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
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