The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis Marc Hayashi, DMD Monica Pellecer, DDS UCLA Hospital Dentistry Clinic April 12, 2014 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 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 Osteoradionecrosis (ORN) Most important risk factor: surgical trauma Other factors: periodontal disease, denture irritation, spontaneous Incidence increases w/ increased dosage More common w/ brachytherapy Treatment Conservative tx often employed Abx, local wound irrigation, debridement and gentle sequestrectomy Treatment Established ORN: HBO often considered tx of choice Recent insights to pathophysiology of ORN Radiation-induced fibroatrophic process (RIF) 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 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 arm No 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 ORN Advanced ORN requires aggressive surgical therapy Some benefit to HBO in early/intermediate ORN 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 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 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 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 cellularised fibroatrophy Subject 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 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 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 radiationrelated injuries GI and allergy related issues 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 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 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 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 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 Results Case No. 1 2 3 4 5 6 7 8 Age (Years) 71 79 68 70 62 45 55 70 9 10 11 12 13 75 77 73 74 72 Site Treatment Cause Left Lingual Mandible Left Lingual Mandible Anterior Mandible Right Mandible Left Mandible Right Maxilla Bilateral Lingual Mandible Bilateral Posterior Mandible Left Retromolar Area Right Mandible Right Mandible Right Mandible Right Mandible XRT + Chemo XRT + Chemo XRT XRT XRT + Chemo XRT + Chemo XRT + Chemo XRT + Chemo Spontaneous Extraction Spontaneous Spontaneous Spontaneous Periodontal Extraction Spontaneous Resolution Time (months) 4 1 31 12 11 12 2 15 XRT + Chemo XRT + Chemo XRT + Chemo XRT XRT Extraction Periodontal Extraction Spontaneous Periodontal 8 In Progress 33 20 Resection 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 Conclusion Medical approach appears safe and efficacious Tolerance and compliance satisfactory Further randomized and controlled clinical trials are necessary to validate our findings Thank You Dr. Monica Pellecer Dr. Eric Sung Dr. Evelyn Chung References Annane D, Depondt J, Aubert P, Villart M, Gehanno P, Gajdos P, Chvret S. 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