Efficacy of Pentoxifylline/Tocopherol Combination in Osteoradionecrosis Treatment

1. The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis Marc Hayashi, DMD Monica Pellecer, DDSUCLA Hospital Dentistry Clinic April 12, 2014

2. Learning Objectives • Summarize the radiation-induced fibroatrophic pathogenesis model of ORN • Understand the rationale for utilizing pentoxifylline and tocopherol in the management of ORN • Evaluate the effectiveness and safety of pentoxifylline and tocopherol

3. 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 maxilla • Trismus, pain, xerostomia, dysgeusia, dysphagia • Superficial to pathological fracture

4. Osteoradionecrosis (ORN) • Most important risk factor: surgical trauma • Other factors: periodontal disease, denture irritation, spontaneous • Incidence increases w/ increased dosage • More common w/ brachytherapy

5. Treatment • Conservative tx often employed • Abx, local wound irrigation, debridement and gentle sequestrectomy

6. Treatment • Established ORN: HBO often considered tx of choice • Recent insights to pathophysiology of ORN • Radiation-induced fibroatrophic process (RIF)

7. Hyperbaric Oxygen Therapy • Based on three H principle (Marx) • Hypoxia, Hypocellularity, Hypovascularity as cause of ORN • HBO alone can arrest ORN, but not resolve it • Aggressive surgical management required in most cases • Marx’s initial study, 41/58 patients (70% required resection and grafting) • Mixed success rates

8. 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 ClinOncol2004 • At 1 year, 19% had recovered in HBO arm, 32% in placebo arm • No benefit for overt mandibularosteoradionecrosis

9. 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 ORN • Advanced ORN requires aggressive surgical therapy • Some benefit to HBO in early/intermediate ORN

10. Update to Pathophysiology of ORN • Radiation-induced fibroatrophic process (RIF) as outlined by Delanian et al • Targeted treatment • Antioxidant pathway • Pentoxifylline and Tocopherol (Vitamin E) • 3 successive clinical and histopathologic phases

11. Pathophysiology • Pre-Fibrotic Phase • First few months after XRT, asymptomatic • Endothelial cells (EC) release chemokines • Chronic non-specific inflammation, increasing vascular permeability and edema formation • Vascular thrombosis, causing necrosis of microvessels with localized ischemia • CT exposed, triggering fibroblastic activation • Fibroblasts differentiate to myofibroblasts

12. Pathophysiology • Constitutive Phase • Organized fibrotic sequelae, thickening and hardening of the tissues • RIF tissues made of fibroblasts/myofibroblasts and ECM • Combined damage to EC and CT cells, with increased action of cytokines, leads to persistent state of RIF • Myofibroblasts persist, radiation induced fibrous swellings

13. Pathophysiology • Late Fibroatrophy Phase • Lasts 5-30 years after XRT • Retractile atrophy, gradual destruction of tissues within field • Density increases by successive remodeling of ECM deposits • Tissues are friable, developing poorly vascularized and cellularisedfibroatrophy • Subject to late reactivated inflammation after physicochemical trauma

14. 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.

15. PENTOCLO • Delanian et al • Pentoxifylline-Tocopherol-Clodronate (PENTOCLO) combination demonstrated impressive results in resolving ORN • Well tolerated, no adverse effects noted • Most recent trial, all 54 patients treated achieved complete recovery in a median 9 months

16. PENTO • Pentoxifylline • Methylxanthine derivative • Decreases blood viscosity, increases erythrocyte flexibility, increases tissue oxygen levels • Opposes certain inflammatory mediators (TNF-α) • Shown to accelerate healing w/ late radiation-related injuries • GI and allergy related issues

17. PENTO • Tocopherol (Vitamin E) • Methylated phenol compound • Antioxidant properties, decreasing oxidative damage from XRT • Protects cell membranes against lipid peroxidation • Partly inhibits TGF-beta1 and procollagen gene expression

18. PENTO • In 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 day • Total duration of treatment time not yet determined • <12 months, partial rebound effect • >2-3 years, appeared necessary for advanced cases

20. Method • Chart review of hospital dentistry group • 13 patients • All had exposed bone after cancerocidal doses of XRT for oropharyngeal cancers • Pentoxifylline 400mg BID and Tocopherol 1000 IU QD • All XRT over 60Gy; 9 additionally received Chemo • Reviewed chart entries, noting improvement/resolution or worsening/adverse effects • Ethical approval obtained from IRB

21. Results • 12 Male: 1 Female • Age: 45-79 • 12 in mandible, 1 in maxilla • 6 spontaneous, 4 extractions, 3 periodontal • 7 had h/o EtOH/Tob use

22. Results (continued) • 11 patients healed • One currently undergoing treatment • One demonstrated no improvement after 22 months, opting for segmental resection • No adverse effects noted • Avg. treatment time: 13.5 months • Treatment Time Range: 1-33 months

23. Results

24. Discussion • 11/13 of our patients resolved (84%) • No adverse effects noted, well tolerated • Limitations: • Small sample size • Staging of ORN lesions w/ Epstein system or SOMA score • Clodronate not utilized

25. Conclusion • Medical approach appears safe and efficacious • Tolerance and compliance satisfactory • Further randomized and controlled clinical trials are necessary to validate our findings

26. Thank You • Dr. Monica Pellecer • Dr. Eric Sung • Dr. Evelyn Chung

27. References • Annane 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 ClinOncol. 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 mandibularosteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): A phase II trial. Int J RadiatOncolBiol 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 MaxillofacSurg 1987;45:104-110. • Epstein J, van derMeij E, McKenzie M, Wong F, Lepawsky M, Stevenson-Moore P. Postradiationosteoradionecrosis of the mandible: A long-term follow-up study. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 1997;83:657-62. • Fritz GW, Gunsolley JC, Abubaker O, Laskin DM. Efficacy of Pre- and Postirradiation Hyperbaric Oxygen Therapy in the Prevention of PostextractionOsteoradionecrosis: A Systematic Review. J Oral MaxillofacSurg 2010;68:2653-2660.

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