. One patient needed a mandibular resection and formal reconstruction. Long wave US was introduced in 1997. This 45 kHz frequency US has low

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

4

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

Fig. 3 e Notani Classification II.

intensities between 27 and 39 mW/cm2, increases the depth of penetration to several centimetres and does not produce heat or intravascular damage. The protocol advised 40e50v(10 min) US sessions.31 Low intensity pulsed ultrasound aims to speed up fracture healing in broken bones by stimulating bone cells to grow and repair. This has the potential to aid in the management of patients with ORN. To date there is a large volume of date available on this subject with conflicting results.32

Hyperbaric oxygen Hyperbaric oxygen (HBO) therapy was described as an adjunctive treatment modality in the management of ORN in 1973.33 The rationale for HBO is the requirement of oxygen in wound healing. It results in an increase in tissue oxygen tension and improves collagen synthesis, angiogenesis and epithialization.34 Angiogenesis is stimulated by the increase in PO2 differential (oxygen tension) between the environment and the hypoxic area. HBO is inhibitory to aerobic and anaerobic bacteria.35 Its use in the management of ORN is controversial. A protocol that combines surgery and HBO

Fig. 4 e Notani Classification III.

therapy was introduced by Marx in 1983 and he concluded that HBO therapy alone cannot usually heal osteonecrotic wounds.12 This statement has been supported by several studies.4,5,7,36e38 The target tissue in HBO therapy is compromised ‘living tissue’, which has great metabolic demands to remain viable. There should not be necrotic bone or soft tissue. As a result, HBO is an adjunctive and not a “stand alone” therapy.39 In a retrospective study by D'Souza et al. (2007) it was concluded that HBO therapy was of little benefit.40 Twenty-three patients were divided into three grades of ORN based on the classification system of Notani et al., 2003.41 HBO was given to 10 out of 13 grade one patients and was beneficial for 2 of them. For 4 out of 6 grade two patients there was no reported benefit. Finally two out of four grade three patients received HBO and all have to receive resection and reconstruction. Interestingly, the two patients that were cured hadn't received HBO. It has been suggested that there was a negative selection bias for the HBO group in this study and this might have influenced the results.42 Maier et al. (2000) demonstrated that post-operative HBO therapy is not effective for severe ORN and that HBO can not be the management option, if surgery fails to treat ORN.43 A randomised, double-blind trial by Annane et al. in 2004 was terminated early as there was no evidence for the use of HBO therapy over a placebo.44 The sample size was 68. At year one, 6 out of the 31 patients (19%) had recovered in the HBO arm and 12 of 37 (32%) had recovered in the placebo arm. Feldmeier et al. in 2004 highlighted that Annane et al. did not follow the accepted standard of using HBO as an adjunct to surgery.38 A recent Cochrane meta-analysis also highlights several issues with Annane et al.'s study. It was suggested that the trial did not follow the usual treatment regime for management of ORN and therefore may not be comparable with other trials; treatment failure in the study was defined by a need for surgery; whether or not full recovery was eventually achieved was not taken into consideration. Additionally severe forms of ORN were not included in this trial.45 The conclusion from this meta-analysis suggest that for people with late radiation tissue injury, HBO therapy is associated with an improved outcome.45

Multimodality approach (hyperbaric oxygen and surgery) The multimodality approach of surgery and hyperbaric oxygen for the management of ORN has been widely reported. A retrospective study by Freiberger et al. in 2009 reviewed pretreatment to post-treatment changes in 65 ORN patients, who had similar presentations and treatment histories.37 Sixty-one patients had a combination of HBO and surgical interventions. At the time of follow up, 82% of the observed wounds were resolved or improved by Epstein's criteria/classification5 (in twenty patients the result was unknown). The mean duration of improvement after HBO was 86 months in non-smokers and those who remained cancer free. This study had no control group but the authors argued that the patients could serve as their own controls considering the lack of healing with their prior therapies. Another drawback was the limited information available for follow-up data. Ang et al. in 2003 also supports the multimodality approach.15 In this retrospective study, they observed that none of the patients

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

5

Pathogenesis of osteoradionecrosis The understanding of the pathogenesis of ORN has developed over the years. In 1970, Meyer proposed the classic triad of ORN; radiation, trauma and infection.48 He suggested that trauma, such as a dental extraction, provided openings that acted as passages for the entrance of oral bacterial flora into the underlying irradiated bone. ORN developed due to the rapid spread of microbes in irradiated bone. Meyer's theory was questioned by Marx in 1983, who proposed the formation of hypoxic-hypovascular-hypocellular tissue after RT.10 He concluded that ORN is not a primary infection of irradiated bone and that microorganisms only play a contaminant role.10

Fig. 5 e Notani Classification III.

who had received prior HBO therapy, developed any major complications. This study concluded that a course of preoperative HBO therapy, if logistically practical, is recommended to improve local circulation, with wide resection of necrotic bone and immediate free-flap reconstruction. Marx in 1982 reported a 91% success rate with the multimodality approach.46 Chang et al. in 2001, on the other hand, reported that in advanced cases of ORN using HBO therapy may not be beneficial.17 According to Gal et al. in 2003, HBO does not revive dead bone or resuscitate impaired bone and the margins of resected ORN bone should not be reduced by its use.20 He concluded that microvascular reconstruction without the use of HBO is a successful approach to the management of ORN. Conflicting evidence regarding the multimodality approach makes the development of a standard protocol on the use of HBO and surgery an impossible task. HBO therapy has been questioned and the fibroatrophic theory of the pathophysiology of ORN has challenged the concept of ischaemia as the primary mechanism for ORN.47

Fig. 6 e Maxillary ORN.

Radiation induced fibroatrophic process Radiation-induced fibroatrophic process (RIF) is the current theory that accounts for radiation tissue injury. Three distinct phases have been described and are summarised in Table 2. The first phase, pre-fibrotic phase, comprises of chronic inflammation resulting in the presence of collagen degradation products and destruction of endothelial cells. This triggers fibroblastic activation. In the second phase, constitutive organised phase, abnormal fibroblastic activity predominates with disorganisation of the extracellular matrix. The third phase, late fibroatrophic phase, describes the formation of tissues that are friable and poorly vascularised following attempted tissue remodelling. These fragile tissues may be subjected to late reactivated inflammation after any local injury.11 The RIF theory challenges Marx's conclusion that persistent tissue hypoxia had caused the described changes.10 The interaction of radiation with living tissue generates reactive oxygen species (ROS) originating from the initial inflammation process. Collagen degradation products stimulate polymorphonuclear cells and macrophages and as a result further ROS are released. The current theory proposes that ROS causes endothelial cell injury. This associated with vascular thrombosis may lead to necrosis of the microvessels, local ischaemia and tissue loss.11,49 To reverse damage caused by ROS, new therapeutic regimes have been developed.50 Pentoxifylline is a methylxanthine derivative that exerts an anti-tumour necrosis factor-a effect, inhibits inflammatory reaction in vivo and increases collagenase activity. This is administered with tocopherol, which scavenges the ROS. These two drugs act synergistically as potent antifibrotic agents.49 In a recent study 89% of patients with ORN recovered with complete healing using pentoxifylline and tocopherol and the most seriously affected patients were given clodronate.50 The latter is a bisphosphonate which reduces chronic inflammation, osteoclastic resorption, in vitro fibroblastic proliferation and which shorten osteoclast lifespan.51,52 Combined pentoxifylline, tocopherol and clodronate demonstrated 100% regression.53 Sequestrectomy was required in two-thirds of the patients. This study concluded that extensive surgery is reserved for salvage cases, for example cellulitis, fracture with displacement and extensive exposed bone 17 ± 8 mm.53 The findings in the latter study was supported by a case report but not by a retrospective case series where usage of pentoxifylline and tocopheral alone didn't give

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

6

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

Table 2 e Radiation induced fibroatrophic process.11 Phase 1. Pre-fibrotic 2. Constitutive organised 3. Late fibroatrophic

promising results.54 The main difference in this approach was the absence of clodronate in the treatment regime.55

Surgery Surgical options include removal of small sequestra, sequestrectomy, alveolectomy with primary closure, closure of orocutaneous fistula and large resections. In advanced or refractory cases of ORN, surgical treatment is indicated.15,21 This includes radiographically evident osteolysis of the inferior border, a pathological fracture, orocutaneous fistula or failure of conservative treatments.14,21,43 These circumstances necessitate radical resection of the involved segment up to viable bone. Significant segmental bone loss and soft tissue defects require reconstruction to restore mandibular continuity for functional and cosmetic reasons.14,17 Reconstruction techniques comprise the use of reconstruction plates, autogenous bone grafts, regional flaps and free tissue transfer.15,21,56,57 Vascularised bone flaps are the most effective reconstructive modality.15,21 Donor sites include fibula, scapula, iliac crest and radical forearm. The radial forearm flap has gained in popularity but the limitation is the size and the calibre of the bone graft that can be safely harvested without donor site morbidity.14,58 The fibula flap is the first choice due to the quality and quantity of the bone. Distraction osteogenesis has also been described as a reconstruction technique but there has been conflicting reports on its success.59e62 Surgery, up until the development of the new drug regime, was the only treatment option available, if conservative measures and HBO therapy failed to control ORN.

Biological molecules The use of biological molecules for the treatment of ORN has also been investigated.63e65 Autogeneous grafts have long been considered as the gold standard in most osseous regenerative procedures.63,66 Bone substitutes and angiogenic cytokines are designed to enhance grafting techniques or as an alternative to bone harvesting, potentially improving grafts or avoiding donor-site surgery and morbidity.66 In the latter article iliac marrow aspirate cultured ex-vivo generates large amounts of early-stage mesenchymal, endothelial, haematopoietic stem, and progenitor cells. Three cases of advanced craniofacial diseases were selected for this study, one including a pathologic fracture of mandible as a result of ORN. Necrotic tissue was excised and mandibular reconstruction plate was placed. The wound was closed after cell flushing and inoculation into the skin, muscle and areas adjacent to the facial nerve. The result was early osteogenesis, total recovery from alveolar nerve anaesthesia, facial nerve

Description Chronic inflammation and destruction of endothelial cells Abnormal fibroblastic activity and destruction of extracellular matrix Fragile and poorly vascularised tissues

reinnervation and skin regeneration.66 This is very early investigation and may be something for the future.

Discussion ORN is a debilitating complication of radiation therapy. The most effective treatment of ORN is prevention.2 Pre-radiation dental evaluation and close collaboration by a multidisciplinary team can be invaluable for radiation patients.2,6,7,25,67 Avoidance of smoking and alcohol is of the utmost importance.4,8,9,18,68 The treatment strategy for ORN should be similar regardless of the cancer lesion site in the head and neck region.69 Surgery has aided the successful management of ORN over the years.17,19e21,43,56 Harris' study of US therapy had successful results.12,27 In this study 48% of cases were successfully treated with debridement and US alone. For Marx, HBO alone achieved complete healing of ORN in 15% of cases, and 70% required resection and major reconstruction.12 The understanding of the pathogenesis of ORN has lead to the development of the radiation-induced fibroatrophic process (RIF) theory. As discussed earlier RIF results in endothelial cell injury leading to necrosis of microvessles. US, known to induce angiogenesis, has potential benefit in managing ORN according to the RIF theory. US machines are readily available in hospitals and this may be a more cost effective treatment option than HBO therapy. From reviewing the literature there is no up-to-date studies on the role and use of US therapy for management of ORN. The experimental research for the use of HBO is scarce, and the power of clinical research is limited because of the lack of randomised control trials. The latter can be difficult to plan and ethical issues are often involved. HBO therapy is expensive, inconvenient and not widely available. It is time consuming, not suitable for patients with claustrophobia and can often delay the more appropriate therapy. Owing to the lack of strong evidence regarding HBO therapy and economic issues, it may be difficult to justify the use of this treatment modality.3,4,7,40,44 Based on current understanding of the pathophysiology of ORN, the radiation-induced fibroatrophic process, the new therapeutic regime may eliminate the need for surgery except in the cases of cellulitis, fracture with displacement and extensive exposed bone (17 ± 8 mm).53 The therapeutic regime, pentoxifylline, tocopherol and clodronate, is based on retrospective data in case reports compiled by the same author and uses the anti-tumour necrosis factor-a effect, inhibits inflammatory reaction, increases collagenase activity and scavenges reactive oxygen species.50,53,70 Prospective

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

randomised control trials are necessary to confirm these results. The cost implications of managing ORN are an important consideration. Conservative management consisting of multiple HBO dives and surgical debridement can become very costly. HBO, in particular is extremely expensive in comparison to the new therapeutic regime using a combination of drugs.71 Conservative management is generally only effective in lower grades of ORN. It has been suggested that using conservative approaches in more advanced cases is futile, not-economical and often delaying surgical resection and reconstruction. Advancing directly to a surgical approach, in suitable cases, will dramatically decrease the financial burden and psychosocial stress the patient must undertake.72 The use of biological molecules is in early infancy in its development and a considerable amount of work is being done in this area. Surgical approaches such as small sequestra removal and debridement of superficial bone until bleeding occurs are regarded in many studies as conservative management.5,14,15,18,19,37,40,73 In advanced or refractory cases of ORN surgical treatment, including microvascular reconstructive techniques for bone and soft tissue, remains the only option available.

references

1. Day TA, Davis BK, Gillespie MB, Joe JK, Kibbey M, MartinHarris B, et al. Oral cancer treatment. Curr Treat Options Oncol 2003;4(1):27e41. 2. Brody S, Omer O, McLoughlin J, Stassen L. The dentist's role within the multi-disciplinary team maintaining quality of life for oral cancer patients in light of recent advances in radiotherapy. J Ir Dent Assoc 2013;59(3):137e46. 3. Wong JK, Wood RE, McLean M. Conservative management of osteoradionecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84(1):16e21. 4. Reuther T, Schuster T, Mende U, Ku¨bler A. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patientsea report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003;32(3):289e95. 5. Epstein JB, Wong FL, Stevenson-Moore P. Osteoradionecrosis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 1987;45(2):104e10. 6. Morrish RB, Chan E, Silverman S, Meyer J, Fu KK, Greenspan D. Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer 1981;47(8):1980e3. 7. Curi MM, Dib LL. Osteoradionecrosis of the jaws: a retrospective study of the background factors and treatment in 104 cases. J Oral Maxillofac Surg 1997;55(6):540e4. discussion 5e6. 8. Kluth EV, Jain PR, Stuchell RN, Frich JC. A study of factors contributing to the development of osteoradionecrosis of the jaws. J Prosthet Dent 1988;59(2):194e201. 9. Thorn JJ, Hansen HS, Specht L, Bastholt L. Osteoradionecrosis of the jaws: clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg 2000;58(10):1088e93. discussion 93e5. 10. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41(5):283e8. 11. Delanian S, Lefaix JL. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol 2004;73(2):119e31.

7

12. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41(6):351e7. 13. Schwartz HC, Kagan AR. Osteoradionecrosis of the mandible: scientific basis for clinical staging. Am J Clin Oncol 2002;25(2):168e71. 14. Militsakh ON, Wallace DI, Kriet JD, Tsue TT, Girod DA. The role of the osteocutaneous radial forearm free flap in the treatment of mandibular osteoradionecrosis. Otolaryngol Head Neck Surg 2005;133(1):80e3. 15. Ang E, Black C, Irish J, Brown DH, Gullane P, O'Sullivan B, et al. Reconstructive options in the treatment of osteoradionecrosis of the craniomaxillofacial skeleton. Br J Plast Surg 2003;56(2):92e9. 16. Chrcanovic BR, Reher P, Sousa AA, Harris M. Osteoradionecrosis of the jawsea current overviewePart 2: dental management and therapeutic options for treatment. Oral Maxillofac Surg 2010;14(2):81e95. 17. Chang DW, Oh HK, Robb GL, Miller MJ. Management of advanced mandibular osteoradionecrosis with free flap reconstruction. Head Neck 2001;23(10):830e5. 18. Oh HK, Chambers MS, Martin JW, Lim HJ, Park HJ. Osteoradionecrosis of the mandible: treatment outcomes and factors influencing the progress of osteoradionecrosis. J Oral Maxillofac Surg 2009;67(7):1378e86. 19. Curi MM, Oliveira dos Santos M, Feher O, Faria JC, Rodrigues ML, Kowalski LP. Management of extensive osteoradionecrosis of the mandible with radical resection and immediate microvascular reconstruction. J Oral Maxillofac Surg 2007;65(3):434e8. 20. Gal TJ, Yueh B, Futran ND. Influence of prior hyperbaric oxygen therapy in complications following microvascular reconstruction for advanced osteoradionecrosis. Arch Otolaryngol Head Neck Surg 2003;129(1):72e6. 21. Shaha AR, Cordeiro PG, Hidalgo DA, Spiro RH, Strong EW, Zlotolow I, et al. Resection and immediate microvascular reconstruction in the management of osteoradionecrosis of the mandible. Head Neck 1997;19(5):406e11. 22. Beumer J, Harrison R, Sanders B, Kurrasch M. Osteoradionecrosis: predisposing factors and outcomes of therapy. Head Neck Surg 1984;6(4):819e27. 23. Gevorgyan A, Wong K, Poon I, Blanas N, Enepekides DJ, Higgins KM. Osteoradionecrosis of the mandible: a case series at a single institution. J Otolaryngol Head Neck Surg 2013;42:46. 24. Cheng SJ, Lee JJ, Ting LL, Tseng IY, Chang HH, Chen HM, et al. A clinical staging system and treatment guidelines for maxillary osteoradionecrosis in irradiated nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 2006;64(1):90e7. 25. Scully C, Epstein JB. Oral health care for the cancer patient. Eur J Cancer B Oral Oncol 1996;32B(5):281e92. 26. Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc 1985;111(1):49e54. 27. Harris M. The conservative management of osteoradionecrosis of the mandible with ultrasound therapy. Br J Oral Maxillofac Surg 1992;30(5):313e8. 28. Dyson M, Franks C, Suckling J. Stimulation of healing of varicose ulcers by ultrasound. Ultrasonics 1976;14(5):232e6. 29. Young SR, Dyson M. The effect of therapeutic ultrasound on angiogenesis. Ultrasound Med Biol 1990;16(3):261e9. 30. Hogan RD, Burke KM, Franklin TD. The effect of ultrasound on microvascular hemodynamics in skeletal muscle: effects during ischemia. Microvasc Res 1982;23(3):370e9. 31. Reher P. Ultrasound for the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1997;55(10):1193e4. 32. Schortinghuis J, Ruben JL, Raghoebar GM, Stegenga B. Ultrasound to stimulate mandibular bone defect healing: a

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

8

33.

34. 35.

36.

37.

38. 39.

40.

41.

42.

43.

44.

45.

46.

47.

48. 49.

50.

51.

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

placebo-controlled single-blind study in rats. J Oral Maxillofac Surg 2004;62(2):194e201. Mainous EG, Boyne PJ, Hart GB. Elimination of sequestrum and healing of osteoradionecrosis of the mandible after hyperbaric oxygen therapy: report of case. J Oral Surg 1973;31(5):336e9. Tompach PC, Lew D, Stoll JL. Cell response to hyperbaric oxygen treatment. Int J Oral Maxillofac Surg 1997;26(2):82e6. Mader JT, Brown GL, Guckian JC, Wells CH, Reinarz JA. A mechanism for the amelioration by hyperbaric oxygen of experimental staphylococcal osteomyelitis in rabbits. J Infect Dis 1980;142(6):915e22. van Merkesteyn JP, Bakker DJ, Borgmeijer-Hoelen AM. Hyperbaric oxygen treatment of osteoradionecrosis of the mandible. Experience in 29 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80(1):12e6. Freiberger JJ, Yoo DS, de Lisle Dear G, McGraw TA, Blakey GH, Padilla Burgos R, et al. Multimodality surgical and hyperbaric management of mandibular osteoradionecrosis. Int J Radiat Oncol Biol Phys 2009;75(3):717e24. Feldmeier JJ. Hyperbaric oxygen for delayed radiation injuries. Undersea Hyperb Med 2004;31(1):133e45. Johnson RP. Discussion: osteoradionecrosis of the jaws: a retrospective study of the background factors and treatment in 104 cases. J Oral Maxillofac Surg 1997;55(6):545e6. D'Souza J, Goru J, Goru S, Brown J, Vaughan ED, Rogers SN. The influence of hyperbaric oxygen on the outcome of patients treated for osteoradionecrosis: 8 year study. Int J Oral Maxillofac Surg 2007;36(9):783e7. Notani K, Yamazaki Y, Kitada H, Sakakibara N, Fukuda H, Omori K, et al. Management of mandibular osteoradionecrosis corresponding to the severity of osteoradionecrosis and the method of radiotherapy. Head Neck 2003;25(3):181e6. Freiberger JJ, Feldmeier JJ. Evidence supporting the use of hyperbaric oxygen in the treatment of osteoradionecrosis of the jaw. J Oral Maxillofac Surg 2010;68(8):1903e6. Maier A, Gaggl A, Klemen H, Santler G, Anegg U, Fell B, et al. Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygenation. Br J Oral Maxillofac Surg 2000;38(3):173e6.
hanno P, Annane D, Depondt J, Aubert P, Villart M, Ge Gajdos P, et al. Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group. J Clin Oncol 2004;22(24):4893e900. Bennett MH, Feldmeier J, Hampson N, Smee R, Milross C. Hyperbaric oxygen therapy for late radiation tissue injury. Cochrane Database Syst Rev 2012;5:CD005005. Marx RE, Ames JR. The use of hyperbaric oxygen therapy in bony reconstruction of the irradiated and tissue-deficient patient. J Oral Maxillofac Surg 1982;40(7):412e20. Rudolph R, Tripuraneni P, Koziol JA, McKean-Matthews M, Frutos A. Normal transcutaneous oxygen pressure in skin after radiation therapy for cancer. Cancer 1994;74(11):3063e70. Meyer I. Infectious diseases of the jaws. J Oral Surg 1970;28(1):17e26. Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg 2008;46(8):653e60. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck 2005;27(2):114e23. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339(6):357e63.

52. Carano A, Teitelbaum SL, Konsek JD, Schlesinger PH, Blair HC. Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J Clin Invest 1990;85(2):456e61. 53. Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL. Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherolclodronate combination (PENTOCLO): a phase II trial. Int J Radiat Oncol Biol Phys 2011;80(3):832e9. 54. Kahenasa N, Sung EC, Nabili V, Kelly J, Garrett N, Nishimura I. Resolution of pain and complete healing of mandibular osteoradionecrosis using pentoxifylline and tocopherol: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113(4):e18e23. 55. McLeod NM, Pratt CA, Mellor TK, Brennan PA. Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience. Br J Oral Maxillofac Surg 2012;50(1):41e4. 56. Hirsch DL, Bell RB, Dierks EJ, Potter JK, Potter BE. Analysis of microvascular free flaps for reconstruction of advanced mandibular osteoradionecrosis: a retrospective cohort study. J Oral Maxillofac Surg 2008;66(12):2545e56. 57. Pitak-Arnnop P, Sader R, Dhanuthai K, Masaratana P, Bertolus C, Chaine A, et al. Management of osteoradionecrosis of the jaws: an analysis of evidence. Eur J Surg Oncol 2008;34(10):1123e34. 58. Militsakh ON, Werle A, Mohyuddin N, Toby EB, Kriet JD, Wallace DI, et al. Comparison of radial forearm with fibula and scapula osteocutaneous free flaps for oromandibular reconstruction. Arch Otolaryngol Head Neck Surg 2005;131(7):571e5. 59. Holmes SB, Lloyd T, Coghlan KM, Newman L. Distraction osteogenesis of the mandible in the previously irradiated patient. J Oral Maxillofac Surg 2002;60(3):305e9. 60. Raghoebar GM, Jansma J, Vissink A, Roodenburg JL. Distraction osteogenesis in the irradiated mandible. A case report. J Craniomaxillofac Surg 2005;33(4):246e50. 61. Gantous A, Phillips JH, Catton P, Holmberg D. Distraction osteogenesis in the irradiated canine mandible. Plast Reconstr Surg 1994;93(1):164e8. 62. Gonzalez-Garcia R, Rodriguez-Campo FJ, Naval-Gias L, SastrePerez J, Diaz-Gonzalez FJ. The effect of radiation in distraction osteogenesis for reconstruction of mandibular segmental defects. Br J Oral Maxillofac Surg 2007;45:314e6. Scotland. 63. Wang H, Springer IN, Schildberg H, Acil Y, Ludwig K, Rueger DR, et al. Carboxymethylcellulose-stabilized collagenous rhOP-1 device-a novel carrier biomaterial for the repair of mandibular continuity defects. J Biomed Mater Res A 2004;68(2):219e26. 64. Abu-Serriah M, Kontaxis A, Ayoub A, Harrison J, Odell E, Barbenel J. Mechanical evaluation of mandibular defects reconstructed using osteogenic protein-1 (rhOP-1) in a sheep model: a critical analysis. Int J Oral Maxillofac Surg 2005;34(3):287e93. 65. Sweeny L, Lancaster WP, Dean NR, Magnuson JS, Carroll WR, Louis PJ, et al. Use of recombinant bone morphogenetic protein 2 in free flap reconstruction for osteonecrosis of the mandible. J Oral Maxillofac Surg 2012;70(8):1991e6. 66. Mendonc¸a JJ, Juiz-Lopez P. Regenerative facial reconstruction of terminal stage osteoradionecrosis and other advanced craniofacial diseases with adult cultured stem and progenitor cells. Plast Reconstr Surg 2010;126(5):1699e709. 67. Bagan J, Scully C, Zapater E, Basterra J, Bagan L. Osteoradionecrosis of the Jaws. Clin Rev Bone Min Metab 2011;9(1):47e53. € tz KW. Radionecrosis of the mandibula: a 68. Glanzmann C, Gra retrospective analysis of the incidence and risk factors. Radiother Oncol 1995;36(2):94e100.

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003

t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e9

69. Coskunfirat OK, Wei FC, Huang WC, Cheng MH, Yang WG, Chang YM. Microvascular free tissue transfer for treatment of osteoradionecrosis of the maxilla. Plast Reconstr Surg 2005;115(1):54e60. 70. Delanian S, Balla-Mekias S, Lefaix JL. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 1999;17(10):3283e90. 71. D'Souza J, Lowe D, Rogers SN. Changing trends and the role of medical management on the outcome of patients treated for osteoradionecrosis of the mandible: experience from a

9

regional head and neck unit. Br J Oral Maxillofac Surg 2014;52(4):356e62. 72. Kelishadi SS, St-Hilaire H, Rodriguez ED. Is simultaneous surgical management of advanced craniofacial osteoradionecrosis cost-effective? Plast Reconstr Surg 2009;123(3):1010e7. 73. Wang L, Su YX, Liao GQ. Quality of life in osteoradionecrosis patients after mandible primary reconstruction with free fibula flap. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108(2):162e8.

Please cite this article in press as: Rice N, et al., The management of osteoradionecrosis of the jaws e A review, The Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.07.003