Presentation is loading. Please wait.

Presentation is loading. Please wait.

The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis Marc Hayashi, DMD Monica Pellecer, DDS UCLA Hospital Dentistry.

Similar presentations


Presentation on theme: "The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis Marc Hayashi, DMD Monica Pellecer, DDS UCLA Hospital Dentistry."— Presentation transcript:

1 The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis Marc Hayashi, DMD Monica Pellecer, DDS UCLA 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 Marxs 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 Clin Oncol 2004 At 1 year, 19% had recovered in HBO arm, 32% in placebo arm No benefit for overt mandibular osteoradionecrosis

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 cellularised fibroatrophy 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

19

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: 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 Case No. Age (Years) SiteTreatmentCause Resolution Time (months) 171Left Lingual MandibleXRT + ChemoSpontaneous4 279Left Lingual MandibleXRT + ChemoExtraction1 368Anterior MandibleXRTSpontaneous31 470Right MandibleXRTSpontaneous12 562Left MandibleXRT + ChemoSpontaneous11 645Right MaxillaXRT + ChemoPeriodontal12 755Bilateral Lingual MandibleXRT + ChemoExtraction2 870 Bilateral Posterior Mandible XRT + ChemoSpontaneous15 975Left Retromolar AreaXRT + ChemoExtraction8 1077Right MandibleXRT + ChemoPeriodontalIn Progress 1173Right MandibleXRT + ChemoExtraction Right MandibleXRTSpontaneous Right MandibleXRTPeriodontalResection

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 Clin Oncol. 2004;22: Beumer J, Curtis TA. Radiation therapy of head and neck tumors: Oral Effects and Dental Manifestations. Maxillofacial Rehabilitation. St. Louis, CV Mosby, 1979, pp Beumer J, Harrison R, Sanders B, Kurrasch M. Osteoradionecrosis: Predisposing factors and outcomes of therapy. Head and Neck Surgery 1984;6: Chiao TB, Lee AJ. Role of Pentoxifylline and Vitamin E in Attenuation of Radiation-Induced Fibrosis. The Annals of Pharmacotherapy 2005;39: Delanian S, Lefaix J-L. Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate. The British Journal of Radiology 2002;75: 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: 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: Delanian S, Lefaix J-L. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiotherapy and Oncology 2004;73: Epstein JB, Wong FL, Stevenson-Moore P. Osteoradionecrosis: Clinical Experience and a Proposal for Classification. J Oral Maxillofac Surg 1987;45: 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: 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:

28 References (continued) Futran ND, Trotti A, Gwede CG. Pentoxifylline in the Treatment of Radiation-Related Soft Tissue Injury: Preliminary Observations. The Laryngoscope 1997;107: Jacobson AS, Buchbinder D, Hu K, Urken ML. Paradigm shifts in the management of osteoradionecrosis of the mandible. Oral Oncology 2010;46: 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: Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41: Marx RE. Osteoradionecrosis: A New Concept of Its Pathophysiology. J Oral Maxillofac Surg 1983;41: 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: 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: /j.bjoms Singh N, Scully C, Joyston-Bechal S. Oral Complications of Cancer Therapies: Prevention and Management. Clinical Oncology 1996;8: 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: 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: 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):

29


Download ppt "The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis Marc Hayashi, DMD Monica Pellecer, DDS UCLA Hospital Dentistry."

Similar presentations


Ads by Google