The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of OsteoradionecrosisMarc Hayashi, DMDMonica Pellecer, DDSUCLA Hospital Dentistry ClinicApril 12, 2014

Learning Objectives

Summarize the radiation-induced fibroatrophic pathogenesis model of ORNUnderstand the rationale for utilizing pentoxifylline and tocopherol in the management of ORNEvaluate the effectiveness and safety of pentoxifylline and tocopherol

Osteoradionecrosis (ORN)Consequence of radiation therapy in head and neck cancer treatment“Bone necrosis that can occur in association with radiation treatment for cancer in the absence of recurrent or metastatic disease”Incidence of 5-15%Mandible more than maxillaTrismus, pain, xerostomia, dysgeusia, dysphagiaSuperficial to pathological fracture

Osteoradionecrosis (ORN)Most important risk factor: surgical traumaOther factors: periodontal disease, denture irritation, spontaneous Incidence increases w/ increased dosageMore common w/ brachytherapy

TreatmentConservative tx often employed

Abx, local wound irrigation, debridement and gentle sequestrectomy

TreatmentEstablished ORN: HBO often considered tx of choice

Recent insights to pathophysiology of ORNRadiation-induced fibroatrophic process (RIF)

Hyperbaric Oxygen TherapyBased on three H principle (Marx)Hypoxia, Hypocellularity, Hypovascularity as cause of ORNHBO alone can arrest ORN, but not resolve itAggressive surgical management required in most casesMarx’s initial study, 41/58 patients (70% required resection and grafting)Mixed success rates

Review Article“Hyperbaric Oxygen Therapy for Radionecrosis of the Jaw: A Randomized, Placebo-Controlled, Double-Blind Trial From the ORN96 Study Group.”

Annane et al. J Clin Oncol 2004

At 1 year, 19% had recovered in HBO arm, 32% in placebo armNo benefit for overt mandibular osteoradionecrosis

Review Article

“Paradigm shifts in the management of osteoradionecrosis of the mandible.”

Jacobson et al. Oral Oncology 2010

HBO alone has minimal if any benefit in the treatment of advanced ORNAdvanced ORN requires aggressive surgical therapySome benefit to HBO in early/intermediate ORN

Update to Pathophysiology of ORNRadiation-induced fibroatrophic process (RIF) as outlined by Delanian et alTargeted treatmentAntioxidant pathwayPentoxifylline and Tocopherol (Vitamin E)3 successive clinical and histopathologic phases

PathophysiologyPre-Fibrotic Phase

First few months after XRT, asymptomaticEndothelial cells (EC) release chemokinesChronic non-specific inflammation, increasing vascular permeability and edema formationVascular thrombosis, causing necrosis of microvessels with localized ischemia CT exposed, triggering fibroblastic activationFibroblasts differentiate to myofibroblasts

PathophysiologyConstitutive Phase

Organized fibrotic sequelae, thickening and hardening of the tissuesRIF tissues made of fibroblasts/myofibroblasts and ECMCombined damage to EC and CT cells, with increased action of cytokines, leads to persistent state of RIFMyofibroblasts persist, radiation induced fibrous swellings

PathophysiologyLate Fibroatrophy Phase

Lasts 5-30 years after XRTRetractile atrophy, gradual destruction of tissues within fieldDensity increases by successive remodeling of ECM depositsTissues are friable, developing poorly vascularized and cellularised fibroatrophySubject to late reactivated inflammation after physicochemical trauma

Suryawanshi A, Kumar SN, Dolas RS, Khindria R, Pawar V, Singh M. Review Article: Maxillofacial osteoradionecrosis. Journal of Dental Research and Review. 2014:1:1:42-49.

PENTOCLO

Delanian et alPentoxifylline-Tocopherol-Clodronate (PENTOCLO) combination demonstrated impressive results in resolving ORNWell tolerated, no adverse effects notedMost recent trial, all 54 patients treated achieved complete recovery in a median 9 months

PENTO

PentoxifyllineMethylxanthine derivativeDecreases blood viscosity, increases erythrocyte flexibility, increases tissue oxygen levelsOpposes certain inflammatory mediators (TNF-α)Shown to accelerate healing w/ late radiation-related injuriesGI and allergy related issues

PENTO

Tocopherol (Vitamin E)Methylated phenol compoundAntioxidant properties, decreasing oxidative damage from XRTProtects cell membranes against lipid peroxidationPartly inhibits TGF-beta1 and procollagen gene expression

PENTOIn combination, demonstrated positive synergistic effect on inflammation progression and fibrosis Delanian et al determined dose to be 800mg Pentoxifylline and 1,000 IU Tocopherol per dayTotal duration of treatment time not yet determined

<12 months, partial rebound effect>2-3 years, appeared necessary for advanced cases

MethodChart review of hospital dentistry group13 patientsAll had exposed bone after cancerocidal doses of XRT for oropharyngeal cancersPentoxifylline 400mg BID and Tocopherol 1000 IU QDAll XRT over 60Gy; 9 additionally received ChemoReviewed chart entries, noting improvement/resolution or worsening/adverse effectsEthical approval obtained from IRB

Results

12 Male: 1 FemaleAge: 45-7912 in mandible, 1 in maxilla6 spontaneous, 4 extractions, 3 periodontal 7 had h/o EtOH/Tob use

Results (continued)

11 patients healedOne currently undergoing treatmentOne demonstrated no improvement after 22 months, opting for segmental resectionNo adverse effects notedAvg. treatment time: 13.5 monthsTreatment Time Range: 1-33 months

ResultsCase No.

Age (Years)

Site Treatment Cause Resolution Time (months)

1 71 Left Lingual Mandible XRT + Chemo Spontaneous 4 2 79 Left Lingual Mandible XRT + Chemo Extraction 13 68 Anterior Mandible XRT Spontaneous 314 70 Right Mandible XRT Spontaneous 125 62 Left Mandible XRT + Chemo Spontaneous 116 45 Right Maxilla XRT + Chemo Periodontal 127 55 Bilateral Lingual Mandible XRT + Chemo Extraction 28 70 Bilateral Posterior

MandibleXRT + Chemo Spontaneous 15

9 75 Left Retromolar Area XRT + Chemo Extraction 810 77 Right Mandible XRT + Chemo Periodontal In Progress11 73 Right Mandible XRT + Chemo Extraction 3312 74 Right Mandible XRT Spontaneous 2013 72 Right Mandible XRT Periodontal Resection

Discussion

11/13 of our patients resolved (84%)No adverse effects noted, well toleratedLimitations:

Small sample sizeStaging of ORN lesions w/ Epstein system or SOMA scoreClodronate not utilized

Conclusion

Medical approach appears safe and efficaciousTolerance and compliance satisfactoryFurther randomized and controlled clinical trials are necessary to validate our findings

Thank YouDr. Monica Pellecer

Dr. Eric SungDr. Evelyn Chung

ReferencesAnnane D, Depondt J, Aubert P, Villart M, Gehanno P, Gajdos P, Chvret S. Hyperbaric Oxygen Therapy for Radionecrosis of the Jaw: A Randomized, Placebo-Controlled, Double-Blind Trial From the ORN96 Study Group. J Clin Oncol. 2004;22:4893-4900.Beumer J, Curtis TA. Radiation therapy of head and neck tumors: Oral Effects and Dental Manifestations. Maxillofacial Rehabilitation. St. Louis, CV Mosby, 1979, pp 23-89.Beumer J, Harrison R, Sanders B, Kurrasch M. Osteoradionecrosis: Predisposing factors and outcomes of therapy. Head and Neck Surgery 1984;6:819-827.Chiao TB, Lee AJ. Role of Pentoxifylline and Vitamin E in Attenuation of Radiation-Induced Fibrosis. The Annals of Pharmacotherapy 2005;39:516-522.Delanian S, Lefaix J-L. Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate. The British Journal of Radiology 2002;75:467-469.Delanian S, Chatel C, Porcher R, Depondt J, Lefaix J-L. Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): A phase II trial. Int J Radiat Oncol Biol Phys 2011;80:3:832-839.Delanian S, Depondt J, Lefaix J-L. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: A phase II trial. Head Neck 2005;27:114-123.Delanian S, Lefaix J-L. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiotherapy and Oncology 2004;73:119-131.Epstein JB, Wong FL, Stevenson-Moore P. Osteoradionecrosis: Clinical Experience and a Proposal for Classification. J Oral Maxillofac Surg 1987;45:104-110.Epstein J, van der Meij E, McKenzie M, Wong F, Lepawsky M, Stevenson-Moore P. Postradiation osteoradionecrosis of the mandible: A long-term follow-up study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:657-62.Fritz GW, Gunsolley JC, Abubaker O, Laskin DM. Efficacy of Pre- and Postirradiation Hyperbaric Oxygen Therapy in the Prevention of Postextraction Osteoradionecrosis: A Systematic Review. J Oral Maxillofac Surg 2010;68:2653-2660.

References (continued)Futran ND, Trotti A, Gwede CG. Pentoxifylline in the Treatment of Radiation-Related Soft Tissue Injury: Preliminary Observations. The Laryngoscope 1997;107:391-395.Jacobson AS, Buchbinder D, Hu K, Urken ML. Paradigm shifts in the management of osteoradionecrosis of the mandible. Oral Oncology 2010;46:795-801.Kahenasa N, Sung EC, Nabili V, Kelly J, Gerret 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:e18-e23.Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. British Journal of Oral and Maxillofacial Surgery 2008;46:653-660.Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41:351-357.Marx RE. Osteoradionecrosis: A New Concept of Its Pathophysiology. J Oral Maxillofac Surg 1983;41:283-288.Mcleod NMH, Pratt CA, Brennan PA. Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience. British Journal of Oral and Maxillofacial Surgery 2012;50:41-44.Shaw RJ, Dhanda J. Hyperbaric oxygen in the management of late radiation injury to the head and neck. Part I: treatment. Br J Oral Maxillofac Surg (2010),doi:10.1016/j.bjoms.2009.10.036.1-7.Singh N, Scully C, Joyston-Bechal S. Oral Complications of Cancer Therapies: Prevention and Management. Clinical Oncology 1996;8:15-24.Spiegelberg L, Djasim UM, van Neck HW, Wolvius EB, van der Wal KG. Hyperbaric Oxygen Therapy in the Management of Radiation-Induced Injury in the Head and Neck Region: A Review of the Literature. J Oral Maxillofac Surg 2010;68:1732-1739.Suryawanshi A, Kumar SN, Dolas RS, Khindria R, Pawar V, Singh M. Review Article: Maxillofacial osteoradionecrosis. Journal of Dental Research and Review. 2014:1:1:42-49.Vissink A, Burlage FR, Spijkervet FKL, Jansma J, Coppes RP. Prevention and Treatment of the Consequences of Head and Neck Radiotherapy. Crit Rev Oral Biol Med 2003;14(3):213-225.