Vol. 113 No.

3 March 2012

Sunitinib related osteonecrosis of jaw: a case report

Yoram Fleissig, DMD,a Eran Regev, DMD, MD,b and Hadas Lehman, DMD, MSc,c Jerusalem, Israel
HADASSAH-HEBREW UNIVERSITY MEDICAL CENTER

A 58-year-old woman presented to the Oral and Maxillofacial Surgery Clinic experiencing severe limited mouth
opening and exposed bone in the socket of the right mandibular third molar 8 months following the extraction of the tooth.
The patient had been treated during the year before her presentation with sunitinib, an antiangiogenic drug, for renal cell
carcinoma. The clinical, radiographic, and histologic picture of a chronic nonhealing extraction socket was consistent with
osteonecrosis of the jaw (ONJ), although she had never been treated with bisphosphonates or corticosteroids. The treatment
with sunitinib was discontinued and the patient was treated with antibiotics and physiotherapy for 12 weeks with complete
recovery. Sunitinib may cause osteonecrosis of the jaw after oral surgical interventions with no previous exposure to
bisphosphonates. The pathogenesis may be related to its antiangiogenic mechanism and impaired wound healing. Full
recovery may require long-term cessation of the insulting drug combined with prolonged antibiotic treatment. (Oral Surg Oral
Med Oral Pathol Oral Radiol 2012;113:e1-e3)

Osteonecrosis of the jaw (ONJ), a chronic nonhealing CASE REPORT

and painful wound, may be the result of radiotherapy,1
chemotherapy,2 and a complication of osteomyelitis.3
As a unique phenomena to the jawbones, the main
predisposing factors to develop ONJ in all these con-
ditions are oral surgical intervention and oral mucosa
breakdown. Although treatment modalities vary from
extensive resection to conservative treatment, depend-
ing on the cause, the prevention of such a complication
is preferred.
In recent years, there has been a growing clinical
and basic research interest in the entity of bisphos-
phonate-related osteonecrosis of the jaw (BRONJ).
Although clinically and histologically it may resem-
ble other conditions of ONJ, the pathogenesis of
BRONJ has not yet been elucidated.4 Nevertheless,
several potential factors have been suggested that
increase the risk of developing BRONJ in combina-
tion with bisphosphonates (BPs). One such drug
group is the antiangiogenic drugs.4
We present here a patient who was treated with
sunitinib for renal cell carcinoma and developed osteo-
necrosis of the mandible with no history of bisphos-
phonate treatment.
a
Resident, Department of Oral and Maxillofacial Surgery, Hadassah-
Hebrew University Medical Center, Jerusalem, Israel.
b
Senior Lecturer, Department of Oral and Maxillofacial Surgery,
Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
c
Attending, Department of Oral and Maxillofacial Surgery, Hadas-
sah-Hebrew University Medical Center, Jerusalem, Israel.
Received for publication Mar 20, 2011; returned for revision Jun 15,
2011; accepted for publication Jun 23, 2011.
© 2012 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
doi:10.1016/j.tripleo.2011.06.023
A 58-year-old woman presented to the Oral and Maxillo-
facial Surgery Clinic at Hadassah-Hebrew University Faculty
of Dental Medicine, complaining of limited mouth opening
and pain on the right lower jaw of 2 months’ duration. Eight
months before her presentation she had her right lower third
molar extracted because of deep caries and recurrent episodes
of pericoronitis (Fig. 1).
The patient was diagnosed with renal cell carcinoma 12
years before her initial presentation for which she underwent
a left total nephrectomy followed by right partial nephrec-
tomy 3 times because of recurrences. In the past year she had
been treated with cycles of 50 mg sunitinib once a day for
4 weeks followed by 2 weeks drug-free. The rest of her
medical history was positive for hypothyroidism treated
with thyroxine sodium. She also had osteoporosis but had
never been treated with bisphosphonates or corticosteroids
and had never received radiotherapy to the head and neck
region.
Review of the clinic record revealed that the extraction
took place on the 14th day of the treatment-free period, which
was extended by another 14 days after the extraction. There-
fore, she had a total of 4 weeks without sunitinib before
resuming the drug. On follow-up visits several weeks after the
extraction, there was partial healing in the socket, but she
failed to return for further appointments.
On presentation, the patient stated that she experienced
episodes of limited mouth opening, apparently correlated with
the sunitinib treatment courses, following but also before the
extraction.
On extraoral examination on the admission day, she had
a slight right submandibular swelling and local redness
without skin fistula. Maximal mouth opening was 5 mm
between the incisors. Intraoral examination revealed local
inflammation around the socket of the right lower third
molar, slight pus excretion, and a small area of exposed
bone. A panorex taken on admission revealed incomplete
bone remodeling of the right lower third molar socket
(Fig. 2). A computed tomography (CT) scan demonstrated

e1
ORAL AND MAXILLOFACIAL SURGERY
e2 Fleissig et al.
Fig. 1. Preoperative panorex with mandibular right third mo-
lar vertically impacted.
Fig. 2. Panorex taken 8 months after extraction. Note the
unsatisfactory bone remodeling of the extraction socket and
cortex disappearance.
Fig. 3. CT scan coronal reconstruction showing irregular
remodeling and cortical bone disappearance after extraction
of the mandibular right third molar.
irregularity of the alveolar cortical margin in the location of
the lower third molar (Fig. 3) and moderate inflammatory
changes of the subcutaneous adipose tissue adjacent to the
right side of the mandible and the submental region, sugges-
tive of cellulitis. There were also several enlarged lymph
nodes, up to 16 mm in diameter, in the right submandibular
region.
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March 2012
With the differential diagnosis of osteomyelitis or metas-
tasis, the patient was admitted for intravenous (IV) antibiotics
(amoxicillin and clavulanate) and a biopsy of the exposed
bone was performed. Sunitinib was discontinued.
The histopathology examination revealed necrotic bone
and colonies of gram-positive bacteria, morphologically con-
sistent with Actinomyces; however, the microbiology culture
could not confirm Actinomyces species. The patient was dis-
charged for home IV therapy with penicillin-G 16 million U
every 24 hours for 6 weeks followed by 6 weeks of oral
antibiotics (amoxicillin) and physiotherapy for the limited
mouth opening.
The patient returned for weekly follow-up visits. The ex-
traoral signs resolved after 3 weeks of antibiotic treatment.
The intraoral wound was healing and her mouth opening
improved progressively until complete recovery after 6
weeks.
DISCUSSION
Since its approval by the Food and Drug Administra-
tion in 2006 and the introduction for the treatment of
advanced kidney cancer, sunitinib has shown improved
survival rate over the previous cytokine treatment.5,6
Sunitinib is an orally administered multitargeted recep-
tor tyrosine kinase (RTK) inhibitor, including vascular
endothelial growth factor receptor (VEGFR) and platelet-
derived growth factor receptor (PDGFR), which are over-
expressed in tumors.5,6
RTKs are cell surface receptors that initiate growth,
differentiation, and survival of various cell types, in-
cluding endothelial and tumor cells. Inhibition of these
receptors impairs proliferation, migration, differentia-
tion, neoangiogenesis, and invasion of cancer cells,
thus providing an attractive target for cancer therapy.7
The common sunitinib treatment protocol consists of
6-week cycles of 50 mg/d for 4 weeks followed by 2
weeks off treatment. Following a single oral dose, peak
plasma sunitinib levels are reached after 6 to 12 hours.
Sunitinib and its primary metabolite, SU12662, have
half-lives of 40 and 80 hours, respectively.5
In contrast to conventional chemotherapy, which is
given in courses over a defined period, treatment with
sunitinib may be given as a maintenance drug over a
longer period, sometimes for years.8
Previous reports have already highlighted the haz-
ardous potential for osteonecrosis of the jaw when
combining bisphosphonates and antiangiogenic drugs.
It is assumed that the incidence of ONJ in antiangio-
genic-treated patients who are exposed to bisphospho-
nates is 0.9% to 2.4%.9 Several case reports indicated
that sunitinib specifically may increase the risk of
BRONJ or worsen it.8,10-12 It was suggested that the
additive toxic effect of antiangiogenic drugs in patients
receiving bisphosphonates causes ONJ because of oral
mucosa breakdown, impaired angiogenesis, and bone
remodeling.13 Mucositis, another side effect of sunitinib,
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Volume 113, Number 3
may also be a contributing factor of BRONJ when com-
bined with bisphosphonates.8
Review of the English literature14 revealed only 1
similar case report of ONJ in a patient treated with
sunitinib with no previous exposure to bisphospho-
nates. These 2 cases, in addition to the reports on the
association of bisphosphonates and antiangiogenic
drugs, may raise the possibility that sunitinib, indepen-
dently, can cause ONJ.
Unlike BRONJ, in which the pathogenesis is not yet
clear, the role of antiangiogenic drugs in ONJ seems
intuitive. Because VEGF and PDGF are well-known
factors in normal jawbone remodeling and wound re-
pair, inhibition of their activity could lead to ONJ.
Other antiangiogenic drugs have already been sus-
pected of having a similar effect. For example, bevaci-
zumab (Avastin), a monoclonal antibody that binds to
VEGF and inhibits angiogenesis, was reported to cause
wound-healing complications,15 as well as ONJ, with a
calculated risk of up to 0.2%.9,16,17 The current litera-
ture suggests a treatment window of bevacizumab of 6
to 8 weeks before and 4 weeks after surgery to lower
the risk of surgical wound-healing complications.15
The perioperative treatment holiday of 4 weeks that
was done in our case was based on the experience with
bevacizumab and on the half-life of sunitinib. Appar-
ently this treatment protocol may not be sufficient.
According to sunitinib clinical outcome success, it is
anticipated that its use will increase and encompass
other cancers as well, potentially resulting in more
cases of ONJ.
In conclusion, there is emerging evidence that
sunitinib is independently related to osteonecrosis of
the jaw, and that discontinuation may lead to clinical
improvement; however, more research is needed to
support these findings. Because long-term side effects
of sunitinib are still not known, these first reports of
ONJ should raise a red flag, and oncologists as well as
dentists and oral and maxillofacial surgeons should be
aware of the potential for development of ONJ as a
result of surgical intervention under sunitinib treatment.
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Reprint requests:
Yoram Fleissig, DMD
Department of Oral and Maxillofacial Surgery
Hebrew University-Hadassah School of Dental Medicine
Jerusalem 91129, Israel
yoram77@gmail.com