1. 4/1/ :17 PM
The Efficacy of Pentoxifylline/Tocopherol Combination in the Treatment of Osteoradionecrosis
Marc Hayashi, DMD
Monica Pellecer, DDS UCLA Hospital Dentistry Clinic
April 12, 2014
© 2006 Microsoft Corporation. All rights reserved.
This presentation is for informational purposes only. Microsoft makes no warranties, express or implied, in this summary.

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 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
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 Case No. Age (Years) Site Treatment Cause
Resolution Time (months) 1 71
Left Lingual Mandible
XRT + Chemo
Spontaneous 4 2 79
Extraction 3 68
Anterior Mandible
XRT 31 70
Right Mandible 12 5 62
Left Mandible 11 6 45
Right Maxilla
Periodontal 7 55
Bilateral Lingual Mandible 8
Bilateral Posterior Mandible 15 9 75
Left Retromolar Area 10 77
In Progress 73 33 74 20 13 72
Resection

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;50:41-44.
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: /j.bjoms
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:
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):