Pharmacologic Modalit ies inthe Treatment ofOsteoradionecrosis of the Jaw

James Anthony McCaul, PhD, FRCS(OMFS), FRCS, FDSRCPSa,b,*

KEYWORDS

� Osteoradionecrosis � Radiation-induced fibroatrophy � Pentoxifylline � Tocopherol � Clodronate

KEY POINTS

� Managing osteoradionecrosis (ORN) of the facial bones is a challenge in maxillofacial head andneck surgical practice.

� Changes in understanding of ORN of the jaws has led to new studies using novel therapeutic mo-dalities to manage this disorder.

� These treatment regimens may allow medical management to replace major reconstructive surgeryfor some patients who have already undergone chemoradiotherapy or combined modality therapyfor head and neck cancer.

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INTRODUCTION

Osteoradionecrosis (ORN) of the jaws was firstdescribed in the 1920s and remains the mostproblematic complication occurring after the useof radiotherapy to treat head and neck cancer.1

The condition has been defined as exposed andnecrotic bone associated with ulcerated ornecrotic soft tissue that persists for greater than3 months in an area that has been previously irra-diated, and is not caused by tumor recurrence.2

According to the current medical literature, ap-proximately 20.0% (range, 0.9%–35.0%) ofpatients have radiotherapy as part of their headand neck cancer treatment.3 This incidence maybe declining.4 The condition affects the mandiblemost frequently, and diagnosis depends on clinicalfeatures, including a history of exposure to greaterthan 50 Gy of ionizing radiation. Symptoms includepain, trismus, and dysesthesia. Clinical signsinclude ulceration and/or necrosis of the oral mu-cosa, exposure of underlying bone, malodor,and, in advanced stages, ulceration of overlyingskin and pathologic fracture.5

a Maxillofacial/Head and Neck Surgery, The Royal MarsFaces Maxillofacial Surgical Specialty Lead for Research,* Maxillofacial/Head and Neck Surgery, The Royal MarsdE-mail address: jim.mccaul@mac.com

Oral Maxillofacial Surg Clin N Am 26 (2014) 247–252http://dx.doi.org/10.1016/j.coms.2014.02.0021042-3699/14/$ – see front matter � 2014 Elsevier Inc. All

PATHOGENESIS

Four hypotheses have been described for thedevelopment of ORN. Watson and Scarborough6

first described the sequence of radiation exposure,local injury, and infection as a possible cause, andthis hypothesis was further popularized byMeyer.7

Later Marx8 described the “Three-H” hypo-thesis: wherein the area shows a hypocellular, hyp-oxic, and hypovascular state. This condition isthought to be consequent to microvasculaturedamage, resulting in endarteritis, thrombosis, andvessel obliteration.

A more recently described hypothesis is thatof suppression of osteoclast mediated bone turn-over, wherein irradiation-induced loss of osteoclastfunction results in the clinical features describedearlier. This idea is supported by the evidencefrom antiresorptive therapy–related osteonecrosisof the jaws, which occurs after administration of bi-sphosphonates and other antiresorptive agents insome patients.

Delanian and Lefaix9,10 proposed a fourth hy-pothesis of fibroatrophic bone change in 2004

den Hospital, London, UK; b UK RCS/BAOMS/SavingLondon, UKen Hospital, London, UK.

rights reserved. oralmaxsurgery.thecli

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based on enhanced understanding of the cellularand molecular biology of the histopathologic fea-tures seen in ORN. Earlier, in 1998, the first reportemerged of bone healing in a patient with ORN ofthe sternum after receiving radiotherapy for carci-noma of the breast 29 years previously treatedwith pharmacologic therapy based upon thisnew hypothesis. With this hypothesis, bone andsoft tissue damage is proposed to be caused byradiation-induced fibrosis, and this has beensummarized by Lyons and Ghazali.11 Threephases of tissue injury are described, whichmirror those in healing of chronic traumaticwounds12: the initial predominantly acute inflam-matory phase with endothelial changes, a secondphase of abnormal fibroblast activity with extra-cellular matrix disruption, and a third late fibroa-trophic phase. At this late phase, the healedtissues are friable and undergo late reactivationof the acute inflammatory response after injury.In the proposed fibroatrophic mechanism, the

key event in ORN progression is described asactivation and dysregulation of fibroblast activity,resulting in tissue atrophy and fibrosis.Radiation-induced endothelial injury initiates

Fig. 1. Activation and dysregulation of fibroblast activityinduced fibroatrophic process: therapeutic perspectiv2004;73(2):119–31.)

cytokine release, including tumor necrosis factora (TNF-a); fibroblast growth factor b; platelet-derived growth factor; interleukin (IL) 1, 2, and 4;connective tissue growth factor; and transforminggrowth factor b1 (TGF-b1). This process producesa predominance of the myofibroblast phenotype,with attendant high rates of cellular proliferationand release of abnormal extracellular matrix(ECM) components.13 These myofibroblasts alsodemonstrate impaired ability to breakdown theabnormal ECM. This is shown diagrammaticallyin Fig. 1. This fibroblast process is similarlydescribed in fibrotic processes in the lungs andliver after tissue injury of various types.14

Ionizing radiation produces osteoblast cell deathand prevents repopulation of this cellular com-ponent of bone. Together with excess myofibro-blast proliferation and abnormal ECM formation, areduction in bony hard tissue matrix and an excessof fibrous tissue is described. Four possible me-chanisms of bony destruction are suggested byDelanian and colleagues15 in an article describ-ing microradiographic analysis of ORN bone.These mechanisms are progressive macrophage-mediated osteoclast loss with no accompanying

. (Modified from Delanian S, Lefaix JL. The radiation-e via the antioxidant pathway. Radiother Oncol

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osteogenesis; periosteocytic lysis; extensive de-mineralization; and accelerated bone aging.

Therefore, after radiotherapy, bone has reducednumbers of viable cells, is poorly vascularized, andis fibrosed compared with normal healthy bone.Apoptosis of the myofibroblast component re-duces cellularity further.14 This tissue is then atrisk of the development of ORN after any physicalor chemical trauma, which induces the late acuteinflammatory response described earlier. Fig. 2summarizes this process.

PHARMACOLOGIC AGENTS IN ORNMANAGEMENT

The initial infection-based hypothesis resulted intreatment based on antibiotic therapy and surgical

Fig. 2. The ionizing radiation–induced fibroatrophic procerosis of the jaws: current understanding of its pathop2008;46(8):653–60.)

debridement. Later work by Marx described bac-teria as a superinfection rather than as beinginvolved in pathogenesis, but nonetheless antibi-otic therapy in acute episodes of pyogenic in-fection in ORN, guided by microbiologic samplesand culture and sensitivity assays, remains acornerstone of treatment.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy is still widely used forORN prevention and management, although thispractice has had recent challenges.5,16,17 In theUnited Kingdom, the Medicines and HealthcareProducts Regulatory Agency considers hyperbaricoxygen a medicinal product, and therefore inspecttrials involving this modality (eg, the HOPON

ss. (Modified from Lyons A, Ghazali N. Osteoradionec-hysiology and treatment. Br J Oral Maxillofac Surg

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trial; Professor Richard Shaw, personal com-munication). This modality is discussed elsewherein this issue.

Pentoxifylline and Tocopherol

PentoxifyllinePentoxifylline is a methylxanthine derivative thathas multiple effects considered advantageous inORN management, including vascular dilatationand increased erythrocyte flexibility effects, bothof which enhance blood flow. Furthermore, pen-toxifylline has anti–TNF-a activity and is thoughtto reduce the cytokine cascade driving the ORNprocess. It has also been shown to reduce prolifer-ation of dermal fibroblasts and limit ECM produc-tion by these cells. In vitro experiments have alsoshown promotion of collagenase activity in thesecells.18

TocopherolTocopherol is a fat-soluble vitamin (vitamin E) andis a weak antioxidant agent. Therefore, tocopherolis capable of scavenging reactive oxygen speciesinvolved in the pathogenesis of ORN, wherein theyinduce cell membrane peroxidation among otherdeleterious effects. Tocopherol also shows partialinhibition of TGF-b1 and an antifibrotic effectmediated by procollagen genes.11

ClodronateThis agent is a first-generation, nonnitrogenous bi-sphosphonate approved for use in osteoporosis,hyperparathyroidism, hypercalcemia of malig-nancy, and multiple myeloma. Clodronate reducesbone resorption through reducing osteoclastnumbers and activity. It is also known to reduce in-flammatory cytokines IL-1b, IL-6, and TNF-a.Although bisphosphonates are clearly implicatedin antiresorptive therapy–related osteonecrosis ofthe jaws, clodronate has been used in Frenchstudies of severe ORN cases and been describedas effective (see next section).18,19 Notably anduniquely among this group of agents, clodronatealso has been shown to act on osteoblasts to in-crease bone formation20 and reduce fibroblastproliferation.21

Pentoxifylline and Tocopherol CombinedTherapy With or Without Clodronate

Experiments in vitro and animal studies have beenunable to show that either pentoxifylline or tocoph-erol alone can reduce reactive oxygen species.Combination therapy with these agents has beendescribed in several radiation-associated tissueinjury studies, including small placebo-controlledrandomized trials.22,23 These reports show benefitfor combination therapy over placebo treatment

and single-agent therapy, and also that reboundtissue injury can occur if treatment is too short(<3 months).Delanian and colleagues18,19 have described

2 phase II trials of combined therapy for ORN ofthe mandible. In the first, 18 consecutive patientswere treated with pentoxifylline and tocopherol.Each had at least 13.4 mm of exposed mandibularbone and all had been prescribed pentoxifylline,400 mg twice daily and tocopherol, 1000 IU orallyfor 6 to 24 months.18 The worst affected cases(n 5 8) were also given clodronate, 1600 mg dailyfor 5 days per week. The second trial,19 publishedin 2011, reported on 54 patients who received ra-diation for head and neck cancer a mean of 5 yearsbefore the onset of ORN. In this report, the termPENTOCLO was coined for the treatment regimenincluding all 3 agents. This treatment regimen hadevolved to combined pentoxifylline and tocopherolas described earlier, with clodronate, 1600 mggiven 5 days per week, and prednisone, 20 mgwith ciprofloxacin given on the other 2 days. Thisstudy showed that prolonged treatment (16 �9 months) was safe and well tolerated. All patientsin the study experienced improvement, with anexponential progressive and significant reductionin exposed bone (P<.0001). A total of 36 patientsunderwent spontaneous sequestrectomy duringthe course of treatment. All patients in this serieswere shown to experience complete recovery ina median time of 9 months. The investigatorsconcluded that the treatment is safe and effective,and recommended that a randomized controlledtrial be conducted.In a retrospective series of 12 patients treated

with pentoxifylline and tocopherol without clo-dronate, McLeod and colleagues1 show moremodest treatment outcomes. These patientswere treated for a mean of 14.8 months (range,4.0–46.0 months). One patient stopped treatmentbecause of side effects to pentoxifylline, and 3 re-ported difficulty in swallowing the large pentoxifyl-line tablets, and resorted to crushing them, againstpharmaceutical advice. Epstein scoring showedthat 5 patients improved, 5 were unchanged,and 2 had become worse. Three patients deterio-rated and subsequently underwent resection andcomposite free flap reconstruction surgery. Theseauthors acknowledge that they did not use clodro-nate for any of the cases in this short retrospectiveseries.The Bradford Teaching Hospitals series reports

on 18 patients with ORN after radiotherapyor chemoradiotherapy administered as part ofhead and neck cancer therapy (McCaul andcolleagues, unpublished data, 2014). These pro-spectively followed patients all received

Fig. 3. (A) 62-year-old man underwent chemoradiotherapy for a T4,N3 right oropharynx squamous carcinoma.This tumor exhibited complete response and was followed up according to protocol. (B) In November of 2010he presented complaining of pain from the right lower third of his face and had exposed bone and pus discharg-ing intraorally. No evidence was seen of new primary cancer at this site and the bone exposure persisted for morethan 3 months. He was managed initially with antibiotic therapy and local intraoral measures. He thencommenced pentoxifylline, 400 mg twice daily and tocopherol, 1000 IU daily. His ORN remained quiescent butprogressed. (C) Autosequestrectomy occurred after this time and his symptoms settled to a firm fibrous nonunionwith good function. He did not require surgical intervention. (D) The patient later developed a new primary can-cer of the right lateral tongue, which required lip split mandibulotomy for access to resect and reconstruct, andthis healed without incident. (E) He remained on pentoxifylline and tocopherol throughout this process.

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combined therapy with pentoxifylline and tocoph-erol only, and not clodronate for similar reasonsas in the cases reported by McLeod and col-leagues.1 Two patients could not tolerate therapyand did not continue with the agents, and16 continued with therapy. ORN resolved in 7 pa-tients (44% of patients completing therapy); in3 with medical therapy alone and in 3 with medi-cal therapy and surgical debridement. Three pa-tients received hyperbaric oxygen therapy aspart of ORN management. In 1 patient, medicaltherapy resulted in a symptom-free fibrous bonyunion of the right body of the mandible (Fig. 3).No adverse events have been associated withvitamin E and pentoxifylline therapy in the Brad-ford series. None of these patients have experi-enced progression on therapy, and none haverequired major resection and reconstruction forORN in the past 8 years. The Bradford centertreats 240 new head and neck cancers per year,

two-thirds of which require radiotherapy or che-moradiotherapy as part of treatment for cure.

SUMMARY

Recent changes in understanding of the patho-genesis of ORN have led to the emergence ofsome exciting new pharmacologic therapies. Up-take of these agents has been generally slowworldwide, despite the success of the Delaniangroup18,19 in France, perhaps partly because ofthe previous acceptance that ORN of the mandibleis a surgical disease for which hyperbaric oxygentherapy can be of utility. However, there is a clearreluctance among surgeons who are faced with anincreasing burden of antiresorptive agent–inducedosteonecrosis of the jaw to introduce clodronateinto the therapeutic armamentarium for ORN.Clodronate seems to be unique among the bi-sphosphonate group in that it can stimulate

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osteoblast function and reduce inflammatory cyto-kine expression. Small, randomized studies haveshown the effectiveness of the pentoxifyllinetocopherol combination versus placebo andsingle-agent therapy in radiation-induced traumaat other body sites. It is clear, however, thathigh-quality, randomized, controlled trial evidencefor this approach is currently lacking for ORNaffecting the human mandible. The PENTOCLOregimen offers an exciting, potentially curativetherapy for mandibular ORN for some cancer sur-vivors, and requires high-quality clinical trialevaluation.

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