Current Treatment Options in Oncology DOI 10.1007/s11864-014-0289-1
Sarcoma (SH Okuno, Section Editor)
Giant Cell Tumor of Bone: Current Treatment Options Keith M. Skubitz, MD Address Department of Medicine, University of Minnesota Medical School, and the Masonic Cancer Center, Box 286University Hospital, Minneapolis, MN, USA Email: [email protected]
* Springer Science+Business Media New York 2014
Keywords Giant cell tumor I GCTB I Bone I Denosumab I Bisphosphonate I Surgery I Radiation therapy Chemotherapy I Paracrine signaling I RANK I RANKL I Monoclonal antibody I Osteoclast
I
Opinion statement Giant cell tumor of bone (GCTB) comprises up to 20 % of benign bone tumors in the US. GCTB are typically locally aggressive, but metastasize to the lung in ~5 % of cases. Malignant transformation occurs in a small percentage of cases, usually following radiation therapy. Historically, GCTB have been treated primarily with surgery. When the morbidity of surgery would be excessive, radiation therapy may achieve local control. In most cases the primary driver of the malignant cell appears to be a mutation in H3F3A leading to a substitution of Gly34 to either Trp or Leu in Histone H3.3. This change presumably alters the methylation of the protein, and thus, its effect on gene expression. The malignant stromal cells of GCTB secrete RANKL, which recruits osteoclast precursors to the tumor and stimulates their differentiation to osteoclasts. The elucidation of the biology of GCTB led to trials of the anti-RANKL monoclonal antibody denosumab in this disease, with a clear demonstration of beneficial clinical effect. Surgery remains the primary treatment of localized GCTB. When surgery is not possible or would be associated with excessive morbidity, denosumab is a good treatment option. The optimal length of treatment and schedule of denosumab is unknown, but recurrences after apparent complete responses have been observed after stopping denosumab, and long-term follow-up of denosumab treatment may reveal unrecognized effects. The role of denosumab in the preoperative or adjuvant setting will require clinical trials. In some cases local radiation therapy may be useful, although long term effects should be considered.
Introduction Giant cell tumor of bone (GCTB), also known as osteoclastoma, seems to have been first described by Cooper and Travers in 1818 [1], and more formally by Bloodgood in 1912 [2]. GCTB comprises up to 20 % of benign bone tumors in the US. GCTB typically occurs at the ends of long bones and is locally aggressive, osteolytic, and often associated with pain, but metastases occur in only about 5 % of cases [3–6, 7•, 8–12]. Both benign
and malignant GCTB are recognized. Transformation to a high–grade sarcoma occurs rarely spontaneously, and with higher frequency after radiation therapy. The tumor is composed of both malignant stromal tumor cells, as well as osteoclasts and osteoclast precursor cells recruited by RANKL secreted by the tumor cells (Fig. 1). Mutations in histone H3.3 are the most likely driver mutation in this disease. The malignant stromal cells
Sarcoma (SH Okuno, Section Editor) Fig. 1. Top, low power view of GCTB showing multiple giant cells interspersed among malignant stromal cells and mononuclear osteoclast precursors. Bottom, higher power view showing multinucleate osteoclast (giant) cells. The author holds the copyright to these images.
of GCTB secrete RANKL, which recruits osteoclasts to the tumor, forming the rationale for treatment with denosumab, a monoclonal antibody to RANKL. Changes in the malignant stromal cells following treatment with denosumab suggests a paracrine loop between the malignant cells and the osteoclasts. For primary local-
ized disease, surgery is the standard therapy. Strong clinical evidence supports the use of denosumab in advanced or metastatic disease. Osteoclast like giant cells can be present in many other conditions, including reactive conditions and other benign and malignant tumors [13], and only GCTB is considered here.
Epidemiology GCTB most commonly occurs in the epiphyses of long bones, but may occur in other bones, and on rare occasions may be multi-centric. GCTB usually occurs in skeletally mature patients between 20 and 40 years old, comprising up to 20 % of benign bone tumors in the US [9, 10, 12]. The rate of GCTB is slightly higher in women than men (1.5 to 1 ratio) [14], and may be higher in China than the US [7•]. Familial clustering of GCTB and Paget’s disease has been reported [15, 16]. In most cases the primary driver of the malignant cell appears to be a mutation in H3F3A leading to a substitution of Gly34 to either Trp or Leu in Histone H3.3 [17••].
Pathogenesis Bone undergoes constant remodeling by osteoclasts that dissolve bone, and osteoblasts that form new bone. The osteoclasts develop from circulating
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osteoclast progenitor cells, first identified by the pioneering work of Walker [18, 19]. This work provided the first demonstration of the existence of stem cells in blood for nonhematopoietic tissue, and also paved the way for a better understanding of the biology of GCTB. There is cross-talk between osteoblasts and osteoclasts during normal bone physiology, with osteoblasts producing receptor activator of nuclear factor kappa B ligand (RANKL) (Fig. 2). Osteoclasts and their progenitors are dependent on RANKL and in its absence undergo apoptosis. During normal bone remodeling, osteoclasts in the cutting cone move through removing old bone, and are closely followed by osteoblasts laying down new bone, suggesting signaling from the osteoclast to the osteoblast as well. GCTB express genes expressed by osteoclasts, but also high levels of RANKL, that is produced by the stromal tumor cells, which have characteristics of osteoblasts [20–25]. These observations led to the hypothesis that elimination of osteoclasts by removal of RANKL could both eliminate osteoclasts in the tumor, and also unknown factors produced by the osteoclast that might have trophic effects on the stromal tumor cells (Fig. 2). Consistent with this hypothesis, in vitro growth of isolated GCTB stromal cells results in rapid loss of RANKL expression, suggesting that RANKL expression is at least partly dependent on factors produced by other cells [23]. Since a monoclonal antibody to RANKL was developed for use in osteoporosis and cancer metastatic to bones, a drug was available to test this hypothesis [11]. Clinical trials of denosumab in GCTB found that denosumab treatment resulted in a marked reduction in giant cells, as expected, but also led to replacement of the spindle shaped dense stroma with a less cellular stroma with new osteoid formation, providing further support for this pathophysiology [26]. The transforming event in GCTB appears to be a mutation in H3F3A; genomic analysis has found mutations in H3F3A in 49 of 53 cases of GCTB [17••]. All mutations involved glycine 54, with 48 encoding Gly34Trp and 1 encoding Gly34Leu alterations. In the same study, mutations in H3F3A or H3F3B, that reside on different chromosomes but encode identical histone H3.3 proteins, were found in chondroblastoma. In the chondroblastomas, that like GCTB typically arise in the epiphysis, histone H3.3 mutations were found in 73 of 77 cases. All 73 mutations involved lysine 36, with 68 in H3F3B and 5 in H3F3A. In GCTB, these histone H3.3 mutations were found exclusively in the stromal cell population, and not in the osteoclasts or osteoclast precursors [17••]. In contrast, histone H3.3 mutations were only found in 2 of 103 osteosarcomas (1 in HF3A and 1 in H3F3B), and 1 of 75 conventional chondrosarcomas. H3F3A mutations are also commonly found in pediatric brain tumors, but rarely in other cancers [17••]. The association of each tumor type with a specific histone H3.3 mutation is not understood, but it is possible that specific histone H3.3 mutations could result in a growth advantage for specific cell lineages [17••].
Presentation GCTB patients typically present with pain at the site of tumor, typically at the end of a long bone. Tumors are usually radiolucent without sclerotic mar-
Sarcoma (SH Okuno, Section Editor) Fig. 2. Panel A, the GCTB stromal cells produce RANKL that recruits monocytic osteoclast precursors from blood to the tumor, and stimulates differentiation into multinucleate osteoclast (“giant”) cells. Panel B, during bone remodeling osteoclasts move through bone, followed closely by osteoblasts forming new bone. This suggests there may an interaction between osteoclasts and osteoblasts, possibly in which osteoclasts produce a factor or factors that have a trophic effect on osteoblasts. Panel C, it is possible that osteoclasts produce a factor or factors that have a trophic effect on the malignant stromal cells of GCTB. Removing RANKL with denosumab would eliminate the osteoclasts, and concomitantly any factors produced by the osteoclasts. Elimination of osteoclast products could have an effect on the malignant GCTB stromal cells. The author holds the copyright to these images.
gins. Pathologic fractures are common, and axial tumors may present with neurologic symptoms. Up to 5 % of patients present with metastatic disease, usually in the lung.
Diagnosis GCTB can often be suspected based on imaging with plain films, CT, or MRI, but diagnosis requires a biopsy. In many cases, definitive surgery can be performed at the time of the biopsy. Although the vast majority of GCTB have benign histologic features, a small percentage present as a malignant GCTB with a more aggressive cytologic appearance. Because osteoclast like giant cells can be present in many other conditions, including reactive conditions and other benign and malignant tumors [13], evaluation should be performed by a pathologist ex-
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perienced in this field to exclude other diagnoses such as giant cell rich osteosarcoma, brown tumor of hyperparathyroidism, etc. Staging requires chest imaging with either a noncontrast chest CT or x-ray.
Prognosis En block excision of the primary tumor has a recurrence rate of G20 % whereas intralesional curettage has been reported to have much higher recurrence rates. Metastatic disease does not usually respond well to chemotherapy and may cause death, although in many cases repeated surgical excision may be beneficial [27].
Treatment Depending on the extent of disease, the primary treatment of GCTB is surgery. When surgery is not possible or would be associated with unacceptable toxicity, treatment with denosumab or radiation therapy may be useful.
Surgical management of localized disease For localized primary disease, surgery is standard treatment. En block excision of the primary tumor has a recurrence rate of G20 % whereas intralesional curettage has been reported to result in recurrence rates up to 40 %–50 % in some series [8, 28]. In addition to intralesional curettage, the cavity can be treated with various agents, such as phenol or cryotherapy [3, 29–32] to try to decrease recurrence. The heat generated by polymerization of methyl methacrylate cement may have a local antitumor effect as well [6, 28, 33]. The risk of recurrence after primary surgery correlates with the surgical treatment, and to a lesser extent with the Campanacci staging system [8], where stage I tumors do not involve the bone cortex, stage II tumors impinge on but do not penetrate the cortex, and stage III tumors extend to soft tissue. Embolization may also be useful in some cases [34, 35].
Surgical management of metastatic disease Metastatic disease in GCTB is uncommon and usually involves the lung. Many of these patients can achieve long term remission or cure by resection of lung metastases, depending on the number of lesions and rate of growth.
Adjunctive therapies Pharmacologic Denosumab A phase II study of denosumab, a fully human monoclonal antibody to RANKL, demonstrated a tumor response in 30/35 patients with GCTB [26]. Treatment resulted in the near complete elimination of giant cells in posttreatment specimens relative to baseline, and post-treatment samples showed
Sarcoma (SH Okuno, Section Editor) a replacement of the spindle-shaped dense stroma with a less cellular stroma with new osteoid formation lined by RANKL-expressing cells [26]. The changes in the immature state of the neoplastic stromal cells associated with elimination of osteoclasts, provided confirmation for the hypothesis that the neoplastic cells receive growth/differentiation signals from the osteoclasts. In addition, clinical benefit as manifest by reduced pain and increased function were observed [26]. Formal analysis by histology, of samples from patients in the initial study demonstrated both loss of giant cells, but also in many cases a decrease in proliferative, densely cellular tumor stromal cells, and replacement with nonproliferative, differentiated densely new woven bone [26, 36•]. These striking results lead to a larger multinational phase II trial. Since RECIST criteria are of limited use in bone lesions, lack of progression, and loss of giant cells determined by histology were measures of efficacy in the first trial of denosumab in GCTB [26], whereas EORTC and inverse Choi criteria were also used in the second trial. An interim analysis of the second phase II trial found 163/169 patients with “surgically unsalvageable” GCTB had no disease progression at a median follow-up of 13 months [37••]. In a second cohort of patients with surgically salvageable disease in whom surgery was felt to be associated with severe morbidity, seventy-four out of one-hundred patients had no surgery and 16/26 who had surgery had a less morbid procedure than initially planned at a median follow-up of 9.2 months [37••]. This first interim analysis found a response rate of ~25 % by modified RECIST, and ~75 % by EORTC or inverse Choi criteria [37••]. In addition to objective measures of tumor response, clinically relevant pain reduction was reported by ~30 % of patients during the first week of treatment, and by ~50 % of patients at each study visit from months 2–30 [38•]. Serious adverse events were reported in 9 % of patients in this trial, and denosumab was discontinued in 5 % of patients in this trial because of toxicity. Adverse events were as expected from larger trials of denosumab in metastatic cancer [39, 40, 41•, 42]. Serious adverse events leading to stopping treatment included osteonecrosis of the jaw (ONJ) (1 %), hypocalcemia (none serious) (5 %), hypophosphatemia (3 %), serious infection (2 %), and new primary malignancy (1 %); the most common grade 3–4 adverse events included hypophosphatemia (3 %), anemia, back pain, and pain in the extremities, each occurring in 1 % of patients [37••]. Denosumab is a good option for patients with unresectable disease or in patients in whom surgery would be a very morbid procedure. However, in these cases tumor control may require lifelong denosumab, and there is limited experience with long term treatment. The optimal schedule if long term treatment is needed remains to be defined. In addition, patients should not become pregnant while on denosumab. Data at present do not currently suggest an increased risk of malignant transformation. Use of denosumab in young patients whose growth plates have not yet closed could result in changes similar to osteopetrosis. One case report of a 10-year-old girl with metastatic GCTB who responded well to denosumab, noted the development of dense metaphyseal bands on x-ray and generalized increased bone mineral density, raising concern about long term effects in prepubertal children, although her growth velocity remained
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normal for her age and gender [43]. An earlier report described osteopetrosis induced by treatment of a peripubertal child with bisphosphonates [44].
Bisphosphonates Bisphosphonates have also been used in GCTB, although reports have been limited to retrospective and uncontrolled series, and case reports [45, 46, 47•, 48]. One case report clearly demonstrated a response of a GCTB in the cervical spine to i.v. zoledronic acid over a 3-year period [47•]. A randomized phase II trial is ongoing to determine if adjuvant zoledronic acid improves the 2 year recurrence rate of “high risk” GCTB compared with standard care (NCT00889590). Questions remain about the optimal approach to unresectable or metastatic GCTB. Normal bone is constantly undergoing resorption and replacement, a process regulated by coupling of osteoclast and osteoblast activity. Suppression of bone resorption is followed by an inhibition of bone production within a few months by an unknown mechanism, presumably because of signaling between osteoclasts and osteoblasts [49]. Both the production of unknown factors by the osteoclasts and release of growth factors from the bone matrix, which is known to contain osteoblast growth factors, may be involved on osteoclast signaling to the osteoblast [49]. The Wnt/beta-catenin signaling pathway plays an important role in regulating bone formation [49– 51]. For example, the Wnt pathway regulates osteoblast differentiation, maturation, and number, and this signaling is inhibited by factors, including sclerostin and Dickkopf-1 (DKK1), that bind Wnt co-receptors [49–51]. Sclerostin is primarily expressed in osteocytes and expression is decreased by mechanical loading or parathyroid hormone, which may promote bone formation [49, 52, 53]. Although DKK1 is widely expressed in embryonic mice, it is expressed primarily in osteoblasts and maturing osteocytes in adults [49, 54], although it is expressed in some pathologic states such as myeloma and rheumatoid arthritis [49]. Denosumab treatment of postmenopausal osteoporosis resulted in increased serum sclerostin and decreased DKK1 [49]. Chronic bisphosphonate treatment has also been reported to increase serum sclerostin [49, 55]. Thus, the decrease in bone formation after some months of bisphosphonate treatment could in part be because of an increase in sclerostin [49]. In contrast to sclerostin, denosumab treatment resulted in a decrease in serum DKK1 whereas bisphosphonate treatment did not [49]. Bisphosphonates act mostly on mature osteoclasts as they degrade matrix, and leads to an increase in osteoclast precursors [49, 56], whereas denosumab treatment also blocks recruitment and differentiation of osteoclast precursors. It has been hypothesized that with denosumab, the increase in sclerostin would tend to decrease bone formation, whereas the decrease in DKK1 may limit this effect on bone formation [49]. An important toxicity of bisphosphonates is osteonecrosis of the jaw (ONJ), and this is also a toxicity of denosumab [40, 42, 57•]. The risk of ONJ is time dependent. In larger trials of denosumab in other malignancies the risk of ONJ was about ~1 % at 1 year and ~4 % after 3 years [57•]. ONJ was much more frequent with bisphosphonates before routine preventive approaches were used. Finally, given the reported lym-
Sarcoma (SH Okuno, Section Editor) phoid defects in mice that lack RANKL [58], other long term toxicities of denosumab may exist. Thus, even though the results of trials of denosumab in GCTB are impressive, consideration should be given to a randomized trial of denosumab, which is easier to give and has no recognized nephrotoxicity, vs a bisphosphonate, which is currently cheaper, in select GCTB cases. A randomized trial of denosumab compared with bisphosphonates that allows cross-over would answer the question of which approach would be more effective for GCTB not amenable to surgical treatment.
Cytotoxic chemotherapy A number of reports have described the use of cytotoxic chemotherapy and interferon in GCTB [59–63]. Given the typically benign nature of GCTB and the toxicities of these agents, this approach has been replaced by the use of denosumab in all but rare cases.
Radiation therapy There is limited data on the use of radiation therapy in GCTB, but in select cases it may be useful. Although malignant transformation of GCTB can occur with reported rates of 1.5 %–15 %, most are associated with previous radiation therapy [64]. In 1 series, 26/407 GCTBs were malignant (19 after initial treatment and 7 at diagnosis); of the 19 malignant GCTB in this series, 18 (~95 %) had received radiation therapy 4–39 years earlier [64]. Rates of malignant transformation after radiation therapy of between 7 %–33 % have been reported [64], and the observed rates could be influenced by length of follow-up. More recent reports using more modern techniques confirm that radiation induced sarcoma remains an issue [65]. In a study of 25 patients between 1956–2000, 2 developed osteosarcoma at 11–12 years, with a median follow-up of 8.8 years (0.67–34 years), and a disease free survival rate of 58 % [65]. A retrospective review of 26 tumors in 24 patients between 1972– 1996 reported local control in 20/26 cases and 1 radiation induced sarcoma 22 years after treatment [66]. In a series of patients deemed poor candidates for surgery and treated with megavoltage radiotherapy between 1985–2007 with a median follow-up time of 58 months, local control was achieved in 65/77 and 12/77 progressed in the radiated field; 2 developed malignant transformation [67]. In another recent study of 34 patients treated with megavoltage therapy (13 after gross total surgical resection) between 1973–2008, and a median follow-up of 16.8 years, local control was reported in ~85 % at 5 years, with 3 developing lung metastases and 1 malignant transformation [68]. It is possible that IMRT may offer an advantage in some cases; 1 report observed local control in 4/5 cases at a median follow-up of 46 months [69]. In addition to the effect of follow-up time, many reports of malignant transformation involve relatively small numbers of patients. For instance, if a study of 34 patients with “adequate” follow-up had an observed event rate of 1/34 or 3 %, the 95 % confidence interval (CI) of the rate would be ~G1 %–9 %, and with an event rate of 2/34 or 5 % the 95 % CI would be ~G1 %–14 %. In a study of 77 patients with an event rate of 2/77 or
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2.5 %, the 95 % CI would be ~G1 %–6 %, and with an event rate of 3/77 or 4 %, the 95 % CI would be ~G1 %–8 %.
Diet and lifestyle There is no evidence to support any role for diet and lifestyle changes in the treatment of GCTB.
Compliance with Ethics Guidelines Conflict of Interest Keith Skubitz has been a consultant for Amgen, Ariad/Merck, Novartis, Onyxx, Johnson & Johnson, Pfizer/ Schering-Plough, Systems Medicine, and Seattle Genetics; owns publicly traded stock in Johnson & Johnson; has received research funding from Amgen, Novartis, GSK, Ariad/Merck, Celgene, Cell Therapeutics, Systems Medicine, Infinity, Schering-Plough, Bayer, Pfizer, and Daiichi; and provided expert testimony on the role of bisphosphonates in osteonecrosis of the jaw. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors other than reviews of other studies.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2.
3.
4.
5.
6.
Cooper A, Travers B. On exostosis. In: Surgical essays. London: Cox and Sons; 1818. p. 167–224. Bloodgood II JC. The conservative treatment of giantcell sarcoma, with the study of bone transplantation. Ann Surg. 1912;56:210–39. Balke M, Schremper L, Gebert C, Ahrens H, Streitbuerger A, Koehler G, et al. Giant cell tumor of bone: treatment and outcome of 214 cases. J Cancer Res Clin Oncol. 2008;134:969–78. Errani C, Ruggieri P, Asenzio MA, Toscano A, Colangeli S, Rimondi E, et al. Giant cell tumor of the extremity: a review of 349 cases from a single institution. Cancer Treat Res. 2010;36:1–7. Gupta R, Seethalakshmi V, Jambhekar NA, Prabhudesai S, Merchant N, Puri A, et al. Clinicopathologic profile of 470 giant cell tumors of bone from a cancer hospital in western India. Ann Diagn Pathol. 2008;12:239–48. Kivioja AH, Blomqvist C, Hietaniemi K, Trovik C, Walloe A, Bauer HC, et al. Cement is recommended in intralesional surgery of giant cell tumors: a Scandinavian sarcoma group study of 294 patients
followed for a median time of 5 years. Acta Orthop. 2008;79:86–93. 7.• Niu X, Zhang Q, Hao L, Ding Y, Li Y, Xu H, et al. Giant cell tumor of the extremity: retrospective analysis of 621 Chinese patients from one institution. J Bone Joint Surg Am. 2012;94:461–7. This retrospective study of 621 patients provides epidemiologic and outcome data on a large number of Chinese patients 8. Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;69:106–14. 9. Raskin KA, Schwab JH, Mankin HJ, Springfield DS, Hornicek FJ. Giant cell tumor of bone. J Am Acad Orthop Surg. 2013;21:118–26. 10. Szendroi M. Giant-cell tumor of bone. J Bone Joint Surg (Br). 2004;86:5–12. 11. Thomas DM, Skubitz KM. Giant cell tumor of bone. Curr Opin Oncol. 2009;21:338–44. 12. WHO. Pathology and genetics of tumors of soft tissue and bone. Lyon: IARC Press; 2002.
Sarcoma (SH Okuno, Section Editor) 13.
Skubitz KM, Manivel JC. Giant cell tumor of the uterus: case report and response to chemotherapy. BMC Cancer. 2007;7. 14. Zheng MH, Robbins P, Xu J, Huang L, Wood DJ, Papadimitriou JM. The histogenesis of giant cell tumor of bone: a model of interaction between neoplastic cells and osteoclasts. Histol Histopathol. 2001;16:297–307. 15. Jacobs TP, Michelsen J, Polay JS, D'Adamo AC, Canfield RE. Giant cell tumor in Paget's disease of bone: familial and geographic clustering. Cancer. 1979;44:742–7. 16. Rendina D, Mossetti G, Soscia E, Sirignano C, Insabato L, Viceconti R, et al. Giant cell tumor and Paget's disease of bone in one family: geographic clustering. Clin Orthop Relat Res. 2004;421:218–24. 17.•• Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, et al. Distinct h3f3a and h3f3b driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013;45:1479–82. This important paper identifies the likely driver mutations that result in GCTB and chondroblastoma. The transforming event in GCTB appears to be a mutation in H3F3A (found in 49 of 53 cases). In the same study, mutations in H3F3A or H3F3B, that reside on different chromosomes but encode identical histone H3.3 proteins, were found in chondroblastoma (histone H3.3 mutations were found in 73 of 77 cases, with 68 in H3F3B and 5 in H3F3A) 18. Walker DG. Congenital osteopetrosis in mice cured by parabiotic union with normal siblings. Endocrinology. 1972;91:916–20. 19. Walker DG. Control of bone resorption by hematopoietic tissue. The induction and reversal of congenital osteopetrosis in mice through use of bone marrow and splenic transplants. J Exp Med. 1975;142:651–63. 20. Atkins GJ, Haynes DR, Graves SE, Evdokiou A, Hay S, Bouralexis S, et al. Expression of osteoclast differentiation signals by stromal elements of giant cell tumors. J Bone Miner Res. 2000;15:640–9. 21. Goldring SR, Roelke MS, Petrison KK, Bhan AK. Human giant cell tumors of bone identification and characterization of cell types. J Clin Invest. 1987;79:483–91. 22. Huang L, Xu J, Wood DJ, Zheng MH. Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of nf-kappab in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation. Am J Pathol. 2000;156:761–7. 23. Morgan T, Atkins GJ, Trivett MK, Johnson SA, Kansara M, Schlicht SL, et al. Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kappab. Am J Pathol. 2005;167:117–28. 24. Roux S, Amazit L, Meduri G, Guiochon-Mantel A, Milgrom E, Mariette X. Rank (receptor activator of
nuclear factor kappa b) and rank ligand are expressed in giant cell tumors of bone. Am J Clin Pathol. 2002;117:210–6. 25. Skubitz KM, Cheng EY, Clohisy DR, Thompson RC, Skubitz AP. Gene expression in giant-cell tumors. J Lab Clin Med. 2004;144:193–200. 26. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumor of bone: an open-label, phase 2 study. Lancet Oncol. 2010;11:275–80. 27. Siebenrock KA, Unni KK, Rock MG. Giant-cell tumor of bone metastasizing to the lungs. A long-term follow-up. J Bone Joint Surg (Br). 1998;80:43–7. 28. Becker WT, Dohle J, Bernd L, Braun A, Cserhati M, Enderle A, et al. Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy. J Bone Joint Surg Am. 2008;90:1060–7. 29. Durr HR, Maier M, Jansson V, Baur A, Refior HJ. Phenol as an adjuvant for local control in the treatment of giant cell tumor of the bone. Eur J Surg Oncol. 1999;25:610–8. 30. Malawer MM, Bickels J, Meller I, Buch RG, Henshaw RM, Kollender Y. Cryosurgery in the treatment of giant cell tumor. A long-term follow-up study. Clin Orthop Relat Res. 1999;359:176–88. 31. Zhen W, Yaotian H, Songjian L, Ge L, Qingliang W. Giant-cell tumor of bone. The long-term results of treatment by curettage and bone graft. J Bone Joint Surg (Br). 2004;86:212–6. 32. Zwolak P, Manivel JC, Jasinski P, Kirstein MN, Dudek AZ, Fisher J, et al. Cytotoxic effect of zoledronic acidloaded bone cement on giant cell tumor, multiple myeloma, and renal cell carcinoma cell lines. J Bone Joint Surg Am. 2010;92:162–8. 33. Klenke FM, Wenger DE, Inwards CY, Rose PS, Sim FH. Recurrent giant cell tumor of long bones: analysis of surgical management. Clin Orthop Relat Res. 2011;469:1181–7. 34. Hosalkar HS, Jones KJ, King JJ, Lackman RD. Serial arterial embolization for large sacral giant-cell tumors: mid- to long-term results. Spine. 2007;32:1107–15. 35. Lin PP, Guzel VB, Moura MF, Wallace S, Benjamin RS, Weber KL, et al. Long-term follow-up of patients with giant cell tumor of the sacrum treated with selective arterial embolization. Cancer. 2002;95:1317– 25. 36.• 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;18:4415–24. This study describes pathologic changes in GCTB after treatment with denosumab 37.•• Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for
Giant Cell Tumor of Bone adults and skeletally mature adolescents with giant cell tumor of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901–8. This study provides data on the use of denosumab in a large number of patients with GCTB from a phase II trial. The data confirm the results of the earlier proof-of-concept trial, and document the efficacy of denosumab in GCTB 38.• Broto JM, Cleeland C, Glare P, Engellau J, Skubitz K, Blum R, 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; [In press]. This study describes the effect of denosumab treatment on pain in GCTB in a large number of patients from a phase II trial, documenting rapid and prolonged improvement in pain. 39. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castrationresistant prostate cancer: a randomized, double-blind study. Lancet. 2011;377:813–22. 40. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. 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. 2011;29:1125–32. 41.• Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomized, phase 3 trials. Eur J Cancer. 2012;48:3082–92. This analysis from 3 large randomized trials provides data on skeletal events and adverse events with denosumab compared with zoledronic acid in a large number of patients 42. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. 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. 2010;28:5132–9. 43. 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:e200–2. 44. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003;349:457–63. 45. Balke M, Campanacci L, Gebert C, Picci P, Gibbons M, Taylor R, et al. Bisphosphonate treatment of aggressive primary, recurrent and metastatic giant cell tumor of bone. BMC Cancer. 2010;10. 46. Chaudhary P, Khadim H, Gajra A, Damron T, Shah C. Bisphosphonate therapy is effective in the treatment of sacral giant cell tumor. Onkologie. 2011;34:702–4. 47.• Gille O, Oliveira Bde A, Guerin P, Lepreux S, Richez C, Vital JM. Regression of giant cell tumor of the
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cervical spine with bisphosphonate as single therapy. Spine. 2012;37:E396–9. This case report clearly demonstrates a response of GCTB to zoledronic acid over a 3-year period. This case report clearly demonstrates a response of GCTB to zoledronic acid over a 3-year period 48. 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;42:68–73. 49. Gatti D, Viapiana O, Fracassi E, Idolazzi L, Dartizio C, Povino MR, et al. Sclerostin and dkk1 in postmenopausal osteoporosis treated with denosumab. J Bone Miner Res. 2012;27:2259–63. 50. Baron R, Rawadi G. Targeting the wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43. 51. Ott SM. Sclerostin and wnt signaling—the pathway to bone strength. J Clin Endocrinol Metab. 2005;90:6741–3. 52. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology. 2005;146:4577–83. 53. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/ sclerostin. J Biol Chem. 2008;283:5866–75. 54. Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. Rank is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A. 2000;97:1566–71. 55. Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S. The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of dkk1. J Clin Endocrinol Metab. 2011;96:1555–9. 56. Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med. 2009;360:53–62. 57.• Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasisfree survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebocontrolled trial. Lancet. 2012;379:39–46. This large randomized trial of denosumab provides data on control of skeletal events and also adverse events 58. Kim N, Odgren PR, Kim DK, Marks Jr SC, Choi Y. Diverse roles of the tumor necrosis factor family member trance in skeletal physiology revealed by trance deficiency and partial rescue by a lymphocyteexpressed trance transgene. Proc Natl Acad Sci U S A. 2000;97:10905–10. 59. Dominkus M, Ruggieri P, Bertoni F, Briccoli A, Picci P, Rocca M, et al. Histologically verified lung metas-
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60.
61.
62.
63.
64.
tases in benign giant cell tumors—14 cases from a single institution. Int Orthop. 2006;30:499–504. Kaiser U, Neumann K, Havemann K. Generalised giant-cell tumor of bone: successful treatment of pulmonary metastases with interferon alpha, a case report. J Cancer Res Clin Oncol. 1993;119:301–3. Maloney WJ, Vaughan LM, Jones HH, Ross J, Nagel DA. Benign metastasizing giant-cell tumor of bone. Report of three cases and review of the literature. Clin Orthop Relat Res. 1989;243:208–15. Osaka S, Toriyama M, Taira K, Sano S, Saotome K. Analysis of giant cell tumor of bone with pulmonary metastases. Clin Orthop Relat Res. 1997;335:253–61. Stewart DJ, Belanger R, Benjamin RS. Prolonged disease-free survival following surgical debulking and high-dose cisplatin/doxorubicin in a patient with bulky metastases from giant cell tumor of bone refractory to "standard" chemotherapy. Am J Clin Oncol. 1995;18:144–8. Rock MG, Sim FH, Unni KK, Witrak GA, Frassica FJ, Schray MF, et al. Secondary malignant giant-cell tumor of bone. Clinicopathological assessment of
65.
66.
67.
68.
69.
nineteen patients. J Bone Joint Surg Am. 1986;68:1073–9. Caudell JJ, Ballo MT, Zagars GK, Lewis VO, Weber KL, Lin PP, et al. Radiotherapy in the management of giant cell tumor of bone. Int J Radiat Oncol Biol Phys. 2003;571:158–65. Feigenberg SJ, Marcus Jr RB, Zlotecki RA, Scarborough MT, Berrey BH, Enneking WF. Radiation therapy for giant cell tumors of bone. Clin Orthop Relat Res. 2003;411:207–16. Ruka W, Rutkowski P, Morysinski T, Nowecki Z, Zdzienicki M, Makula D, et al. The megavoltage radiation therapy in treatment of patients with advanced or difficult giant cell tumors of bone. Int J Radiat Oncol Biol Phys. 2010;78:494–8. Shi W, Indelicato DJ, Reith J, Smith KB, Morris CG, Scarborough MT, et al. Radiotherapy in the management of giant cell tumor of bone. Am J Clin Oncol. 2013;36:505–8. Roeder F, Timke C, Zwicker F, Thieke C, Bischof M, Debus J, et al. Intensity modulated radiotherapy (IMRT) in benign giant cell tumors—a single institution case series and a short review of the literature. Radiat Oncol. 2010;5:18.
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Giant Cell Tumor of Bone: Current Treatment Options Keith M. Skubitz, MD Address Department of Medicine, University of Minnesota Medical School, and the Masonic Cancer Center, Box 286University Hospital, Minneapolis, MN, USA Email: [email protected]
* Springer Science+Business Media New York 2014
Keywords Giant cell tumor I GCTB I Bone I Denosumab I Bisphosphonate I Surgery I Radiation therapy Chemotherapy I Paracrine signaling I RANK I RANKL I Monoclonal antibody I Osteoclast
I
Opinion statement Giant cell tumor of bone (GCTB) comprises up to 20 % of benign bone tumors in the US. GCTB are typically locally aggressive, but metastasize to the lung in ~5 % of cases. Malignant transformation occurs in a small percentage of cases, usually following radiation therapy. Historically, GCTB have been treated primarily with surgery. When the morbidity of surgery would be excessive, radiation therapy may achieve local control. In most cases the primary driver of the malignant cell appears to be a mutation in H3F3A leading to a substitution of Gly34 to either Trp or Leu in Histone H3.3. This change presumably alters the methylation of the protein, and thus, its effect on gene expression. The malignant stromal cells of GCTB secrete RANKL, which recruits osteoclast precursors to the tumor and stimulates their differentiation to osteoclasts. The elucidation of the biology of GCTB led to trials of the anti-RANKL monoclonal antibody denosumab in this disease, with a clear demonstration of beneficial clinical effect. Surgery remains the primary treatment of localized GCTB. When surgery is not possible or would be associated with excessive morbidity, denosumab is a good treatment option. The optimal length of treatment and schedule of denosumab is unknown, but recurrences after apparent complete responses have been observed after stopping denosumab, and long-term follow-up of denosumab treatment may reveal unrecognized effects. The role of denosumab in the preoperative or adjuvant setting will require clinical trials. In some cases local radiation therapy may be useful, although long term effects should be considered.
Introduction Giant cell tumor of bone (GCTB), also known as osteoclastoma, seems to have been first described by Cooper and Travers in 1818 [1], and more formally by Bloodgood in 1912 [2]. GCTB comprises up to 20 % of benign bone tumors in the US. GCTB typically occurs at the ends of long bones and is locally aggressive, osteolytic, and often associated with pain, but metastases occur in only about 5 % of cases [3–6, 7•, 8–12]. Both benign
and malignant GCTB are recognized. Transformation to a high–grade sarcoma occurs rarely spontaneously, and with higher frequency after radiation therapy. The tumor is composed of both malignant stromal tumor cells, as well as osteoclasts and osteoclast precursor cells recruited by RANKL secreted by the tumor cells (Fig. 1). Mutations in histone H3.3 are the most likely driver mutation in this disease. The malignant stromal cells
Sarcoma (SH Okuno, Section Editor) Fig. 1. Top, low power view of GCTB showing multiple giant cells interspersed among malignant stromal cells and mononuclear osteoclast precursors. Bottom, higher power view showing multinucleate osteoclast (giant) cells. The author holds the copyright to these images.
of GCTB secrete RANKL, which recruits osteoclasts to the tumor, forming the rationale for treatment with denosumab, a monoclonal antibody to RANKL. Changes in the malignant stromal cells following treatment with denosumab suggests a paracrine loop between the malignant cells and the osteoclasts. For primary local-
ized disease, surgery is the standard therapy. Strong clinical evidence supports the use of denosumab in advanced or metastatic disease. Osteoclast like giant cells can be present in many other conditions, including reactive conditions and other benign and malignant tumors [13], and only GCTB is considered here.
Epidemiology GCTB most commonly occurs in the epiphyses of long bones, but may occur in other bones, and on rare occasions may be multi-centric. GCTB usually occurs in skeletally mature patients between 20 and 40 years old, comprising up to 20 % of benign bone tumors in the US [9, 10, 12]. The rate of GCTB is slightly higher in women than men (1.5 to 1 ratio) [14], and may be higher in China than the US [7•]. Familial clustering of GCTB and Paget’s disease has been reported [15, 16]. In most cases the primary driver of the malignant cell appears to be a mutation in H3F3A leading to a substitution of Gly34 to either Trp or Leu in Histone H3.3 [17••].
Pathogenesis Bone undergoes constant remodeling by osteoclasts that dissolve bone, and osteoblasts that form new bone. The osteoclasts develop from circulating
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osteoclast progenitor cells, first identified by the pioneering work of Walker [18, 19]. This work provided the first demonstration of the existence of stem cells in blood for nonhematopoietic tissue, and also paved the way for a better understanding of the biology of GCTB. There is cross-talk between osteoblasts and osteoclasts during normal bone physiology, with osteoblasts producing receptor activator of nuclear factor kappa B ligand (RANKL) (Fig. 2). Osteoclasts and their progenitors are dependent on RANKL and in its absence undergo apoptosis. During normal bone remodeling, osteoclasts in the cutting cone move through removing old bone, and are closely followed by osteoblasts laying down new bone, suggesting signaling from the osteoclast to the osteoblast as well. GCTB express genes expressed by osteoclasts, but also high levels of RANKL, that is produced by the stromal tumor cells, which have characteristics of osteoblasts [20–25]. These observations led to the hypothesis that elimination of osteoclasts by removal of RANKL could both eliminate osteoclasts in the tumor, and also unknown factors produced by the osteoclast that might have trophic effects on the stromal tumor cells (Fig. 2). Consistent with this hypothesis, in vitro growth of isolated GCTB stromal cells results in rapid loss of RANKL expression, suggesting that RANKL expression is at least partly dependent on factors produced by other cells [23]. Since a monoclonal antibody to RANKL was developed for use in osteoporosis and cancer metastatic to bones, a drug was available to test this hypothesis [11]. Clinical trials of denosumab in GCTB found that denosumab treatment resulted in a marked reduction in giant cells, as expected, but also led to replacement of the spindle shaped dense stroma with a less cellular stroma with new osteoid formation, providing further support for this pathophysiology [26]. The transforming event in GCTB appears to be a mutation in H3F3A; genomic analysis has found mutations in H3F3A in 49 of 53 cases of GCTB [17••]. All mutations involved glycine 54, with 48 encoding Gly34Trp and 1 encoding Gly34Leu alterations. In the same study, mutations in H3F3A or H3F3B, that reside on different chromosomes but encode identical histone H3.3 proteins, were found in chondroblastoma. In the chondroblastomas, that like GCTB typically arise in the epiphysis, histone H3.3 mutations were found in 73 of 77 cases. All 73 mutations involved lysine 36, with 68 in H3F3B and 5 in H3F3A. In GCTB, these histone H3.3 mutations were found exclusively in the stromal cell population, and not in the osteoclasts or osteoclast precursors [17••]. In contrast, histone H3.3 mutations were only found in 2 of 103 osteosarcomas (1 in HF3A and 1 in H3F3B), and 1 of 75 conventional chondrosarcomas. H3F3A mutations are also commonly found in pediatric brain tumors, but rarely in other cancers [17••]. The association of each tumor type with a specific histone H3.3 mutation is not understood, but it is possible that specific histone H3.3 mutations could result in a growth advantage for specific cell lineages [17••].
Presentation GCTB patients typically present with pain at the site of tumor, typically at the end of a long bone. Tumors are usually radiolucent without sclerotic mar-
Sarcoma (SH Okuno, Section Editor) Fig. 2. Panel A, the GCTB stromal cells produce RANKL that recruits monocytic osteoclast precursors from blood to the tumor, and stimulates differentiation into multinucleate osteoclast (“giant”) cells. Panel B, during bone remodeling osteoclasts move through bone, followed closely by osteoblasts forming new bone. This suggests there may an interaction between osteoclasts and osteoblasts, possibly in which osteoclasts produce a factor or factors that have a trophic effect on osteoblasts. Panel C, it is possible that osteoclasts produce a factor or factors that have a trophic effect on the malignant stromal cells of GCTB. Removing RANKL with denosumab would eliminate the osteoclasts, and concomitantly any factors produced by the osteoclasts. Elimination of osteoclast products could have an effect on the malignant GCTB stromal cells. The author holds the copyright to these images.
gins. Pathologic fractures are common, and axial tumors may present with neurologic symptoms. Up to 5 % of patients present with metastatic disease, usually in the lung.
Diagnosis GCTB can often be suspected based on imaging with plain films, CT, or MRI, but diagnosis requires a biopsy. In many cases, definitive surgery can be performed at the time of the biopsy. Although the vast majority of GCTB have benign histologic features, a small percentage present as a malignant GCTB with a more aggressive cytologic appearance. Because osteoclast like giant cells can be present in many other conditions, including reactive conditions and other benign and malignant tumors [13], evaluation should be performed by a pathologist ex-
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perienced in this field to exclude other diagnoses such as giant cell rich osteosarcoma, brown tumor of hyperparathyroidism, etc. Staging requires chest imaging with either a noncontrast chest CT or x-ray.
Prognosis En block excision of the primary tumor has a recurrence rate of G20 % whereas intralesional curettage has been reported to have much higher recurrence rates. Metastatic disease does not usually respond well to chemotherapy and may cause death, although in many cases repeated surgical excision may be beneficial [27].
Treatment Depending on the extent of disease, the primary treatment of GCTB is surgery. When surgery is not possible or would be associated with unacceptable toxicity, treatment with denosumab or radiation therapy may be useful.
Surgical management of localized disease For localized primary disease, surgery is standard treatment. En block excision of the primary tumor has a recurrence rate of G20 % whereas intralesional curettage has been reported to result in recurrence rates up to 40 %–50 % in some series [8, 28]. In addition to intralesional curettage, the cavity can be treated with various agents, such as phenol or cryotherapy [3, 29–32] to try to decrease recurrence. The heat generated by polymerization of methyl methacrylate cement may have a local antitumor effect as well [6, 28, 33]. The risk of recurrence after primary surgery correlates with the surgical treatment, and to a lesser extent with the Campanacci staging system [8], where stage I tumors do not involve the bone cortex, stage II tumors impinge on but do not penetrate the cortex, and stage III tumors extend to soft tissue. Embolization may also be useful in some cases [34, 35].
Surgical management of metastatic disease Metastatic disease in GCTB is uncommon and usually involves the lung. Many of these patients can achieve long term remission or cure by resection of lung metastases, depending on the number of lesions and rate of growth.
Adjunctive therapies Pharmacologic Denosumab A phase II study of denosumab, a fully human monoclonal antibody to RANKL, demonstrated a tumor response in 30/35 patients with GCTB [26]. Treatment resulted in the near complete elimination of giant cells in posttreatment specimens relative to baseline, and post-treatment samples showed
Sarcoma (SH Okuno, Section Editor) a replacement of the spindle-shaped dense stroma with a less cellular stroma with new osteoid formation lined by RANKL-expressing cells [26]. The changes in the immature state of the neoplastic stromal cells associated with elimination of osteoclasts, provided confirmation for the hypothesis that the neoplastic cells receive growth/differentiation signals from the osteoclasts. In addition, clinical benefit as manifest by reduced pain and increased function were observed [26]. Formal analysis by histology, of samples from patients in the initial study demonstrated both loss of giant cells, but also in many cases a decrease in proliferative, densely cellular tumor stromal cells, and replacement with nonproliferative, differentiated densely new woven bone [26, 36•]. These striking results lead to a larger multinational phase II trial. Since RECIST criteria are of limited use in bone lesions, lack of progression, and loss of giant cells determined by histology were measures of efficacy in the first trial of denosumab in GCTB [26], whereas EORTC and inverse Choi criteria were also used in the second trial. An interim analysis of the second phase II trial found 163/169 patients with “surgically unsalvageable” GCTB had no disease progression at a median follow-up of 13 months [37••]. In a second cohort of patients with surgically salvageable disease in whom surgery was felt to be associated with severe morbidity, seventy-four out of one-hundred patients had no surgery and 16/26 who had surgery had a less morbid procedure than initially planned at a median follow-up of 9.2 months [37••]. This first interim analysis found a response rate of ~25 % by modified RECIST, and ~75 % by EORTC or inverse Choi criteria [37••]. In addition to objective measures of tumor response, clinically relevant pain reduction was reported by ~30 % of patients during the first week of treatment, and by ~50 % of patients at each study visit from months 2–30 [38•]. Serious adverse events were reported in 9 % of patients in this trial, and denosumab was discontinued in 5 % of patients in this trial because of toxicity. Adverse events were as expected from larger trials of denosumab in metastatic cancer [39, 40, 41•, 42]. Serious adverse events leading to stopping treatment included osteonecrosis of the jaw (ONJ) (1 %), hypocalcemia (none serious) (5 %), hypophosphatemia (3 %), serious infection (2 %), and new primary malignancy (1 %); the most common grade 3–4 adverse events included hypophosphatemia (3 %), anemia, back pain, and pain in the extremities, each occurring in 1 % of patients [37••]. Denosumab is a good option for patients with unresectable disease or in patients in whom surgery would be a very morbid procedure. However, in these cases tumor control may require lifelong denosumab, and there is limited experience with long term treatment. The optimal schedule if long term treatment is needed remains to be defined. In addition, patients should not become pregnant while on denosumab. Data at present do not currently suggest an increased risk of malignant transformation. Use of denosumab in young patients whose growth plates have not yet closed could result in changes similar to osteopetrosis. One case report of a 10-year-old girl with metastatic GCTB who responded well to denosumab, noted the development of dense metaphyseal bands on x-ray and generalized increased bone mineral density, raising concern about long term effects in prepubertal children, although her growth velocity remained
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normal for her age and gender [43]. An earlier report described osteopetrosis induced by treatment of a peripubertal child with bisphosphonates [44].
Bisphosphonates Bisphosphonates have also been used in GCTB, although reports have been limited to retrospective and uncontrolled series, and case reports [45, 46, 47•, 48]. One case report clearly demonstrated a response of a GCTB in the cervical spine to i.v. zoledronic acid over a 3-year period [47•]. A randomized phase II trial is ongoing to determine if adjuvant zoledronic acid improves the 2 year recurrence rate of “high risk” GCTB compared with standard care (NCT00889590). Questions remain about the optimal approach to unresectable or metastatic GCTB. Normal bone is constantly undergoing resorption and replacement, a process regulated by coupling of osteoclast and osteoblast activity. Suppression of bone resorption is followed by an inhibition of bone production within a few months by an unknown mechanism, presumably because of signaling between osteoclasts and osteoblasts [49]. Both the production of unknown factors by the osteoclasts and release of growth factors from the bone matrix, which is known to contain osteoblast growth factors, may be involved on osteoclast signaling to the osteoblast [49]. The Wnt/beta-catenin signaling pathway plays an important role in regulating bone formation [49– 51]. For example, the Wnt pathway regulates osteoblast differentiation, maturation, and number, and this signaling is inhibited by factors, including sclerostin and Dickkopf-1 (DKK1), that bind Wnt co-receptors [49–51]. Sclerostin is primarily expressed in osteocytes and expression is decreased by mechanical loading or parathyroid hormone, which may promote bone formation [49, 52, 53]. Although DKK1 is widely expressed in embryonic mice, it is expressed primarily in osteoblasts and maturing osteocytes in adults [49, 54], although it is expressed in some pathologic states such as myeloma and rheumatoid arthritis [49]. Denosumab treatment of postmenopausal osteoporosis resulted in increased serum sclerostin and decreased DKK1 [49]. Chronic bisphosphonate treatment has also been reported to increase serum sclerostin [49, 55]. Thus, the decrease in bone formation after some months of bisphosphonate treatment could in part be because of an increase in sclerostin [49]. In contrast to sclerostin, denosumab treatment resulted in a decrease in serum DKK1 whereas bisphosphonate treatment did not [49]. Bisphosphonates act mostly on mature osteoclasts as they degrade matrix, and leads to an increase in osteoclast precursors [49, 56], whereas denosumab treatment also blocks recruitment and differentiation of osteoclast precursors. It has been hypothesized that with denosumab, the increase in sclerostin would tend to decrease bone formation, whereas the decrease in DKK1 may limit this effect on bone formation [49]. An important toxicity of bisphosphonates is osteonecrosis of the jaw (ONJ), and this is also a toxicity of denosumab [40, 42, 57•]. The risk of ONJ is time dependent. In larger trials of denosumab in other malignancies the risk of ONJ was about ~1 % at 1 year and ~4 % after 3 years [57•]. ONJ was much more frequent with bisphosphonates before routine preventive approaches were used. Finally, given the reported lym-
Sarcoma (SH Okuno, Section Editor) phoid defects in mice that lack RANKL [58], other long term toxicities of denosumab may exist. Thus, even though the results of trials of denosumab in GCTB are impressive, consideration should be given to a randomized trial of denosumab, which is easier to give and has no recognized nephrotoxicity, vs a bisphosphonate, which is currently cheaper, in select GCTB cases. A randomized trial of denosumab compared with bisphosphonates that allows cross-over would answer the question of which approach would be more effective for GCTB not amenable to surgical treatment.
Cytotoxic chemotherapy A number of reports have described the use of cytotoxic chemotherapy and interferon in GCTB [59–63]. Given the typically benign nature of GCTB and the toxicities of these agents, this approach has been replaced by the use of denosumab in all but rare cases.
Radiation therapy There is limited data on the use of radiation therapy in GCTB, but in select cases it may be useful. Although malignant transformation of GCTB can occur with reported rates of 1.5 %–15 %, most are associated with previous radiation therapy [64]. In 1 series, 26/407 GCTBs were malignant (19 after initial treatment and 7 at diagnosis); of the 19 malignant GCTB in this series, 18 (~95 %) had received radiation therapy 4–39 years earlier [64]. Rates of malignant transformation after radiation therapy of between 7 %–33 % have been reported [64], and the observed rates could be influenced by length of follow-up. More recent reports using more modern techniques confirm that radiation induced sarcoma remains an issue [65]. In a study of 25 patients between 1956–2000, 2 developed osteosarcoma at 11–12 years, with a median follow-up of 8.8 years (0.67–34 years), and a disease free survival rate of 58 % [65]. A retrospective review of 26 tumors in 24 patients between 1972– 1996 reported local control in 20/26 cases and 1 radiation induced sarcoma 22 years after treatment [66]. In a series of patients deemed poor candidates for surgery and treated with megavoltage radiotherapy between 1985–2007 with a median follow-up time of 58 months, local control was achieved in 65/77 and 12/77 progressed in the radiated field; 2 developed malignant transformation [67]. In another recent study of 34 patients treated with megavoltage therapy (13 after gross total surgical resection) between 1973–2008, and a median follow-up of 16.8 years, local control was reported in ~85 % at 5 years, with 3 developing lung metastases and 1 malignant transformation [68]. It is possible that IMRT may offer an advantage in some cases; 1 report observed local control in 4/5 cases at a median follow-up of 46 months [69]. In addition to the effect of follow-up time, many reports of malignant transformation involve relatively small numbers of patients. For instance, if a study of 34 patients with “adequate” follow-up had an observed event rate of 1/34 or 3 %, the 95 % confidence interval (CI) of the rate would be ~G1 %–9 %, and with an event rate of 2/34 or 5 % the 95 % CI would be ~G1 %–14 %. In a study of 77 patients with an event rate of 2/77 or
Giant Cell Tumor of Bone
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2.5 %, the 95 % CI would be ~G1 %–6 %, and with an event rate of 3/77 or 4 %, the 95 % CI would be ~G1 %–8 %.
Diet and lifestyle There is no evidence to support any role for diet and lifestyle changes in the treatment of GCTB.
Compliance with Ethics Guidelines Conflict of Interest Keith Skubitz has been a consultant for Amgen, Ariad/Merck, Novartis, Onyxx, Johnson & Johnson, Pfizer/ Schering-Plough, Systems Medicine, and Seattle Genetics; owns publicly traded stock in Johnson & Johnson; has received research funding from Amgen, Novartis, GSK, Ariad/Merck, Celgene, Cell Therapeutics, Systems Medicine, Infinity, Schering-Plough, Bayer, Pfizer, and Daiichi; and provided expert testimony on the role of bisphosphonates in osteonecrosis of the jaw. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors other than reviews of other studies.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2.
3.
4.
5.
6.
Cooper A, Travers B. On exostosis. In: Surgical essays. London: Cox and Sons; 1818. p. 167–224. Bloodgood II JC. The conservative treatment of giantcell sarcoma, with the study of bone transplantation. Ann Surg. 1912;56:210–39. Balke M, Schremper L, Gebert C, Ahrens H, Streitbuerger A, Koehler G, et al. Giant cell tumor of bone: treatment and outcome of 214 cases. J Cancer Res Clin Oncol. 2008;134:969–78. Errani C, Ruggieri P, Asenzio MA, Toscano A, Colangeli S, Rimondi E, et al. Giant cell tumor of the extremity: a review of 349 cases from a single institution. Cancer Treat Res. 2010;36:1–7. Gupta R, Seethalakshmi V, Jambhekar NA, Prabhudesai S, Merchant N, Puri A, et al. Clinicopathologic profile of 470 giant cell tumors of bone from a cancer hospital in western India. Ann Diagn Pathol. 2008;12:239–48. Kivioja AH, Blomqvist C, Hietaniemi K, Trovik C, Walloe A, Bauer HC, et al. Cement is recommended in intralesional surgery of giant cell tumors: a Scandinavian sarcoma group study of 294 patients
followed for a median time of 5 years. Acta Orthop. 2008;79:86–93. 7.• Niu X, Zhang Q, Hao L, Ding Y, Li Y, Xu H, et al. Giant cell tumor of the extremity: retrospective analysis of 621 Chinese patients from one institution. J Bone Joint Surg Am. 2012;94:461–7. This retrospective study of 621 patients provides epidemiologic and outcome data on a large number of Chinese patients 8. Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;69:106–14. 9. Raskin KA, Schwab JH, Mankin HJ, Springfield DS, Hornicek FJ. Giant cell tumor of bone. J Am Acad Orthop Surg. 2013;21:118–26. 10. Szendroi M. Giant-cell tumor of bone. J Bone Joint Surg (Br). 2004;86:5–12. 11. Thomas DM, Skubitz KM. Giant cell tumor of bone. Curr Opin Oncol. 2009;21:338–44. 12. WHO. Pathology and genetics of tumors of soft tissue and bone. Lyon: IARC Press; 2002.
Sarcoma (SH Okuno, Section Editor) 13.
Skubitz KM, Manivel JC. Giant cell tumor of the uterus: case report and response to chemotherapy. BMC Cancer. 2007;7. 14. Zheng MH, Robbins P, Xu J, Huang L, Wood DJ, Papadimitriou JM. The histogenesis of giant cell tumor of bone: a model of interaction between neoplastic cells and osteoclasts. Histol Histopathol. 2001;16:297–307. 15. Jacobs TP, Michelsen J, Polay JS, D'Adamo AC, Canfield RE. Giant cell tumor in Paget's disease of bone: familial and geographic clustering. Cancer. 1979;44:742–7. 16. Rendina D, Mossetti G, Soscia E, Sirignano C, Insabato L, Viceconti R, et al. Giant cell tumor and Paget's disease of bone in one family: geographic clustering. Clin Orthop Relat Res. 2004;421:218–24. 17.•• Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, et al. Distinct h3f3a and h3f3b driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013;45:1479–82. This important paper identifies the likely driver mutations that result in GCTB and chondroblastoma. The transforming event in GCTB appears to be a mutation in H3F3A (found in 49 of 53 cases). In the same study, mutations in H3F3A or H3F3B, that reside on different chromosomes but encode identical histone H3.3 proteins, were found in chondroblastoma (histone H3.3 mutations were found in 73 of 77 cases, with 68 in H3F3B and 5 in H3F3A) 18. Walker DG. Congenital osteopetrosis in mice cured by parabiotic union with normal siblings. Endocrinology. 1972;91:916–20. 19. Walker DG. Control of bone resorption by hematopoietic tissue. The induction and reversal of congenital osteopetrosis in mice through use of bone marrow and splenic transplants. J Exp Med. 1975;142:651–63. 20. Atkins GJ, Haynes DR, Graves SE, Evdokiou A, Hay S, Bouralexis S, et al. Expression of osteoclast differentiation signals by stromal elements of giant cell tumors. J Bone Miner Res. 2000;15:640–9. 21. Goldring SR, Roelke MS, Petrison KK, Bhan AK. Human giant cell tumors of bone identification and characterization of cell types. J Clin Invest. 1987;79:483–91. 22. Huang L, Xu J, Wood DJ, Zheng MH. Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of nf-kappab in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation. Am J Pathol. 2000;156:761–7. 23. Morgan T, Atkins GJ, Trivett MK, Johnson SA, Kansara M, Schlicht SL, et al. Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kappab. Am J Pathol. 2005;167:117–28. 24. Roux S, Amazit L, Meduri G, Guiochon-Mantel A, Milgrom E, Mariette X. Rank (receptor activator of
nuclear factor kappa b) and rank ligand are expressed in giant cell tumors of bone. Am J Clin Pathol. 2002;117:210–6. 25. Skubitz KM, Cheng EY, Clohisy DR, Thompson RC, Skubitz AP. Gene expression in giant-cell tumors. J Lab Clin Med. 2004;144:193–200. 26. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumor of bone: an open-label, phase 2 study. Lancet Oncol. 2010;11:275–80. 27. Siebenrock KA, Unni KK, Rock MG. Giant-cell tumor of bone metastasizing to the lungs. A long-term follow-up. J Bone Joint Surg (Br). 1998;80:43–7. 28. Becker WT, Dohle J, Bernd L, Braun A, Cserhati M, Enderle A, et al. Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy. J Bone Joint Surg Am. 2008;90:1060–7. 29. Durr HR, Maier M, Jansson V, Baur A, Refior HJ. Phenol as an adjuvant for local control in the treatment of giant cell tumor of the bone. Eur J Surg Oncol. 1999;25:610–8. 30. Malawer MM, Bickels J, Meller I, Buch RG, Henshaw RM, Kollender Y. Cryosurgery in the treatment of giant cell tumor. A long-term follow-up study. Clin Orthop Relat Res. 1999;359:176–88. 31. Zhen W, Yaotian H, Songjian L, Ge L, Qingliang W. Giant-cell tumor of bone. The long-term results of treatment by curettage and bone graft. J Bone Joint Surg (Br). 2004;86:212–6. 32. Zwolak P, Manivel JC, Jasinski P, Kirstein MN, Dudek AZ, Fisher J, et al. Cytotoxic effect of zoledronic acidloaded bone cement on giant cell tumor, multiple myeloma, and renal cell carcinoma cell lines. J Bone Joint Surg Am. 2010;92:162–8. 33. Klenke FM, Wenger DE, Inwards CY, Rose PS, Sim FH. Recurrent giant cell tumor of long bones: analysis of surgical management. Clin Orthop Relat Res. 2011;469:1181–7. 34. Hosalkar HS, Jones KJ, King JJ, Lackman RD. Serial arterial embolization for large sacral giant-cell tumors: mid- to long-term results. Spine. 2007;32:1107–15. 35. Lin PP, Guzel VB, Moura MF, Wallace S, Benjamin RS, Weber KL, et al. Long-term follow-up of patients with giant cell tumor of the sacrum treated with selective arterial embolization. Cancer. 2002;95:1317– 25. 36.• 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;18:4415–24. This study describes pathologic changes in GCTB after treatment with denosumab 37.•• Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for
Giant Cell Tumor of Bone adults and skeletally mature adolescents with giant cell tumor of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901–8. This study provides data on the use of denosumab in a large number of patients with GCTB from a phase II trial. The data confirm the results of the earlier proof-of-concept trial, and document the efficacy of denosumab in GCTB 38.• Broto JM, Cleeland C, Glare P, Engellau J, Skubitz K, Blum R, 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; [In press]. This study describes the effect of denosumab treatment on pain in GCTB in a large number of patients from a phase II trial, documenting rapid and prolonged improvement in pain. 39. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castrationresistant prostate cancer: a randomized, double-blind study. Lancet. 2011;377:813–22. 40. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. 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. 2011;29:1125–32. 41.• Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomized, phase 3 trials. Eur J Cancer. 2012;48:3082–92. This analysis from 3 large randomized trials provides data on skeletal events and adverse events with denosumab compared with zoledronic acid in a large number of patients 42. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. 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. 2010;28:5132–9. 43. 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:e200–2. 44. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003;349:457–63. 45. Balke M, Campanacci L, Gebert C, Picci P, Gibbons M, Taylor R, et al. Bisphosphonate treatment of aggressive primary, recurrent and metastatic giant cell tumor of bone. BMC Cancer. 2010;10. 46. Chaudhary P, Khadim H, Gajra A, Damron T, Shah C. Bisphosphonate therapy is effective in the treatment of sacral giant cell tumor. Onkologie. 2011;34:702–4. 47.• Gille O, Oliveira Bde A, Guerin P, Lepreux S, Richez C, Vital JM. Regression of giant cell tumor of the
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cervical spine with bisphosphonate as single therapy. Spine. 2012;37:E396–9. This case report clearly demonstrates a response of GCTB to zoledronic acid over a 3-year period. This case report clearly demonstrates a response of GCTB to zoledronic acid over a 3-year period 48. 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;42:68–73. 49. Gatti D, Viapiana O, Fracassi E, Idolazzi L, Dartizio C, Povino MR, et al. Sclerostin and dkk1 in postmenopausal osteoporosis treated with denosumab. J Bone Miner Res. 2012;27:2259–63. 50. Baron R, Rawadi G. Targeting the wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43. 51. Ott SM. Sclerostin and wnt signaling—the pathway to bone strength. J Clin Endocrinol Metab. 2005;90:6741–3. 52. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology. 2005;146:4577–83. 53. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/ sclerostin. J Biol Chem. 2008;283:5866–75. 54. Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. Rank is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A. 2000;97:1566–71. 55. Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S. The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of dkk1. J Clin Endocrinol Metab. 2011;96:1555–9. 56. Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med. 2009;360:53–62. 57.• Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasisfree survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebocontrolled trial. Lancet. 2012;379:39–46. This large randomized trial of denosumab provides data on control of skeletal events and also adverse events 58. Kim N, Odgren PR, Kim DK, Marks Jr SC, Choi Y. Diverse roles of the tumor necrosis factor family member trance in skeletal physiology revealed by trance deficiency and partial rescue by a lymphocyteexpressed trance transgene. Proc Natl Acad Sci U S A. 2000;97:10905–10. 59. Dominkus M, Ruggieri P, Bertoni F, Briccoli A, Picci P, Rocca M, et al. Histologically verified lung metas-
Sarcoma (SH Okuno, Section Editor)
60.
61.
62.
63.
64.
tases in benign giant cell tumors—14 cases from a single institution. Int Orthop. 2006;30:499–504. Kaiser U, Neumann K, Havemann K. Generalised giant-cell tumor of bone: successful treatment of pulmonary metastases with interferon alpha, a case report. J Cancer Res Clin Oncol. 1993;119:301–3. Maloney WJ, Vaughan LM, Jones HH, Ross J, Nagel DA. Benign metastasizing giant-cell tumor of bone. Report of three cases and review of the literature. Clin Orthop Relat Res. 1989;243:208–15. Osaka S, Toriyama M, Taira K, Sano S, Saotome K. Analysis of giant cell tumor of bone with pulmonary metastases. Clin Orthop Relat Res. 1997;335:253–61. Stewart DJ, Belanger R, Benjamin RS. Prolonged disease-free survival following surgical debulking and high-dose cisplatin/doxorubicin in a patient with bulky metastases from giant cell tumor of bone refractory to "standard" chemotherapy. Am J Clin Oncol. 1995;18:144–8. Rock MG, Sim FH, Unni KK, Witrak GA, Frassica FJ, Schray MF, et al. Secondary malignant giant-cell tumor of bone. Clinicopathological assessment of
65.
66.
67.
68.
69.
nineteen patients. J Bone Joint Surg Am. 1986;68:1073–9. Caudell JJ, Ballo MT, Zagars GK, Lewis VO, Weber KL, Lin PP, et al. Radiotherapy in the management of giant cell tumor of bone. Int J Radiat Oncol Biol Phys. 2003;571:158–65. Feigenberg SJ, Marcus Jr RB, Zlotecki RA, Scarborough MT, Berrey BH, Enneking WF. Radiation therapy for giant cell tumors of bone. Clin Orthop Relat Res. 2003;411:207–16. Ruka W, Rutkowski P, Morysinski T, Nowecki Z, Zdzienicki M, Makula D, et al. The megavoltage radiation therapy in treatment of patients with advanced or difficult giant cell tumors of bone. Int J Radiat Oncol Biol Phys. 2010;78:494–8. Shi W, Indelicato DJ, Reith J, Smith KB, Morris CG, Scarborough MT, et al. Radiotherapy in the management of giant cell tumor of bone. Am J Clin Oncol. 2013;36:505–8. Roeder F, Timke C, Zwicker F, Thieke C, Bischof M, Debus J, et al. Intensity modulated radiotherapy (IMRT) in benign giant cell tumors—a single institution case series and a short review of the literature. Radiat Oncol. 2010;5:18.
