Systemic Therapy in Patients with Resectable and Unresectable Cases of Giant Cell Tumor: A Systematic Review

Abstract

Background: Giant cell tumor (GCT) is a common benign tumor of the appendicular and axial skeleton that represents 5% of all primary bone tumors. In recent years, the combination of conventional aggressive curettage with targeted adjuvant anti-osteoclastic agents including bisphosphonates and denosumab have led to lower recurrence rates in patients with GCT in a small number of retrospective case series. Furthermore, efficacy of the same anti-osteoclastic agents has been shown in cases of unresectable GCT of bone, leading to decreased rates of tumor progression and stabilization of disease. This review assesses whether the current literature weakly, moderately, or strongly supports a targeted systemic treatment as the standard of care in patients with GCT. Methods: We conducted a current search of the MEDLINE database for literature pertaining to systemic GCT treatment. Our inclusion criteria were as follows: 1) studies that reported on a series of patients with resectable or unresectable cases of GCT; 2) a subset of patients must have been treated with systemic bisphosphonate or RANK-L inhibitor therapy; 3) each series had a minimum of 10 patients with histopathologically confirmed GCT; 4) each series stated their follow-up period. Results: Overall 6 studies, reporting on a total of 487 patients, were selected for inclusion in this review. For analysis, these 6 retrospective studies were subdivided into series where all GCT patients had resectable tumors (n = 4) and series where patients had a mix of resectable and unresectable tumors (n = 2). The overall recurrence rate of GCT in patients with resectable tumors treated with adjuvant systemic bisphosphonates was 6.7% compared to 48.4% in patients not treated with adjuvant systemic bisphosphonates (p < 0.0001). In patients with both resectable and unresectable primary aggressive, recurrent, or metastatic GCT disease, systemic bisphosphonate and denosumab demonstrated good efficacy with decreased rates of disease progression and recurrence. In general the side effects of bisphosphonates were mild while denosumab had a more severe side effect profile. Conclusions: Systemic treatment with bisphosphonates or denosumab in cases of GCT is promising, but there is a lack of high-level evidence with sufficient follow-up supporting their use. We believe the current literature provides moderate support to recommend a short course of adjuvant peri-operative systemic bisphosphonate treatment for patients with resectable primary GCT and moderate support to recommend adjuvant peri-operative (resectable) and non-operative (unresectable) use of denosumab in cases of primary aggressive, recurrent, or metastatic GCT. With either systemic treatment, patients should be well counseled on all potential side effects in addition to alternative treatment, which includes the option of no systemic treatment.

Share and Cite:

Kaiser, P. , Compton, J. , Caldwell, J. , Hickernell, T. and Lee, F. (2014) Systemic Therapy in Patients with Resectable and Unresectable Cases of Giant Cell Tumor: A Systematic Review. Journal of Cancer Therapy, 5, 339-353. doi: 10.4236/jct.2014.54041.

1. Introduction

Giant cell tumor (GCT) is a benign tumor of the appendicular or axial skeleton that accounts for approximately 5% of all primary bone tumors, typically occurring in patients aged 20 through 40 years with a slight female predominance [1] [2] . Histologically GCT is comprised of 3 cell types: 1) multinucleated osteoclast-like giant cells; 2) fibroblast-like spindle-shaped (GCT stromal) cells, which represent the neoplastic component of GCT and overproduce ligand for receptor activator of NF-kappa B (RANKL); and 3) mononuclear cells that comprise osteoclast precursor cells [3] [4] -[6] .

While GCT of bone is a benign neoplasm, it has a propensity for aggressive local invasion and destruction with an overall recurrence rate as high as 75% when managed by simple curettage alone [1] [2] [7] . The most common locations of GCT include epiphyseal ends of the distal femur, proximal tibia, and distal radius often adjacent to the joint surface; however, GCT can also be located in the sacrum or mobile spine [1] [3] [4] . Metastases are rare in GCT, occurring in only 2% - 3% of all patients, and are most commonly found in the lung. On radiographs, GCT demonstrates an osteolytic bone destruction pattern, which may be confined to a small area within the bone (stage I), expand the cortex (stage II), or breach the cortex and extend into the soft tissues (stage III) [4] .

Aggressive surgical resection and reconstruction is associated with a low incidence of tumor recurrence: however, joint mobility and functionality may be significantly reduced and long term outcomes of en bloc resection are generally poor [2] . Advancement from simple curettage to aggressive curettage involves the use of a high-speed burr at the tumor-bone interface and chemical agents such as alcohols and thermogenic bone cement within the tumor cavity may enhance marginal excision [2] . High-speed burr use and bone cement filling are both independent factors leading to lower recurrence rates in the surgical treatment of GCT [2] [8] [9] . The current standard of care for resectable GCT, utilizing high-speed burr curettage of the tumor cavity and thermogenic bone cement packing, has led to overall recurrence rates in the literature from 10% to 50%, with some of the variation attributable to tumor location, tumor aggression, and surgical technique [4] [10] . In a study published in 1982 in the American edition of Journal of Bone and Joint Surgery, Sung et al. followed 111 patients with histologically proven GCT and found an overall recurrence of 26.1% [4] [10] . Additionally Sung et al. demonstrated that recurrence rates in patients who underwent curettage and bone-grafting were much higher than patients treated with a more aggressive and morbid resection and fusion, at 41.2% and 7.1% respectively [10] . Recurrence is particularly important and prognostic in certain skeletal areas such as the mobile spine where GCT recurrence may worsen neurologic deficits, increase surgical complexity, or even preclude further surgical treatment [1] . Overall, GCT recurrence in the appendicular or axial skeleton is associated with increased morbidity and poorer outcomes.

The proposed pathophysiological origin of GCT is attributed to partially differentiated osteoblasts that comprise the GCT stromal cells, which over-express RANKL (Ligand for Receptor Activator of NF-Kappa B), cytokines, and chemokines [4] [11] [12] . This over expression of RANKL, a differentiation factor for osteoclasts, drives the formation of multinucleated osteoclast-like giant cells which are responsible for the continued lytic destruction of bone [13] [14] . In recent in vitro studies, bisphosphonates have demonstrated promising results and illustrated the clinical potential for these drugs to reduce recurrence rates and control progression of GCT by inducing apoptosis in the proliferating GCT stromal cells [1] [3] [15] . Denosumab, a RANK Ligand inhibitor antibody, is another promising targeted therapy in the systemic treatment of GCT. Denosumab directly affects the proliferation and lytic destruction of the multi-nucleated giant cells by interfering with the RANK-L/RANK pathway but whether it has efficacy against the neoplastic stromal cell component of GCT is still under investigation.

Historically, these systemic anti-osteoclastic agents have been used with good efficacy in the treatment of other osteolytic bone disease such as multiple myeloma and carcinomas that have spread to bone [16] [17] . In recent years, a small number of non-randomized studies have demonstrated that the use of adjuvant anti-osteoclastic agents, in combination with conventional treatment (aggressive curettage, and physical and chemical agents within the bone cavity) may lead to lower recurrence rates while maximally preserving native joint mobility and functionality in patients with GCT (see Figure 1) [2] [18] . Additionally, in cases of unresectable and recurrent GCT of bone, systemic medical treatment may be initiated before or even without accompanying surgical intervention, possibly leading to decreased rates of tumor progression and stabilization of disease [17] .

Currently there is no clear consensus regarding the use of systemic bisphosphonates or RANK-L inhibitor treatment in patients with resectable and unresectable cases of GCT. With only a handful of retrospective studies reporting the long-term results of systemic treatment in patients with GCT, it remains challenging to establish an evidence-based systemic treatment protocol for this primary bone tumor. The purpose of this study was to conduct a systematic review of the literature to evaluate the efficacy and safety profiles of systemic treatments by looking at recurrence rates, patient reported outcomes, and complications. Our review examined the existing literature on patients undergoing systemic bisphosphonate or RANK-L inhibitor in cases of both resectable and unresectable GCT to address the following questions:

1) What are the current systemic therapy regimens reported in the literature?

2) Are there differences in recurrence rates or outcomes in patients receiving systemic treatment for GCT with respect to controls?

3) Is there a role for systemic therapies in unresectable cases of GCT?

4) What are the reported side effects and complications of systemic therapy?

5) Does the current literature weakly, moderately, or strongly support a systemic treatment as the standard of care in patients with GCT?

2. Materials and Methods

We searched the MEDLINE database using the PUBMED electronic search engine from January 1950 through

Figure 1. Surgical excision of giant cell tumors.

January 2014 using the search terms and their respective combinations listed in Table 1.

Only articles that were published in the English language and could be retrieved were included. Studies reporting clinical outcomes in patients with GCT, of which at least one subgroup received systemic bisphophonate or RANK-L inhibitor treatment, were eligible for inclusion in our review. Our inclusion criteria were as follows: 1) studies that reported on a series of patients with resectable or unresectable cases of GCT 2) a subset of patients must have been treated with systemic bisphosphonate or RANK-L inhibitor therapy 3) each series had a minimum of 10 patients with histopathologically confirmed GCT 4) each series stated their follow-up period.

The titles and abstracts of all articles (n = 998) obtained during our MEDLINE database search were reviewed to determine their relevancy to our search inquiry. To minimize reviewer bias, effort was made to conceal all institutional and author information. In total 24 articles published in English were selected for further full text review. Articles that did not report patient specific data or outcomes following systemic treatment for GCT were excluded. In some cases, multiple studies from the same institution reported on the same group of patients undergoing systemic treatment for GCT. In these instances, only the most recent and largest series of patients were included in this review.

Eight studies met our inclusion criteria. Two studies were excluded since they utilized a redundant patient population. This yielded a total of 6 retrospective studies reporting on the outcomes of patients with cases of resectable or unresectable GCT receiving systemic bisphosphonate or RANK-L inhibitor treatment (Figure 2). For analysis, these 6 retrospective studies were subdivided into series where all GCT patients had resectable tumors (n = 4) and series where patients had a mix of resectable and unresectable tumors (n = 2).

Background information was obtained for each article in our review, which included year of publication, authorship, journal of publication, and level of evidence. Retrieved clinical data from each study included patient demographics, GCT location and grade, whether the GCT was resectable or unresectable, type and regimen of

Table 1. Search Terms entered into MEDLINE database from Time Period January 1950 to January 2014.

Figure 2. Flow diagram for systematic review literature search.

systemic treatment, surgical technique in resectable cases, additional treatments, patient clinical outcomes, follow-up radiographic, recurrence rates, and complications related to systemic therapy.

3. Results

Overall six papers, reporting on a total of 487 patients, were selected for inclusion in this review. Each study reported clinical outcomes of patients who had histologically confirmed GCT, in which at least one subgroup of patients were treated with systemic bisphosphonate or RANK-L inhibitor therapy. Systemic therapy in resectable cases was pre-operative, post-operative, or a combination of both (peri-operative). Each series explicitly stated their inclusion and exclusion criteria as well their favored regimen of medical therapy. All studies selected were retrospective reviews (level 4) and, when suitable, homogeneous outcomes across studies were aggregated for meta-analysis. For our analysis, studies were subdivided into series where all patients had resectable GCT (n = 4) or series where patients had either resectable or unresectable GCT (n = 2).

4. Resectable GCT Studies

4.1. Demographics and Adjuvant Systemic Treatment Type

A total of 4 studies, comprising 180 patients (range: 16 to 102 per study) were included in this portion of the review and systemic treatment in these 4 studies was comprised of varying adjuvant (pre-operative, post-operative, and peri-operative) regimens of bisphophonates [1] -[4] . Two studies [1] [4] (n = 146) used a regimen of preoperative and post-operative bisphosphonates (peri-operative) while the remaining two studies [2] [3] (n = 34) used a course of pre-operative or post-operative bisphosphonate treatment only. The bisphosphonate route of administration was either oral or parenteral (intravenous). The demographic data presented in Table 2 shows the mean weighted patient age was 34.1 years (range: 11 to 78 years). In 3 of 4 studies [1] [2] [4] (n = 162) that reported patient gender, 56.8% (92 of 162) of patients were female and 43.2% (70 of 162) were male. In total, 89 (49.4%) GCT patients were treated with adjuvant systemic bisphosphonate therapy and 91 (50.6%) GCT patients did not receive any systemic bisphosphonate therapy. Of note, these 4 studies are largely based on patient populations in Asia (China and Hong Kong) which have an inherently higher incidence of GCT, accounting for approximately 20% of all primary bone tumors [4] .

4.2. Giant Cell Tumor Characteristics

The heterogeneous characteristics of resectable GCT were reported in 3 of 4 studies (n = 162) and are outlined in Table 3. Overall 78.4% (127 of 162) of patients had primary cases of GCT and 21.6% (35 of 162) of patients were being treated for a recurrence. GCT most commonly arose near the epiphyses of the distal femur, proximal tibia, or distal radius but a large series of patients (n = 102) had confirmed GCT in the mobile spine. Campanacci or Enneking tumor classification was reported in 3 of 4 studies (n = 162).

Table 2. Resectable GCT studies—patient demographics and adjuvant systemic treatment type.

NR = not reported, *Weighted average.

Table 3. Resectable GCT studies—tumor characteristics.

4.3. Adjuvant Systemic Regimens, Surgical Technique, and Additional Treatments

Adjuvant systemic treatment regimens used in each series are reported in Table 4. Two studies [1] [4] (n = 146) used a regimen of pre-operative and post-operative bisphosphonates (peri-operative) while the remaining two studies [2] [3] (n = 36) employed a course of pre-operative or post-operative bisphosphonate treatment only. The bisphosphonate route of administration was either oral or parenteral (intravenous) or combined (oral and intravenous) and duration of systemic treatment varied between 6 weeks and 2 years. Curettage was performed in all cases of resectable appendicular skeletal tumors while spondylectomy or subtotal resection was performed in cases of GCT in the mobile spine. Additional neoadjuvant, adjuvant, and intra-operative treatments included high-speed burr use for aggressive curettage, exothermic bone cement filling of the tumor cavity, selective artery embolization, local treatment with cisplatin or methotrexate, and radiotherapy.

4.4. Adjuvant Systemic Treatment Follow-Up and Recurrence Rates

In total, 89 (49.4%) GCT patients were treated with adjuvant systemic bisphosphonate therapy and 91 (50.6%) GCT patients did not receive adjuvant systemic bisphosphonate therapy. The duration of follow-up and overall recurrence rates are reported in Table 5. The mean follow-up duration reported for 162 patients was 49.9 months (range 2 - 192 months) and the length of follow-up for the systemic treatment group and no systemic treatment group were similar. Only 4 of 180 patients (2.2%) were lost to follow-up. The overall recurrence rate of GCT in patients with resectable tumors treated with adjuvant systemic bisphosphonates was 6.7% (6 of 89) compared to 48.4% (44 of 91) in patients not treated with adjuvant systemic bisphosphonates. The difference in recurrence rate of GCT was statistically significant using Chi-Squared analysis (p < 0.0001). Recurrence rates in the adjuvant systemic treatment groups ranged from 0% to 10.8%, while recurrence rates in groups who did not receive adjuvant systemic treatment ranged from 30% to 66.7% during their respective follow-up periods. Independently, three studies with control groups were powered to show a statistically significant benefit in recurrence free survival (RFS) in patients who were treated with bisphosphonates compared to patients who were not treated with bisphosphonate therapy [1] [3] [4] . In cases of GCT recurrence, the time from surgery to recurrence was typically 14 to 21 months.

4.5. Patient Outcomes and Radiographic Follow-Up

Additional patient outcomes and follow-up measures along with reported radiographic data is summarized in Table 6. In general, functional outcomes in GCT patients improved following surgery but the reported results were heterogeneous and did not allow for formal meta-analysis.

4.6. Side Effects of Adjuvant Systemic Treatment and Study Limitations

The side effects related to adjuvant systemic bisphosphonate treatment were reported in 3 of 4 series [1] [2] [4] (n = 77 of 162) and all 4 series (n = 180) reported study limitations, which are outlined in Table 7. Side effects related to systemic bisphosphonates were unanimously mild and included 2 patients (2.6%) who reported acid reflux and mild gastrointestinal distress from alendronate treatment. Monitoring of renal function reported by two studies [1] [4] of patients (n = 61) receiving bisphosphonates therapy was unremarkable. In general, reported limitations included short follow-up time, retrospective design of the studies, and small sample sizes with possibility of confounding variables.

Table 4. Resectable GCT studies—adjuvant systemic treatment regimen, surgical technique, and additional treatments.

Table 5. Resectable GCT studies—adjuvant systemic treatment follow-up and recurrence rates.

NR = not reported, NA = not applicable, *Weighted average.

Table 6. Resectable GCT studies—patient outcomes and radiographic follow-up.

5. Resectable and Unresectable GCT Studies

5.1. Demographics and Systemic Treatment Type

A total of 2 studies, comprising 307 patients (range: 25 to 282 per study) were included in this portion of the review and systemic treatment in these studies was comprised of varying regimens of peri-operative or post-operative bisphosphonates and the RANK-L inhibitor antibody, denosumab [18] [19] . The route of administration for bisphosphonates was either oral or parenteral (intravenous) while denosumab was administered subcutaneously. The demographic data presented in Table 8 show the mean weighted patient age was 33.7 years (range: 15 to 75 years) with a female predominance of 58.6% (180 of 307) compared to males who comprised 41.4% (127 of 307) of GCT patients. In these series, 100% (307 of 307) of GCT patients were assigned to systemic bisphosphonate or denosumab therapy and therefore comparison against a control group was not possible. In the trial by Chawla et al., patients were stratified into 3 cohorts: 1) patients with unresectable GCT, 2) patients with resectable GCT and planned surgery associated with severe morbidity, and 3) a small cohort of patients remaining from a previous denosumab study still with GCT burden [18] .

5.2. Giant Cell Tumor Characteristics

The heterogeneous characteristics of resectable and unresectable GCT were reported in both studies (n = 307) and are outlined in Table 9. Inherently, by study design, this group of patients had a greater propensity for recurrent and primary aggressive cases of GCT. Overall 38.4% (118 of 307) of patients had primary cases of GCT and 61.6% (189 of 307) of patients were being treated for a recurrence. In the study by Chawla et al., 68.8% (194 of 282) of patients were originally identified as having unresectable cases of GCT [18] . The location of GCT in these two series was heterogeneous, reported throughout the appendicular and axial skeleton along with cases that were multi-focal or metastatic often involving the lung. Enneking tumor staging was only reported by Balke et al. [19] .

5.3. Systemic Treatment Regimen, Surgical Technique, and Additional Treatments

Systemic regimens used in the two series are reported in Table 10. In the study by Balke et al. the bisphosphonate regimen varied considerably [19] . The route of administration was either oral or parenteral (intravenous) or combined (oral and intravenous) and duration of bisphosphonate treatment varied between 6 weeks and 5 years.

Table 7. Resectable GCT studies—side effects of adjuvant systemic treatment and study limitations.

Table 8. Resectable and unresectable GCT studies—patient demographics and systemic treatment type.

*Weighted average. One patient from the Cohort I in the denosumab group did not receive systemic treatment and was therefore excluded from subsequent analysis.

Table 9. Resectable and unresectable GCT studies—tumor characteristics.

*Primary tumors in this patient population were aggressive or metastatic, 3 of which were unresectable.

Table 10. Resectable and unresectable GCT studies—systemic treatment regimen, surgical technique, and additional treatments.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Xu, W., et al. (2012) Factors Affecting Prognosis of Patients with Giant Cell Tumors of the Mobile Spine: Retrospective Analysis of 102 Patients in a Single Center. Annals of Surgical Oncology, 20, 804-810. http://dx.doi.org/10.1245/s10434-012-2707-6
[2] Yu, X. (2012) Clinical Outcomes of Giant Cell Tumor of Bone Treated with Bone Cement Filling and Internal Fixation, and Oral Bisphosphonates. Oncology Letters, 5, 447-451.
[3] Cheng, Y.Y., et al. (2004) Bisphosphonates Induce Apoptosis of Stromal Tumor Cells in Giant Cell Tumor of Bone. Calcified Tissue International, 75, 1-7. http://dx.doi.org/10.1007/s00223-004-0120-2
[4] Tse, L.F., et al. (2008) Bisphosphonates Reduce Local Recurrence in Extremity Giant Cell Tumor of Bone: A Case-Control Study. Bone, 42, 68-73. http://dx.doi.org/10.1016/j.bone.2007.08.038
[5] Kim, Y., Nizami, S., Goto, H. and Lee, F.Y. (2012) Modern Interpretation of Giant Cell Tumor of Bone: Predominantly Osteoclastogenic Stromal Tumor. Clinics in Orthopedic Surgery, 4, 107-116.
http://dx.doi.org/10.4055/cios.2012.4.2.107
[6] Liao, T.S., et al. (2005) Recruitment of Osteoclast Precursors by Stromal Cell Derived Factor-1 (SDF-1) in Giant Cell Tumor of Bone. Journal of Orthopaedic Research, 23, 203-209.
http://dx.doi.org/10.1016/j.orthres.2004.06.018
[7] Klenke, F.M., Wenger, D.E., Inwards, C.Y., Rose, P.S. and Sim, F.H. (2010) Recurrent Giant Cell Tumor of Long Bones: Analysis of Surgical Management. Clinical Orthopaedics and Related Research, 469, 1181-1187. http://dx.doi.org/10.1007/s11999-010-1560-9
[8] Algawahmed, H., Turcotte, R., Farrokhyar, F. and Ghert, M. (2010) High-Speed Burring with and without the Use of Surgical Adjuvants in the Intralesional Management of Giant Cell Tumor of Bone: A Systematic Review and Meta-Analysis. Sarcoma, 2010, 1-5. http://dx.doi.org/10.1155/2010/586090
[9] Kafchitsas, K., Habermann, B., Proschek, D., Kurth, A. and Eberhardt, C. (2010) Functional Results after Giant Cell Tumor Operation near Knee Joint and the Cement Radiolucent Zone as Indicator of Recurrence. Anticancer Research, 30, 3795-3799.
[10] Sung, H.W., et al. (1982) Giant-Cell Tumor of Bone: Analysis of Two Hundred and Eight Cases in Chinese Patients. Journal of Bone and Joint Surgery, 64, 755-761.
[11] Wülling, M., et al. (2001) The Nature of Giant Cell Tumor of Bone. Journal of Cancer Research and Clinical Oncology, 127, 467-474. http://dx.doi.org/10.1007/s004320100234
[12] Huang, L., Teng, X.Y., Cheng, Y.Y., Lee, K.M. and Kumta, S.M. (2004) Expression of Preosteoblast Markers and Cbfa-1 and Osterix Gene Transcripts in Stromal Tumour Cells of Giant Cell Tumour of Bone. Bone, 34, 393-401. http://dx.doi.org/10.1016/j.bone.2003.10.013
[13] Huang, L., Xu, J., Wood, D.J. and Zheng, M.H. (2000) 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. American Journal of Pathology, 156, 761-767. http://dx.doi.org/10.1016/S0002-9440(10)64942-5
[14] Zheng, M.H., et al. (2001) The Histogenesis of Giant Cell Tumour of Bone: A Model of Interaction between Neoplastic Cells and Osteoclasts. Histology and Histopathology, 16, 297-307.
[15] Chang, S.S., et al. (2004) Bisphosphonates May Reduce Recurrence in Giant Cell Tumor by Inducing Apoptosis. Clinical Orthopaedics and Related Research, 426, 103-109.
http://dx.doi.org/10.1097/01.blo.0000141372.54456.80
[16] Lipton, A., et al. (2000) Pamidronate Prevents Skeletal Complications and Is Effective Palliative Treatment in Women with Breast Carcinoma and Osteolytic Bone Metastases: Long Term Follow-Up of Two Randomized, Placebo-Controlled Trials. Cancer, 88, 1082-1090.
http://dx.doi.org/10.1002/(SICI)1097-0142(20000301)88:5<1082::AID-CNCR20>3.0.CO;2-Z
[17] Branstetter, D.G., et al. (2012) Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone. Clinical Cancer Research, 18, 4415-4424.
http://dx.doi.org/10.1158/1078-0432.CCR-12-0578
[18] Chawla, S., et al. (2013) 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 Oncology, 14, 901-908. http://dx.doi.org/10.1016/S1470-2045(13)70277-8
[19] Balke, M., et al. (2010) Bisphosphonate Treatment of Aggressive Primary, Recurrent and Metastatic Giant Cell Tumour of Bone. BMC Cancer, 10, 462. http://dx.doi.org/10.1186/1471-2407-10-462
[20] Thomas, D. M. & Skubitz, K. M. (2009) Giant cell tumour of bone. Current Opinion in Oncology, 21, 338-344. http://dx.doi.org/10.1097/CCO.0b013e32832c951d
[21] Anract, P., De Pinieux, G., Cottias, P., Pouillart, P., Forest, M. and Tomeno, B. (1998) Malignant Giant-Cell Tumours of Bone. Clinico-Pathological Types and Prognosis: A Review of 29 Cases. International Orthopaedics, 22, 19-26. http://dx.doi.org/10.1007/s002640050201
[22] Osaka, S., Toriyama, M., Taira, K., Sano, S. and Saotome, K. (1997) Analysis of Giant Cell Tumor of Bone with Pulmonary Metastases. Clinical Orthopaedics and Related Research, 335, 253-261.
[23] Dominkus, M., Ruggieri, P., Bertoni, F., Briccoli, A., Picci, P., Rocca, M. and Mercuri, M. (2006) Histologically Verified Lung Metastases in Benign Giant Cell Tumours—14 Cases from a Single Institution. International Orthopaedics, 30, 499-504. http://dx.doi.org/10.1007/s00264-006-0204-x
[24] Bertoni, F., Present, D. and Enneking, W.F. (1985) Giant-Cell Tumor of Bone with Pulmonary Metastases. The Journal of Bone and Joint Surgery (American Volume), 67, 890-900.
[25] Singh, R.K., Gutman, M., Bucana, C.D., Sanchez, R., Llansa, N. and Fidler, I.J. (1995) Interferons Alpha and Beta Down-Regulate the Expression of Basic Fibroblast Growth Factor in Human Carcinomas. Proceedings of the National Academy of Sciences of the United States of America, 92, 4562-4566. http://dx.doi.org/10.1073/pnas.92.10.4562
[26] Taylor, J.L. and Grossberg, S.E. (1998) The Effects of Interferon-Alpha on the Production and Action of Other Cytokines. Seminars in Oncology, 25, 23-29.
[27] Kaiser, U., Neumann, K. and Havemann, K. (1993) Generalised Giant-Cell Tumour of Bone: Successful Treatment of Pulmonary Metastases with Interferon Alpha, a Case Report. Journal of Cancer Research and Clinical Oncology, 119, 301-303. http://dx.doi.org/10.1007/BF01212729
[28] Kaban, L.B., Troulis, M.J., Wilkinson, M.S., Ebb, D. and Dodson, T.B. (2007) Adjuvant Antiangiogenic Therapy for Giant Cell Tumors of the Jaws. Journal of Oral and Maxillofacial Surgery, 65, 2018-2024.
[29] Balke, M. (2013) Denosumab Treatment of Giant Cell Tumour of Bone. The Lancet Oncology, 14, 801-802. http://dx.doi.org/10.1016/S1470-2045(13)70291-2
[30] Balke, M. and Hardes, J. (2010) Denosumab: A Breakthrough in Treatment of Giant-Cell Tumour of Bone? The Lancet Oncology, 11, 218-219. http://dx.doi.org/10.1016/S1470-2045(10)70027-9
[31] Purohit, S. and Pardiwala, D.N. (2007) Imaging of Giant Cell Tumor of Bone. The Indian Journal of Orthopaedics, 41, 91-96.
[32] Campanacci, M., Baldini, N., Boriani, S. and Sudanese, A. (1987) Giant-Cell Tumor of Bone. The Journal of Bone and Joint Surgery (American Volume), 69, 106-114.
[33] Mjoberg, B., Pettersson, H., Rosenqvist, R. and Rydholm, A. (1984) Bone Cement, Thermal Injury and the Radiolucent Zone. Acta Orthopaedica, 55, 597-600. http://dx.doi.org/10.3109/1745367840 8992403
[34] Pettersson, H., Rydholm, A. and Persson, B. (1986) Early Radiologic Detection of Local Recurrence after Curettage and Acrylic Cementation of Giant Cell Tumours. European Journal of Radiology, 6, 1-4.
[35] Remedios, D., Saifuddin, A. and Pringle, J. (1997) Radiological and Clinical Recurrence of Giant-Cell Tumour of Bone after the Use of Cement. The Journal of Bone and Joint Surgery (British Volume), 79-B, 26-30.
[36] Lee, F.Y., Chang, S.S., Suratwala, S.J., Jung, K.M., Doppelt, J.D., Zhang, H.Z., Blaine, T.A., Kim, T.W. and Winchester, R.J. (2004) Bisphosphonates May Reduce Recurrence in Giant Cell Tumor by Inducing Apoptosis. Clinical Orthopaedics and Related Research, 426, 103-109.
[37] Cooper, K.L., Beabout, J.W. and Dahlin, D.C. (1984) Giant Cell Tumor: Ossification in Soft-Tissue Implants. Radiology, 153, 597-602.
[38] Lee, M.J., Sallomi, D.F., Munk, P.L., Janzen, D.L., Connell, D.G., O’Connell, J.X., Logan, P.M. and Masri, B.A. (1998) Pictorial Review: Giant Cell Tumours of Bone. Clinical Radiology, 53, 481-489. http://dx.doi.org/10.1016/S0009-9260(98)80166-9
[39] Plosker, G.L. and Goa, K.L. (1994) Clodronate. A Review of Its Pharmacological Properties and Therapeutic Efficacy in Resorptive Bone Disease. Drugs, 47, 945-982.
http://dx.doi.org/10.2165/00003495-199447060-00007
[40] Adami, S. and Zamberlan, N. (1996) Adverse Effects of Bisphosphonates. A Comparative Review. Drug Safety, 14, 158-170. http://dx.doi.org/10.2165/00002018-199614030-00003
[41] Markowitz, G.S., Appel, G.B., Fine, P.L., Fenves, A.Z., Loon, N.R., Jagannath, S., Kuhn, J.A., Dratch, A.D. and D’Agati, V.D. (2001) Collapsing Focal Segmental Glomerulosclerosis Following Treatment with High-Dose Pamidronate. Journal of the American Society of Nephrology, 12, 1164-1172.
[42] Hortobagyi, G.N., Theriault, R.L., Lipton, A., Porter, L., Blayney, D., Sinoff, C., Wheeler, H., Simeone, J.F., Seaman, J.J., Knight, R.D., Heffernan, M., Mellars, K. and Reitsma, D.J. (1998) Long-Term Prevention of Skeletal Complications of Metastatic Breast Cancer with Pamidronate. Protocol 19 Aredia Breast Cancer Study Group. Journal of Clinical Oncology, 16, 2038-2044.
[43] Liberman, U.I. and Hirsch, L.J. (1996) Esophagitis and Alendronate. The New England Journal of Medicine, 335, 1069-1070. http://dx.doi.org/10.1056/NEJM199610033351416
[44] Watts, N., Freedholm, D. and Daifotis, A. (1999) The Clinical Tolerability Profile of Alendronate. International Journal of Clinical Practice (Supplement), 101, 51-61.
[45] Marshall, J.K. (2002) The Gastrointestinal Tolerability and Safety of Oral Bisphosphonates. Expert Opinion on Drug Safety, 1, 71-78. http://dx.doi.org/10.1517/14740338.1.1.71
[46] Diel, I.J., Bergner, R. and Gr?tz, K.A. (2007) Adverse Effects of Bisphosphonates: Current Issues. The Journal of Supportive Oncology, 5, 475-482.
[47] Marx, R.E. (2003) Pamidronate (Aredia) and Zoledronate (Zometa) Induced Avascular Necrosis of the Jaws: A Growing Epidemic. Journal of Oral and Maxillofacial Surgery, 61, 1115-1117.
[48] Bamias, A., Kastritis, E., Bamia, C., Moulopoulos, L.A., Melakopoulos, I., Bozas, G., Koutsoukou, V., Gika, D., Anagnostopoulos, A., Papadimitriou, C., Terpos, E. and Dimopoulos, M.A. (2005) Osteonecrosis of the Jaw in Cancer after Treatment with Bisphosphonates: Incidence and Risk Factors. Journal of Clinical Oncology, 23, 8580-8587. http://dx.doi.org/10.1200/JCO.2005.02.8670
[49] Cummings, S.R., et al. (2009) Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis. The New England Journal of Medicine, 361, 756-765.
http://dx.doi.org/10.1056/NEJMoa0809493
[50] Bone, H.G., et al. (2008) Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women. The Journal of Clinical Endocrinology and Metabolism, 93, 2149-2157. http://dx.doi.org/10.1210/jc.2007-2814
[51] Brown, J.P., et al. (2009) Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women with Low bone Mass: A Randomized, Blinded, Phase 3 Trial. Journal of Bone and Mineral Research, 24, 153-161.
http://dx.doi.org/10.1359/jbmr.0809010
[52] Kendler, D.L., et al. (2010) Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women Transitioning from Alendronate Therapy. Journal of Bone and Mineral Research, 25, 72-81. http://dx.doi.org/10.1359/jbmr.090716
[53] FDA Approves Xgeva for GCTB. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm3 56667.htm

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.