2015A Novel Approach to the Management of a CGCG With Denosumab
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Transcript of 2015A Novel Approach to the Management of a CGCG With Denosumab
Accepted Manuscript
A Novel Approach to the Management of a Central Giant Cell Granuloma withDenosumab: A Case Report and Review of Current Treatments
Dr Benjamin Gupta, BDS BMED MFDS, Norman Stanton, MBBS BDS, HedleyColeman, BDS BChD MDent FCPath FICD, Chris White, MBBS BSc PHD FRACP,Jasvir Singh, MBBS BDS FRACDS (OMS)
PII: S1010-5182(15)00106-7
DOI: 10.1016/j.jcms.2015.04.011
Reference: YJCMS 2035
To appear in: Journal of Cranio-Maxillo-Facial Surgery
Received Date: 10 July 2014
Accepted Date: 10 April 2015
Please cite this article as: Gupta B, Stanton N, Coleman H, White C, Singh J, A Novel Approach to theManagement of a Central Giant Cell Granuloma with Denosumab: A Case Report and Review of CurrentTreatments, Journal of Cranio-Maxillofacial Surgery (2015), doi: 10.1016/j.jcms.2015.04.011.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
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A Novel Approach to the Management of a Central Giant Cell Granuloma with Denosumab: A Case Report and Review of Current Treatments
Benjamin Gupta BDS BMED MFDS1; Norman Stanton MBBS BDS1; Hedley Coleman BDS BChD MDent FCPath FICD 2; Chris White MBBS BSc PHD FRACP3; Jasvir Singh MBBS BDS FRACDS (OMS)1
1 Department of Oral and Maxillofacial Surgery, Prince of Wales Hospital, Randwick, NSW, Australia
2 Department of Tissue Pathology and Diagnostic Oncology, Pathology West and the University of Sydney Westmead Hospital, Westmead, NSW, Australia.
3 Department of Endocrinology, Prince of Wales Hospital, Randwick, NSW, Australia
Financial disclosures: None
Conflicts of Interest: None
Correspondence:
Dr Benjamin Gupta
Department of Oral and Maxillofacial Surgery
Prince of Wales Hospital
Barker St, New South Wales, 2031
Sydney, Australia
Tel: +612 93822245
E-mail: [email protected]
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Abstract
Purpose: To describe the efficacy of denosumab in the treatment of an aggressive giant cell
granuloma of the mandible.
Methods: Denosumab was administered to a patient with a large aggressive giant cell
granuloma of the mandible resistant to standard medical therapy. The effectiveness and
response was measured on the basis of patient symptoms and radiological parameters.
Results: A significant reduction in patient symptoms was reported in association with
tumour regression on follow up radiographs.
Conclusion: This report demonstrates potential use of denosumab in aggressive giant cell
granulomas of the jaws that have been resistant to medical therapy.
Keywords: Central giant cell granuloma, denosumab
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Introduction
The central giant cell granuloma (CGCG) is a benign intraosseous lesion of the jaws. It has
been described variably as a reactive, inflammatory, vascular, endocrine, or even a
neoplastic process. The aetiology of this lesion remains controversial. It most often presents
as a slow growing, painless lesion with cortical expansion resulting in loosening and
displacement of teeth. The CGCG usually occurs anterior to the first molar teeth in patients
aged less than 30 years and is twice as common in females (Whitaker and Waldron 1993, de
Lange et al. 2004).
There are two behavioural variants, aggressive and non-aggressive, that present with
different signs and symptoms. To the best of our knowledge, there are no
immunohistochemical or molecular markers that distinguish the two subtypes. The
aggressive lesions may show characteristics which include 1) size greater than 5 cm, 2) rapid
growth, 3) recurrence after curettage, 4) cortical bone thinning and/or perforation, 5) tooth
displacement and/or resorption (Chuong et al. 1986).
Surgery is the standard management for CGCG. The non-aggressive subtype is often treated
successfully by enucleation and curettage alone. However when the same procedure is
performed on aggressive lesions, recurrence rates of between 37.5 - 70% have been
reported (de Lange et al. 2007). Recurrence rates drop substantially with en bloc resection,
however this may worsen cosmetic and functional outcomes (Bataineh et al. 2002, Infante
Cossio et al. 2007, Tosco et al. 2009)
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Medical therapies can decrease surgical morbidity by reducing lesion size, and consequently
the extent or need for surgical resection. Medical therapies including intra-lesional steroids,
calcitonin and interferon α-2a have been used with variable success. Despite a multitude of
studies, a recent Cochrane review found a lack of randomised studies to support their
use(Suárez-Roa MDL 2009).
The aim of this paper is to review the current literature and report a case of an aggressive
CGCG of the mandible that was treated with denosumab (Xgeva, Amgen Incorporated,
Thousand Oaks, CA, USA).
Case Report
A 33-year-old female of Southern Asian background presented to her general dental
practitioner with pain in the region of tooth 46. The patient also described a jaw-swelling
present since the second trimester of her pregnancy that same year. The dental practitioner
had performed endodontic treatment and eventually extraction due to persistent
symptoms. The patient sought no further treatment or investigations during her pregnancy
due to her understanding that the mandibular swelling was dental in origin. The patient had
no background medical comorbidities. Clinical examination revealed mobile teeth 45, 47
with firm expansive swelling in the right body of mandible. There was no associated
lymphadenopathy or sensory disturbance of the inferior alveolar and lingual nerves on
neurosensory testing.
When comprehensive imaging was obtained, a large radiolucent lesion was noted in the
right body of the mandible, prompting maxillofacial consultation. Cortical perforation was
present however there was no root resorption or tooth displacement of 45, 47 at that time
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(Fig 1). The lesion measured 57 x 39 x 29 mm by computed tomography. The decision was
made to proceed to incisional biopsy to determine the nature of this lesion.
Biopsy showed fragments of cellular fibrous connective tissue with surrounding trabeculae
of reactive vital bone. The stroma was composed of plump spindle-shaped cells with oval
nuclei and small nucleoli. Interspersed areas of extravasated blood were noted with
scattered chronic inflammatory cells and haemosiderin pigment. In addition, localised
collections of multinucleated osteoclastic giant cells were identified within the stroma (Fig
2). A diagnosis of a CGCG was made, along with the recommendation to exclude
hyperparathyroidism. The slides were also reviewed by an experienced orthopaedic
pathologist who concurred with the diagnosis.
Serum analysis revealed vitamin D deficiency characterised by normocalcaemia,
hyperphosphataemia, secondary hyperparathyroidism and anaemia. Vitamin D
supplementation was then prescribed and monitored by her local medical practitioner.
Vitamin D deficiency was deemed the result of wearing traditional Islamic dress limiting
solar exposure and a strict vegan diet. Radionucleotide bone scan and neck/thyroid
ultrasounds were performed for parathyroid assessment to exclude a Brown’s tumour.
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Medical and surgical therapies were discussed with the patient. The patient was reluctant to
proceed with en bloc surgical resection due to its expected morbidity, and concerns
regarding the care for her young children. Following normalisation of parathyroid hormone
levels, it was decided to initiate medical therapy with 6 weeks of intra-lesional steroids
(weekly 20mg of Triamcinolone). This was to reduce the size of the lesion prior to a less
morbid surgical approach with curettage. Despite an improvement in her symptoms, there
was no significant radiological reduction in the lesion size. (Fig 3)
A further biopsy was performed to confirm the prior diagnosis, followed by a second course
of intralesional triamcinolone administered at the higher dose of 40mg weekly. Despite this
regimen, the CGCG continued to expand (Fig 4).
Due to the lack of response to the intra-lesional steroids, alternative medical therapy was
sought. Calcitonin was then initiated at a dose of 100 units daily by subcutaneous injection.
The intra–nasal form was sought but is not available in Australia. The patient was compliant
with the regimen, reporting mild nausea as the only side effect of calcitonin. The response
was suboptimal after five months of therapy, with both an increase in lesion size and
progression of symptoms and pain noted. At this stage, it was thought that extensive and
disfiguring surgery would be required (Fig 5a & b).
Given the recent success of denosumab in the treatment of long bone giant cell tumours,
this was proposed as a last possible medical therapy to potentially arrest the growth of the
lesion and prevent the morbidity of extensive surgery. (Thomas et al. 2010)
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Approval was sought for administering this therapy outside the Therapeutic Goods
Administration guidelines. This was gained from our institution’s drug committee based on
previously published safety and efficacy data. Informed consent was also gained.
The patient was treated with monthly subcutaneous injections of denosumab 120mg for a
total of 6 months. Two loading doses of 120mg were also administered on day 8 and 15 of
the first month.
An early clinical response was observed with resolution of patient symptoms within 10 days.
Follow-up radiographs at 6 months demonstrated ossification of the lesion (Fig 6a & b).
Despite ongoing asymmetry of the right submandibular region, the patient was reluctant to
undergo mandibular recontouring surgery. A follow up biopsy performed 18 months after
denosumab was commenced demonstrated no evidence of residual CGCG (Fig 7a & b).
Approval for the administration of denosumab was initially given for 6 months. Due to the
favourable response achieved, the medication was continued at 120mg subcutaneously 6
monthly for a further two injections. At the time of this report, the patient remains pain free
with stabilisation of the lesion maintained 18 months after denosumab therapy was
commenced. Follow-up will continue with clinical review every 3-6 months and annual cone
beam imaging.
Discussion
Medical therapy in the management of aggressive CGCG aims to reduce surgical morbidity.
However the success of standard agents is variable.
Intralesional corticosteroids were first reported for the treatment of CGCG in 1988 by
Jacoway (Jacoway et al. 1988). Steroids are thought to inhibit the production of bone
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resorption mediating lysosomal proteases by giant cells. Steroids may also induce the
apoptosis of osteoclast-like cells (Carlos and Sedano 2002, Abdo et al. 2005). There have
been reports of both lesion regression and clinical remission (Terry and Jacoway 1994).
However other groups have reported continued CGCG expansion despite steroid therapy
(Pogrel et al. 1999). It has been estimated that 65% of CGCG lesions completely resolve with
corticosteroids, with the remainder either unresponsive to therapy or recurring with more
aggressive behaviour (Marx and Stern 2003).
The use of calcitonin was first described in 1993 by Harris after immunohistochemistry
confirmed that giant cells found in CGCG reacted with monoclonal antibodies specific to
osteoclasts (Harris 1993) (Chambers et al. 1985, Flanagan et al. 1988). Calcitonin is a peptide
hormone produced by the parafollicular cells of the thyroid gland. It contributes to the
hormonal control of calcium metabolism through numerous actions including the inhibition
of osteoclast activity in bone. Through compilation of CGCG cases in the available literature,
Allon et al reported a 65% complete remission rate with calcitonin use, with surgery
reserved for non-responding lesions (Allon et al. 2009). Decreased sensitivity to the effect of
calcitonin is reported with prolonged use, described as an “escape phenomenon” (Vered et
al. 2006). Rachmiel et al used a combined approach with steroids in an attempt to overcome
this. They found a decrease in lesion size after 3 months of combined treatment however
surgery was still required in many cases for definitive management (Rachmiel et al. 2012).
Interferon α-2a (IFN α-2a) was first used for the treatment of CGCG in 1999(Kaban et al.
1999). IFN α-2a is a cytokine with multiple immunomodulatory and anti-angiogenic effects.
CGCG are thought to have a considerable proliferative vascular component so inhibition of
the angiogenesis would lead to a response in the lesion(Kaban et al. 2007). Interferon has
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been used as adjuvant therapy following surgery for aggressive CGCG (Kaban et al. 2002,
Kaban et al. 2007). When administered as primary treatment, IFN α-2a has been shown to
stabilize the rapid growth of CGCGs and even produce a limited reduction in size (de Lange
et al. 2006). There are isolated reports of complete remission (Collins 2000). Unfortunately
there are considerable side effects with IFN α-2a including fatigue, headaches, fevers and
other flu-like symptoms that can be poorly tolerated by patients (Goldman KE 2005).
Other medical therapies have been trialled however published reports remain limited.
Imatinib is a tyrosine kinase inhibitor used primarily to treat a subtype of chronic myeloid
leukaemia and gastrointestinal stromal tumours. Imatinib has been found to inhibit
osteoclasts in vivo through the down regulation of receptor activator of nuclear factor κB
(RANK). Clinically, imatinib has induced regression of CGCG in combination with IFN α-2a (de
Lange et al. 2009). Bisphosphonate therapy has also been proposed in the treatment of
CGCG (Landesberg et al. 2009). A three patient case series on the use of bisphosphonate
therapy reported variable results ranging from complete remission to stabilisation of the
target lesion.
Evidence and indications for Denosumab
Denosumab is a human monoclonal antibody (IgG2) that inhibits bone lysis by binding to
receptor activator of nuclear factor-κB ligand (RANKL), a key protein for the production and
maturation of giant cells and osteoclasts. The binding of denosumab to RANKL inhibits bone
resorption, not only in normal bone turnover but also in tumour mediated bony lysis
(Branstetter et al. 2012, Brown and Coleman 2012).
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RANKL is essential for the normal function and survival of osteoclasts. It is released from
osteoblasts where it binds onto RANK receptors expressed by immature osteoclasts. The
activated osteoclasts subsequently initiate bony resorption. In normal function, excess
RANKL is deactivated by osteoprotegrin also produced by the osteoblasts. This helps to
regulate bone turnover. In an abnormal state of bone turnover, such as in the presence of a
tumour, there is stimulation to produce excess RANKL leading to increased bone lysis
(Branstetter et al. 2012).
At present, Denosumab has been developed and licensed in North America, Europe and
Australia for the treatment of postmenopausal osteoporosis, bone loss associated with
testosterone suppression in prostate cancer, and the prevention of skeletal-related events
(cancer-related bone injuries) in patients with bone metastases from solid tumours.
However given its mode of action, there have been trials exploring denosumab’s
effectiveness in a number of other osteolytic disorders including giant cell tumour of the
bone (GCTB).
A report released by the National Institute of Health Research Horizon Scanning Centre
suggests a role for denosumab in the management of GCTB under specific circumstances;
namely the treatment of aggressive and/or recurrent GCTB. This group of patients includes
those with surgically unsalvageable disease (sacral or spinal GCTB, multiple lesions or
pulmonary metastases), or in cases where planned surgery would result in severe morbidity
(National Institute for Health Research 2012). As of 1st
of April 2014, denosumab has been
funded by the Australian Pharmaceutical Benefits Scheme for the management of
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unresectable giant cell tumour of bone, a development that has occurred since the initial
treatment of the abovementioned case.
The first published study that described the use of denosumab for the treatment of GCTB
was undertaken by Thomas et al (Thomas et al. 2010). This involved a multicentre, phase II
study of 37 patients who all received 120mg denosumab subcutaneously every 4 weeks
after 2 initial loading doses one week apart. The study only included patients with recurrent
or un-resectable GCTBs who had received prior treatment without obtaining tumour
control. The primary endpoint assessed was tumour response, defined either histologically
as an elimination of at least 90% of giant cells when measured between weeks 5 - 25 of
treatment, or radiologically as no disease progression after week 25. There was a clinical
benefit reported in 84% of patients with a reduction in pain or an improvement in functional
status. The authors concluded that based on this small study, denosumab may have a
therapeutic role in cases of otherwise unsalvageable GCT, particularly with pulmonary
metastases and also in the neoadjuvant setting to improve surgical outcomes.
The dosing schedule utilised for our patient was sourced from the study by Thomas et al
(Thomas et al. 2010). This had been demonstrated to be safe and effective in the above
study with a low risk of severe side effects. Our patient had a rapid response to therapy with
significant ossification and reduction in tumour size. The rapidity of response may be
explained by the nature of alveolar bone in the mandible, which has been shown in animal
models to have a 3-6 times higher rate of bone turnover than other skeletal sites such as the
femur.(Huja et al. 2006)
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An important consideration for our patient is the risk of denosumab-induced osteonecrosis
of the jaws. There have been three large double blind, Phase III randomized trials that have
compared zoledronic acid with denosumab for skeletal metastatic disease. The incidence of
osteonecrosis of the jaws was similar for both preparations (1.3% vs. 1.8%) respectively with
a total of 89 cases out of 5677 patients(Lipton et al. 2012). The studies found an increased
incidence due to cumulative dose after 3 years of treatment. Tooth extraction was a major
factor for increased risk, highlighting the need for thorough dental assessment prior to
commencing any anti-resorptive medications (Stopeck et al. , Fizazi et al. 2011, Henry et al.
2011). Bisphosphonate therapy has been proposed as a potential medical therapy for GCTB
due to its prior efficacy in the management of bony metastatic disease. However
interestingly, the phase III trials to date have suggested denosumab to be superior to
zoledronic acid in the management of skeletal related events in metastatic bone disease
(Brown and Coleman 2012). Further data is awaited to confirm the efficacy of denosumab in
the treatment of GCTB.
Recent case reports suggest that the syndrome of atypical midshaft subtrochanteric femoral
fractures that have arisen following long term intravenous and oral bisphosphonate therapy
may also occur following prolonged exposure to denosumab (Park-Wyllie et al. 2011,
Schilcher et al. 2011). While no cases were reported in the original double blind randomized
control trial of denosumab in the treatment of women with postmenopausal osteoporosis,
the subsequent FREEDOM Extension study has since reported isolated cases (Bone et al.
2013). The duration of therapy for our patient will be guided by the emerging data and
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experience accumulated with long-term exposure to this agent in postmenopausal women.
The rational for dose reduction to 6 monthly administrations was based on the safety of the
use of denosumab in osteoporosis.
Denosumab does have a lower incidence of acute phase reactions such as bone pain, fever,
headaches and myalgia when compared with zoledronic acid (8.7 vs. 20%)(Lipton et al.
2012). It also does not have the same deleterious effects on renal function. Although
hypocalcaemia has been reported with denosumab, this can be prevented and treated with
calcium and vitamin D supplements. Indeed for our patient, it was essential to ensure that
the secondary hyperparathyroidism arising from the vitamin D deficiency was adequately
managed and reversed before proceeding to treatment. This was to negate any contribution
of parathyroid stimulation as well as managing the potential for hypocalcaemia.
To our knowledge, there have been two reports on the use of denosumab in the treatment
of CGCG of the jaws. Malmquist & Schow(Malmquist and Schow 2013) have described 2
patients with evidence of decreased lesion size and new bone formation. Schreuder et al
have also published a report of a maxillary CGCG treated successfully with denosumab
(Schreuder et al. 2014). In their case, medical therapy with calcitonin followed by Interferon
had been attempted but was prematurely ceased due to side effects. Denosumab therapy
was then provided for a 12-month period with follow up for 12 months after cessation of
therapy. They reported that the lesion stabilised on follow-up imaging and continued to
regress.
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Conclusion
This case highlights the potential use of this medication for the treatment of aggressive
CGCG of the jaws that has been resistant to other forms of medical therapy. The use of
Denosumab for this indication is off label and experimental, further study with controlled
trials and long-term follow up data are needed to fully evaluate the clinical uses, side
effects, and duration of therapy for denosumab in the treatment of CGCG of the jaws.
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Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay J-Y, Roudier M, Smith J, Ye Z, Sohn W,
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Figure Legends
1. Orthopantomogram (OPG) on presentation with large multilocular radiolucent lesion at right
body of mandible involving posterior alveolus and teeth.
2. Photomicrograph demonstrating clusters of multinucleated osteoclastic giant cells within a
cellular stroma (H&E).
3. OPG following initial steroid treatment, showing no evidence of resolution or shrinkage.
4. OPG following second course of steroid treatment showing progression in size of the CGCG
to involve the first premolar and third molar teeth.
5. Imaging following calcitonin treatment
A. Axial CT scan showing extent of bucco-lingual expansion thinning of cortices.
B. 3D recon CT image demonstrating cortical perforations and mandibular expansion.
6. A. Imaging demonstrating ossification following Denosumab treatment with residual
mandibular expansion.
A. OPG
B. Axial CT
7. A. Post Denosumab – Compact cortical bone with underlying cancellous bone. No evidence
of residual giant cell granuloma (H&E)
B. Post Denosumab - Remodelled cancellous bony trabeculae with surrounding fibrous
marrow. No evidence of residual giant cell granuloma (H&E)
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