Denosumab in Patients with Giant Cell Tumor and Its Recurrence: A Systematic Review

Document Type : SYSTEMATIC REVIEW

Authors

1 Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran

2 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Razavi Cancer Research Center, Razavi Hospital, Imam Reza International University, Mashhad, Iran

Abstract

Recent studies suggest that Denosumab reduces tumor size, therefore, makes the surgery easier with lower
morbidity. However, some studies have reported several complications for this drug. So, this systematic review
was performed to determine the effectiveness and safety of Denosumab in reducing bone destructions activity of
giant cell tumor and skeletal-related events (SRE) in affected patients with giant cell tumor of bone (GCTB) and its
recurrence.
We explored studies in PubMed, and Cochrane Library. For this purpose, articles of various levels were retrieved
until October 22, 2016. Two reviewers assessed the articles independently based on predefined criteria to extract the
relevant data. Primary outcomes associated with skeletal-related event, overall survival, and secondary outcomes
such as pain, quality of life and adverse events were evaluated and analyzed.
The total population of this meta-analysis consisted of 686 patients. Of this population, 55% had primary GCTB and
45% had giant cell tumor recurrence, with 2% experiencing secondary recurrence.
The results showed the effectiveness of Denosumab in reducing the tumor size due to inhibiting the Osteoclastogenesis.
Denosumab didnot show any effect on reducing tumor recurrence, but, in cases where complete tumor surgery is
not possible and tumor residuals may remain, Denosumab can be helpful. Also, the clinicians should consider the
risk benefit of Denosumab.

Keywords

Main Subjects


1. Klenke FM, Wenger DE, Inwards CY, Rose PS, Sim FH.
Giant cell tumor of bone: risk factors for recurrence.
Clin Orthop Relat Res. 2011; 469(2):591-9.
2. Sobti A, Agrawal P, Agarwala S, Agarwal M. Giant cell
tumor of bone-an overview. Arch Bone Jt Surg. 2016;
4(1):2-9.
3. Unni K. Giant cell tumor/malignancy in giant cell
tumor of bone. Dahlin’s bone tumors: general aspects
and data on 11,087 cases. 5th ed. Philadelphia, PA:
Lippincott-Raven; 1996. P. 263-89.
4. Bertoni F, Bacchini P, Staals EL. Malignancy in giant
cell tumor of bone. Cancer. 2003; 97(10):2520-9.
5. Campanacci M, Baldini N, Boriani S, Sudanese A.
Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;
69(1):106-14.
6. Li J, Zhu Y, Wei Y. Fibrosarcoma development 15 years
after curettage and bone grafting of giant cell tumor of
bone. Orthopedics. 2014; 37(5):e512-6.
7. Rock MG, Sim FH, Unni KK, Witrak GA, Frassica FJ,
Schray MF, et al. Secondary malignant giant-cell
tumor of bone. Clinicopathological assessment
of nineteen patients. J Bone Joint Surg Am. 1986;
68(7):1073-9.
8. Briët JP, Becker SJ, Oosterhoff TC, Ring D. Giant cell
tumor of tendon sheath. Arch Bone Jt Surg. 2015;
3(1):19-21.
9. Chawla S, Henshaw R, Seeger L, Choy E, Blay JY,
Ferrari S, et al. Safety and efficacy of Denosumab for
adults and skeletally mature adolescents with giant
cell tumour of bone: interim analysis of an open-label,
parallel-group, phase 2 study. Lancet Oncol. 2013;
14(9):901-8.
10. Thomas DM. RANKL, Denosumab, and giant cell tumor
of bone. Curr Opin Oncol. 2012; 24(4):397-403.
11. Xu SF, Adams B, Yu XC, Xu M. Denosumab and giant
cell tumour of bone: a review and future management
considerations. Curr Oncol. 2013; 20(5):e442-7.
12. Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A
translational study of the neoplastic cells of giant cell
tumor of bone following neoadjuvant Denosumab. J
Bone Joint Surg Am. 2014; 96(15):e127.
13. Higgins J, Green S. Cochrane handbook for systematic
reviews of interventions. London: The Cochrane
Collaboration; 2011.
14. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon
K, Blay JY, et al. Denosumab in patients with giant-cell
tumour of bone: an open-label, phase 2 study. Lancet
Oncol. 2010; 11(3):275-80.
15. Branstetter DG, Nelson SD, Manivel JC, Blay JY,
Chawla S, Thomas DM, et al. Denosumab induces
tumor reduction and bone formation in patients
with giant-cell tumor of bone. Clin Cancer Res. 2012;
18(16):4415-24.
16. Martin-Broto J, Cleeland CS, Glare PA, Engellau J,
Skubitz KM, et al. Effects of denosumab on pain and
analgesic use in giant cell tumor of bone: interim
results from a phase II study. Acta Oncol. 2014;
53(9):1173-9.
17. Ueda T, Morioka H, Nishida Y, Kakunaga S, Tsuchiya
H, Matsumoto Y, et al. Objective tumor response
to Denosumab in patients with giant cell tumor of
bone: a multicenter phase II trial. Ann Oncol. 2015;
26(10):2149-54.
18. Girolami I, Mancini I, Simoni A, Baldi GG, Simi
L, Campanacci D, et al. Denosumab treated
giant cell tumour of bone: a morphological, 
immunohistochemical and molecular analysis of a
series. J Clin Pathol. 2016; 69(3):240-7.
19. Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra
SP, Pienkowski A, et al. Surgical downstaging in an
open-label phase II trial of denosumab in patients
with giant cell tumor of bone. Ann Surg Oncol. 2015;
22(9):2860-8.
20. Traub F, Singh J, Dickson BC, Leung S, Mohankumar
R, Blackstein ME, et al. Efficacy of denosumab in joint
preservation for patients with giant cell tumour of the
bone. Eur J Cancer. 2016; 59:1-12.
21. Rekhi B, Verma V, Gulia A, Nirmala A, Desai S, Juvekar
SL, et al. Clinicopathological features of a series of 27
cases of post-denosumab treated giant cell tumors of
bones: a single institutional experience at a tertiary
cancer referral Centre, India. Pathol Oncol Res. 2017;
23(1):157-64.
22. Wojcik J, Rosenberg AE, Bredella MA, Choy E, Hornicek
FJ, Hornicek FJ, et al. Denosumab-treated giant cell
tumor of bone exhibits morphologic overlap with
malignant giant cell tumor of bone. Am J Surg Pathol.
2016; 40(1):72-80.
23. Michiyuki H, Takahiro T, Hitoshi Y, Osamu H, Kazuhiro
T, Watanabe K, et al. Radiological and pathological
characteristics of giant cell tumor of bone treated
with Denosumab. Diagn Pathol. 2014, 9(1):111.
24. Vaishya R, Agarwal AK, Vijay V. Salvage treatment’ of
aggressive giant cell tumor of bones with denosumab.
Cureus. 2015; 7(7):e291.
25. Karras NA, Polgreen LE, Ogilvie C, Manivel JC, Skubitz
KM, Lipsitz E. Denosumab treatment of metastatic
giant-cell tumor of bone in a 10-year-old girl. J Clin
Oncol. 2013; 31(12):e200-2.
26. Stadler N, Fingernagel T, Hofstaetter SG, Trieb K.
A recurrent giant cell tumor of bone treated with
Denosumab. Clin Pract. 2015; 5(1):697.
27. Keisuke A, Yoshiyuki S, Tatsuya T, Kazuo K, Tsuyoshi
S. Hell-like mineralized recurrent lesion in the
popliteal region after treatment of giant cell tumor
of the bone with Denosumab. Skeletal Radiol. 2014;
43(12):1767-72.
28. Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A
translational study of the neoplastic cells of giant cell
tumor of bone following neoadjuvant denosumab. J
Bone Joint Surg Am. 2014; 96(15):e127.
29. Kajiwara D, Kamoda H, Yonemoto T, Iwata S, Ishii T,
Tsukanishi T, et al. Denosumab for treatment of a
recurrent cervical giant-cell tumor. Asian Spine J.
2016; 10(3):553-7.
30. Yamagishi T, Kawashima H, Ogose A, Sasaki T, Hotta
T, Inagawa S, et al. Disappearance of giant cells and
presence of newly formed bone in the pulmonary
metastasis of a sacral giant‑cell tumor following
Denosumab treatment: a case report. Oncol Lett.
2016; 11(1):243-6.
31. Watanabe N, Matsumoto S, Shimoji T, Ae K, Tanizawa
T, Gokita T, et al. Watanabe et al. Early evaluation of
the therapeutic effect of Denosumab on tartrateresistant
acid phosphatase 5b expression in a giant
cell tumor of bone: a case report. BMC Res Notes.
2014; 7(1):608.
32. Mattei TA, Ramos E, Rehman AA, Shaw A, Patel SR,
Mendel E. Sustained long-term complete regression
of a giant cell tumor of the spine after treatment with
denosumab. Spine J. 2014; 14(7):e15-21.
33. Amit A, Larsen BT, Buadu LD, Dunn J, Crawford R,
Jonathan D, et al. Denosumab chemotherapy for
recurrent giant-cell tumor of bone: a case report of
neoadjuvant use enabling complete surgical resection.
Case Rep Oncol Med. 2013; 2013(4):496351.
34. Boyce BF, Xing L. Biology of RANK, RANKL, and
osteoprotegrin. Arthritis Res Ther. 2007; 9(Suppl
1):S1.
35. Yasko AW. Interferon therapy for vascular tumors of
bone. Curr Opin Orthop. 2001; 12(6):514-8.
36. Miller G, Bettelli G, Fabbri N, Capanna R. Curettage of
giant cell tumor of bone. Introduction—material and
methods. Chir Organi Mov. 1990; 75(Suppl 1):203.
37. Chakarun CJ, Forrester DM, Gottsegen CJ, Patel DB,
White EA, Matcuk GR Jr. Giant cell tumor of bone:
review, mimics, and new developments in treatment.
Radiographics. 2013; 33(1):197-211.
38. Tse LF, Wong KC, Kumta SM, Huang L, Chow TC,
Griffith JF. Bisphosphonates reduce local recurrence
in extremity giant cell tumor of bone: a case–control
study. Bone. 2008; 42(1):68-73.
39. Huang L, Xu J, Wood DJ, Zheng MH. Gene expression
of osteoprotegerin ligand, osteoprotegerin, and
receptor activator of NF-kappaB in giant cell tumour
of bone: possible involvement in tumour cell-induced
osteoclast-like cell formation. Am J Pathol. 2000;
156(3):761-7.
40. Yang SP, Kim TW, Boland PJ, Farooki A. Retrospective
review of atypical femoral fracture in metastatic
bone disease patients receiving Denosumab therapy.
Oncologist. 2017; 22(4):438-44.