Accepted Manuscript A Novel Approach to the Management of a Central Giant Cell Granuloma with Denosumab: A Case Report and Review of Current Treatments Dr Benjamin Gupta, BDS BMED MFDS, Norman Stanton, MBBS BDS, Hedley Coleman, 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 the Management of a Central Giant Cell Granuloma with Denosumab: A Case Report and Review of Current Treatments, 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 to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 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
RI PT
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
Financial disclosures: None Conflicts of Interest: None
Dr Benjamin Gupta
TE D
Correspondence:
M AN U
SC
Department of Endocrinology, Prince of Wales Hospital, Randwick, NSW, Australia
Department of Oral and Maxillofacial Surgery
EP
Prince of Wales Hospital
AC C
Barker St, New South Wales, 2031 Sydney, Australia
Tel: +612 93822245
E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract
Purpose: To describe the efficacy of denosumab in the treatment of an aggressive giant cell granuloma of the mandible.
RI PT
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
SC
response was measured on the basis of patient symptoms and radiological parameters.
Results: A significant reduction in patient symptoms was reported in association with
M AN U
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.
AC C
EP
TE D
Keywords: Central giant cell granuloma, denosumab
ACCEPTED MANUSCRIPT 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
RI PT
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
SC
aged less than 30 years and is twice as common in females (Whitaker and Waldron 1993, de
M AN U
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
TE D
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
EP
displacement and/or resorption (Chuong et al. 1986).
AC C
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)
ACCEPTED MANUSCRIPT 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
RI PT
use(Suárez-Roa MDL 2009).
The aim of this paper is to review the current literature and report a case of an aggressive
SC
CGCG of the mandible that was treated with denosumab (Xgeva, Amgen Incorporated,
M AN U
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
TE D
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
EP
due to her understanding that the mandibular swelling was dental in origin. The patient had
AC C
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
ACCEPTED MANUSCRIPT (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
RI PT
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
SC
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
M AN U
hyperparathyroidism. The slides were also reviewed by an experienced orthopaedic pathologist who concurred with the diagnosis.
TE D
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.
EP
Vitamin D deficiency was deemed the result of wearing traditional Islamic dress limiting
AC C
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.
ACCEPTED MANUSCRIPT 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
RI PT
(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
SC
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
M AN U
of intralesional triamcinolone administered at the higher dose of 40mg weekly. Despite this regimen, the CGCG continued to expand (Fig 4).
TE D
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
EP
with the regimen, reporting mild nausea as the only side effect of calcitonin. The response
AC C
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)
ACCEPTED MANUSCRIPT 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.
RI PT
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.
SC
An early clinical response was observed with resolution of patient symptoms within 10 days.
M AN U
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).
TE D
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
EP
with stabilisation of the lesion maintained 18 months after denosumab therapy was
AC C
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
ACCEPTED MANUSCRIPT 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
RI PT
(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
SC
aggressive behaviour (Marx and Stern 2003).
The use of calcitonin was first described in 1993 by Harris after immunohistochemistry
M AN U
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
TE D
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
EP
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
AC C
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
ACCEPTED MANUSCRIPT 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
RI PT
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).
SC
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
M AN U
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
TE D
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
AC C
EP
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).
ACCEPTED MANUSCRIPT 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
RI PT
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
M AN U
SC
(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
TE D
(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
bone (GCTB).
EP
effectiveness in a number of other osteolytic disorders including giant cell tumour of the
AC C
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
ACCEPTED MANUSCRIPT unresectable giant cell tumour of bone, a development that has occurred since the initial treatment of the abovementioned case.
RI PT
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
SC
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
M AN U
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
TE D
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
AC C
EP
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)
ACCEPTED MANUSCRIPT
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
RI PT
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
SC
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
M AN U
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
TE D
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
AC C
EP
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
ACCEPTED MANUSCRIPT 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.
RI PT
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.
SC
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
M AN U
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
TE D
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
EP
patients with evidence of decreased lesion size and new bone formation. Schreuder et al
AC C
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.
ACCEPTED MANUSCRIPT
Conclusion
This case highlights the potential use of this medication for the treatment of aggressive
RI PT
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
SC
trials and long-term follow up data are needed to fully evaluate the clinical uses, side
AC C
EP
TE D
M AN U
effects, and duration of therapy for denosumab in the treatment of CGCG of the jaws.
ACCEPTED MANUSCRIPT References
AC C
EP
TE D
M AN U
SC
RI PT
Abdo EN, Alves LCF, Rodrigues AS, Mesquita RA and Gomez RS: Treatment of a central giant cell granuloma with intralesional corticosteroid. Br J Oral Maxillofac Surg 43(1): 74-76, 2005. Allon DM, Anavi Y and Calderon S: Central giant cell lesion of the jaw: nonsurgical treatment with calcitonin nasal spray. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107(6): 811-818, 2009. Bataineh A, Al-Khateeb T and Rawashded M: The surgical treatment of central giant cell granuloma of the mandible. J Oral Maxillofac Surg 60(7): 756-761, 2002. Bone H, Chapurlat R, Brandi M, J Brown, ski EC, Krieg M, D Mellström, Radominski S, Reginster J, Resch H, Ivorra JR, Roux C, Vittinghoff E, Daizadeh N, Wang A, Bradley M, Franchimont N, Geller M, Wagman R, Cummings S and Papapoulos S: The Effect of Three or Six Years of Denosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the FREEDOM Extension. J Clin Endocrinol Metab 98: 4483–4492, 2013. Branstetter D, Nelson S, Manivel J, Blay J, Chawla S, Thomas D, S SJ and Jacobs I: Denosumab induces tumour reduction and bone formation in patients with giant cell tumour of the bone. Clin Cancer Res 18: 4415-4424, 2012. Brown JE and Coleman RE: Denosumab in patients with cancer-a surgical strike against the osteoclast. Nat. Rev. Clin. Oncol. 9(2): 110-118, 2012. Carlos R and Sedano HO: Intralesional corticosteroids as an alternative treatment for central giant cell granuloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93(2): 161-166, 2002. Chambers T, Fuller K and McSheeny P: The effects of calcium regulating hormones on bone resorption by isolated human osteoclastoma cells. J Pathol 45: 297–305, 1985. Chuong R, Kaban LB, Kozakewich H and Perez-Atayde A: Central giant cell lesions of the jaws: a clinicopathologic study. J Oral Maxillofac Surg 44(9): 708-713, 1986. Collins A: Experience with anti-angiogenic therapy of giant cell granuloma of the facial bones. Ann Roy Australas Coll Dent Surg 15: 170-175, 2000. de Lange J, van den Akker H, van den Berg H, Richel D and Gortzak R: Limited regression of central giant cell granuloma by interferon alpha after failed calcitonin therapy: a report of two cases. Int J Oral Maxillofac Surg 35: 865–869, 2006. de Lange J, van den Akker HP and Klip H: Incidence and disease-free survival after surgical therapy of central giant cell granulomas of the jaw in The Netherlands: 1990-1995. Head Neck 26(9): 792-795, 2004. de Lange J, van den Akker HP and van den Berg H: Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104: 603-615, 2007. de Lange J, van Rijn RR, van den Berg H and van den Akker HP: Regression of central giant cell granuloma by a combination of imatinib and interferon: a case report. Br J Oral Maxillofac Surg 47: 59–61, 2009. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R and Goessl C: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377(9768): 813-822, 2011. Flanagan A, Tinkler S, Horton M, Williams D and Chambers T: The multinucleate cells in the giant cell granulomas of the jaw are osteoclasts. Cancer 62: 1139–1145, 1988. Goldman KE MM, Alessandrini E, Bernstein ML.: Complications of alpha-interferon therapy for aggressive giant cell lesion of the maxilla. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100: 285-291, 2005. Harris M: Central giant cell granulomas of the jaws regress with calcitonin therapy. Br J Oral Maxillofac Surg 31: 89-94, 1993. Health NIo (2012). Denosumab ( Xgeva) for recurrent or unresectable giant cell tumour of the bone – first or second line N. H. S. Centre. University of Birmingham.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Henry D, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti G, Sleeboom H, Spencer A, Vadhan-Raj S, Moos Rv, Willenbacher W, Woll P, Wang J, Jiang Q, Jun S, Dansey R and Yeh H: Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29: 1125-1132, 2011. Huja SS, Fernandez SA, Hill KJ and Li Y: Remodeling dynamics in the alveolar process in skeletally mature dogs. Anat Rec A Discov Mol Cell Evol Biol 288(12): 1243-1249, 2006. Infante Cossio P, Martinez de Fuentes R, Carranza Carranza A, Torres Lagares D and Gutierrez Perez JL: Recurrent central giant cell granuloma in the mandible: surgical treatment and dental implant restoration. Medicina Oral, Patologia Oral y Cirugia Bucal 12(3): E229-232, 2007. Jacoway J, Howell F and Terry B: Central giant cell granuloma: an alternative to surgical therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 66: 572, 1988. Kaban LB, Mulliken JB, Ezekowitz RA, Ebb D, Smith PS and Folkman J: Antiangiogenic therapy of a recurrent giant cell tumor of the mandible with interferon alfa-2a. Pediatrics 103(6 Pt 1): 1145-1149, 1999. Kaban LB, Troulis MJ, Ebb D, August M, Hornicek FJ and Dodson TB: Antiangiogenic therapy with interferon alpha for giant cell lesions of the jaws. J Oral Maxillofac Surg 60(10): 1103-1111; discussion 1111-1103, 2002. Kaban LB, Troulis MJ, Wilkinson MS, Ebb D and Dodson TB: Adjuvant antiangiogenic therapy for giant cell tumors of the jaws. J Oral Maxillofac Surg 65(10): 2018-2024; discussion 2024, 2007. Landesberg R, Eisig S, Fennoy I and Siris E: Alternative indications for bisphosphonate therapy. J Oral Maxillofac Surg 67(5 Suppl): 27-34, 2009. Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A and Jun S: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48(16): 3082-3092, 2012. Malmquist M and Schow S: Treatment of Central Giant Cell Granuloma With Denosumab Therapy in Two Patients. J Oral Maxillofac Surg 71, e75, 2013. Marx RE and Stern D: Oral and Maxillofacial Pathology. A rationale for Diagnosis and Treatment,First edition Quintessence, 2003. Park-Wyllie L, Mamdani M, Juurlink D, Hawker G, Gunraj N, Austin P, Whelan D, Weiler P and Laupacis A: Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women. JAMA 305(8): 783-789, 2011. Pogrel MA, Regezi JA, Harris ST and Goldring SR: Calcitonin treatment for central giant cell granulomas of the mandible: report of two cases. J Oral Maxillofac Surg 57(7): 848-853, 1999. Rachmiel A, Emodi O, Sabo E, Aizenbud D and Peled M: Combined treatment of aggressive central giant cell granuloma in the lower jaw. Journal of Cranio-Maxillo-Facial Surgery 40(3): 292-297, 2012. Schilcher J, Michaëlsson K and Aspenberg P: Bisphosphonate Use and Atypical Fractures of the Femoral Shaft. N Engl J Med 364: 1728-1737, 2011. Schreuder WH, Coumou AW, Kessler PA and de Lange J: Alternative Pharmacologic Therapy for Aggressive Central Giant Cell Granuloma: Denosumab. J Oral Maxillofac Surg, 2014. Stopeck AT, Lipton A, Body J-J, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S and Braun A: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28(35): 5132-5139, Suárez-Roa MDL RL, Ruíz-Godoy Rivera LM, Asbun-Bojalil J, Dávila-Serapio JE, Menjívar-Rubio AH, Meneses-García A: Interventions for central giant cell granuloma (CGCG) of the jaws (Review). Cochrane Database Syst Rev(4), 2009. Terry B and Jacoway J: Management of central giant cell lesions: An alternative to surgical therapy. Oral Maxillofac Surg Clin N Am 6: 579-601, 1994.
ACCEPTED MANUSCRIPT
RI PT
Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay J-Y, Roudier M, Smith J, Ye Z, Sohn W, Dansey R and Jun S: Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 11(3): 275-280, 2010. Tosco P, Tanteri G, Iaquinta C, Fasolis M, Roccia F, Berrone S and Garzino-Demo P: Surgical treatment and reconstruction for central giant cell granuloma of the jaws: a review of 18 cases. J Craniomaxillofac Surg 37(7): 380-387, 2009. Vered M, Buchner A and Dayan D: Immunohistochemical expression of glucocorticoid and calcitonin receptors as a tool for selecting therapeutic approach in central giant cell granulomas of the jawbones. J Oral Maxillofac Surg 35: 756-760, 2006. Whitaker SB and Waldron CA: Central giant cell lesions of the jaws. A clinical, radiologic, and histopathologic study. Oral Surg Oral Med Oral Pathol 75(2): 199-208, 1993.
SC
Figure Legends
M AN U
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.
TE D
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.
AC C
EP
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)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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 the Management of a Central Giant Cell Granuloma with Denosumab: A Case Report and Review of Current Treatments, 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 to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 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
RI PT
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
Financial disclosures: None Conflicts of Interest: None
Dr Benjamin Gupta
TE D
Correspondence:
M AN U
SC
Department of Endocrinology, Prince of Wales Hospital, Randwick, NSW, Australia
Department of Oral and Maxillofacial Surgery
EP
Prince of Wales Hospital
AC C
Barker St, New South Wales, 2031 Sydney, Australia
Tel: +612 93822245
E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract
Purpose: To describe the efficacy of denosumab in the treatment of an aggressive giant cell granuloma of the mandible.
RI PT
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
SC
response was measured on the basis of patient symptoms and radiological parameters.
Results: A significant reduction in patient symptoms was reported in association with
M AN U
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.
AC C
EP
TE D
Keywords: Central giant cell granuloma, denosumab
ACCEPTED MANUSCRIPT 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
RI PT
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
SC
aged less than 30 years and is twice as common in females (Whitaker and Waldron 1993, de
M AN U
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
TE D
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
EP
displacement and/or resorption (Chuong et al. 1986).
AC C
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)
ACCEPTED MANUSCRIPT 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
RI PT
use(Suárez-Roa MDL 2009).
The aim of this paper is to review the current literature and report a case of an aggressive
SC
CGCG of the mandible that was treated with denosumab (Xgeva, Amgen Incorporated,
M AN U
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
TE D
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
EP
due to her understanding that the mandibular swelling was dental in origin. The patient had
AC C
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
ACCEPTED MANUSCRIPT (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
RI PT
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
SC
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
M AN U
hyperparathyroidism. The slides were also reviewed by an experienced orthopaedic pathologist who concurred with the diagnosis.
TE D
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.
EP
Vitamin D deficiency was deemed the result of wearing traditional Islamic dress limiting
AC C
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.
ACCEPTED MANUSCRIPT 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
RI PT
(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
SC
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
M AN U
of intralesional triamcinolone administered at the higher dose of 40mg weekly. Despite this regimen, the CGCG continued to expand (Fig 4).
TE D
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
EP
with the regimen, reporting mild nausea as the only side effect of calcitonin. The response
AC C
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)
ACCEPTED MANUSCRIPT 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.
RI PT
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.
SC
An early clinical response was observed with resolution of patient symptoms within 10 days.
M AN U
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).
TE D
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
EP
with stabilisation of the lesion maintained 18 months after denosumab therapy was
AC C
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
ACCEPTED MANUSCRIPT 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
RI PT
(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
SC
aggressive behaviour (Marx and Stern 2003).
The use of calcitonin was first described in 1993 by Harris after immunohistochemistry
M AN U
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
TE D
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
EP
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
AC C
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
ACCEPTED MANUSCRIPT 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
RI PT
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).
SC
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
M AN U
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
TE D
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
AC C
EP
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).
ACCEPTED MANUSCRIPT 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
RI PT
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
M AN U
SC
(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
TE D
(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
bone (GCTB).
EP
effectiveness in a number of other osteolytic disorders including giant cell tumour of the
AC C
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
ACCEPTED MANUSCRIPT unresectable giant cell tumour of bone, a development that has occurred since the initial treatment of the abovementioned case.
RI PT
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
SC
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
M AN U
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
TE D
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
AC C
EP
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)
ACCEPTED MANUSCRIPT
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
RI PT
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
SC
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
M AN U
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
TE D
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
AC C
EP
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
ACCEPTED MANUSCRIPT 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.
RI PT
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.
SC
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
M AN U
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
TE D
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
EP
patients with evidence of decreased lesion size and new bone formation. Schreuder et al
AC C
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.
ACCEPTED MANUSCRIPT
Conclusion
This case highlights the potential use of this medication for the treatment of aggressive
RI PT
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
SC
trials and long-term follow up data are needed to fully evaluate the clinical uses, side
AC C
EP
TE D
M AN U
effects, and duration of therapy for denosumab in the treatment of CGCG of the jaws.
ACCEPTED MANUSCRIPT References
AC C
EP
TE D
M AN U
SC
RI PT
Abdo EN, Alves LCF, Rodrigues AS, Mesquita RA and Gomez RS: Treatment of a central giant cell granuloma with intralesional corticosteroid. Br J Oral Maxillofac Surg 43(1): 74-76, 2005. Allon DM, Anavi Y and Calderon S: Central giant cell lesion of the jaw: nonsurgical treatment with calcitonin nasal spray. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107(6): 811-818, 2009. Bataineh A, Al-Khateeb T and Rawashded M: The surgical treatment of central giant cell granuloma of the mandible. J Oral Maxillofac Surg 60(7): 756-761, 2002. Bone H, Chapurlat R, Brandi M, J Brown, ski EC, Krieg M, D Mellström, Radominski S, Reginster J, Resch H, Ivorra JR, Roux C, Vittinghoff E, Daizadeh N, Wang A, Bradley M, Franchimont N, Geller M, Wagman R, Cummings S and Papapoulos S: The Effect of Three or Six Years of Denosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the FREEDOM Extension. J Clin Endocrinol Metab 98: 4483–4492, 2013. Branstetter D, Nelson S, Manivel J, Blay J, Chawla S, Thomas D, S SJ and Jacobs I: Denosumab induces tumour reduction and bone formation in patients with giant cell tumour of the bone. Clin Cancer Res 18: 4415-4424, 2012. Brown JE and Coleman RE: Denosumab in patients with cancer-a surgical strike against the osteoclast. Nat. Rev. Clin. Oncol. 9(2): 110-118, 2012. Carlos R and Sedano HO: Intralesional corticosteroids as an alternative treatment for central giant cell granuloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93(2): 161-166, 2002. Chambers T, Fuller K and McSheeny P: The effects of calcium regulating hormones on bone resorption by isolated human osteoclastoma cells. J Pathol 45: 297–305, 1985. Chuong R, Kaban LB, Kozakewich H and Perez-Atayde A: Central giant cell lesions of the jaws: a clinicopathologic study. J Oral Maxillofac Surg 44(9): 708-713, 1986. Collins A: Experience with anti-angiogenic therapy of giant cell granuloma of the facial bones. Ann Roy Australas Coll Dent Surg 15: 170-175, 2000. de Lange J, van den Akker H, van den Berg H, Richel D and Gortzak R: Limited regression of central giant cell granuloma by interferon alpha after failed calcitonin therapy: a report of two cases. Int J Oral Maxillofac Surg 35: 865–869, 2006. de Lange J, van den Akker HP and Klip H: Incidence and disease-free survival after surgical therapy of central giant cell granulomas of the jaw in The Netherlands: 1990-1995. Head Neck 26(9): 792-795, 2004. de Lange J, van den Akker HP and van den Berg H: Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104: 603-615, 2007. de Lange J, van Rijn RR, van den Berg H and van den Akker HP: Regression of central giant cell granuloma by a combination of imatinib and interferon: a case report. Br J Oral Maxillofac Surg 47: 59–61, 2009. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R and Goessl C: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377(9768): 813-822, 2011. Flanagan A, Tinkler S, Horton M, Williams D and Chambers T: The multinucleate cells in the giant cell granulomas of the jaw are osteoclasts. Cancer 62: 1139–1145, 1988. Goldman KE MM, Alessandrini E, Bernstein ML.: Complications of alpha-interferon therapy for aggressive giant cell lesion of the maxilla. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100: 285-291, 2005. Harris M: Central giant cell granulomas of the jaws regress with calcitonin therapy. Br J Oral Maxillofac Surg 31: 89-94, 1993. Health NIo (2012). Denosumab ( Xgeva) for recurrent or unresectable giant cell tumour of the bone – first or second line N. H. S. Centre. University of Birmingham.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Henry D, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti G, Sleeboom H, Spencer A, Vadhan-Raj S, Moos Rv, Willenbacher W, Woll P, Wang J, Jiang Q, Jun S, Dansey R and Yeh H: Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29: 1125-1132, 2011. Huja SS, Fernandez SA, Hill KJ and Li Y: Remodeling dynamics in the alveolar process in skeletally mature dogs. Anat Rec A Discov Mol Cell Evol Biol 288(12): 1243-1249, 2006. Infante Cossio P, Martinez de Fuentes R, Carranza Carranza A, Torres Lagares D and Gutierrez Perez JL: Recurrent central giant cell granuloma in the mandible: surgical treatment and dental implant restoration. Medicina Oral, Patologia Oral y Cirugia Bucal 12(3): E229-232, 2007. Jacoway J, Howell F and Terry B: Central giant cell granuloma: an alternative to surgical therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 66: 572, 1988. Kaban LB, Mulliken JB, Ezekowitz RA, Ebb D, Smith PS and Folkman J: Antiangiogenic therapy of a recurrent giant cell tumor of the mandible with interferon alfa-2a. Pediatrics 103(6 Pt 1): 1145-1149, 1999. Kaban LB, Troulis MJ, Ebb D, August M, Hornicek FJ and Dodson TB: Antiangiogenic therapy with interferon alpha for giant cell lesions of the jaws. J Oral Maxillofac Surg 60(10): 1103-1111; discussion 1111-1103, 2002. Kaban LB, Troulis MJ, Wilkinson MS, Ebb D and Dodson TB: Adjuvant antiangiogenic therapy for giant cell tumors of the jaws. J Oral Maxillofac Surg 65(10): 2018-2024; discussion 2024, 2007. Landesberg R, Eisig S, Fennoy I and Siris E: Alternative indications for bisphosphonate therapy. J Oral Maxillofac Surg 67(5 Suppl): 27-34, 2009. Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A and Jun S: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48(16): 3082-3092, 2012. Malmquist M and Schow S: Treatment of Central Giant Cell Granuloma With Denosumab Therapy in Two Patients. J Oral Maxillofac Surg 71, e75, 2013. Marx RE and Stern D: Oral and Maxillofacial Pathology. A rationale for Diagnosis and Treatment,First edition Quintessence, 2003. Park-Wyllie L, Mamdani M, Juurlink D, Hawker G, Gunraj N, Austin P, Whelan D, Weiler P and Laupacis A: Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women. JAMA 305(8): 783-789, 2011. Pogrel MA, Regezi JA, Harris ST and Goldring SR: Calcitonin treatment for central giant cell granulomas of the mandible: report of two cases. J Oral Maxillofac Surg 57(7): 848-853, 1999. Rachmiel A, Emodi O, Sabo E, Aizenbud D and Peled M: Combined treatment of aggressive central giant cell granuloma in the lower jaw. Journal of Cranio-Maxillo-Facial Surgery 40(3): 292-297, 2012. Schilcher J, Michaëlsson K and Aspenberg P: Bisphosphonate Use and Atypical Fractures of the Femoral Shaft. N Engl J Med 364: 1728-1737, 2011. Schreuder WH, Coumou AW, Kessler PA and de Lange J: Alternative Pharmacologic Therapy for Aggressive Central Giant Cell Granuloma: Denosumab. J Oral Maxillofac Surg, 2014. Stopeck AT, Lipton A, Body J-J, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S and Braun A: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28(35): 5132-5139, Suárez-Roa MDL RL, Ruíz-Godoy Rivera LM, Asbun-Bojalil J, Dávila-Serapio JE, Menjívar-Rubio AH, Meneses-García A: Interventions for central giant cell granuloma (CGCG) of the jaws (Review). Cochrane Database Syst Rev(4), 2009. Terry B and Jacoway J: Management of central giant cell lesions: An alternative to surgical therapy. Oral Maxillofac Surg Clin N Am 6: 579-601, 1994.
ACCEPTED MANUSCRIPT
RI PT
Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay J-Y, Roudier M, Smith J, Ye Z, Sohn W, Dansey R and Jun S: Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 11(3): 275-280, 2010. Tosco P, Tanteri G, Iaquinta C, Fasolis M, Roccia F, Berrone S and Garzino-Demo P: Surgical treatment and reconstruction for central giant cell granuloma of the jaws: a review of 18 cases. J Craniomaxillofac Surg 37(7): 380-387, 2009. Vered M, Buchner A and Dayan D: Immunohistochemical expression of glucocorticoid and calcitonin receptors as a tool for selecting therapeutic approach in central giant cell granulomas of the jawbones. J Oral Maxillofac Surg 35: 756-760, 2006. Whitaker SB and Waldron CA: Central giant cell lesions of the jaws. A clinical, radiologic, and histopathologic study. Oral Surg Oral Med Oral Pathol 75(2): 199-208, 1993.
SC
Figure Legends
M AN U
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.
TE D
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.
AC C
EP
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)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
