Surgical Downstaging in an Open-Label Phase II Trial of Denosumab in Patients with Giant Cell Tumor of Bone Denosumab May Increase the Risk of Local Recurrence in Patients with Giant-Cell Tumor of Bone Treated with Curettage Interest of Denosumab for the Treatment of Giant-cells Tumors and Aneurysmal Bone Cysts of the Spine. About Nine Cases Giant cell tumors of the spine: has denosumab changed the treatment paradigm? 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. Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone. Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone Publication bias in clinical research Clinical use of denosumab for the treatment for postmenopausal osteoporosis Morphologic evaluation of the effect of denosumab on giant cell tumors of bone and a new grading scheme. Effects of denosumab on pain and analgesic use in giant cell tumor of bone: Interim results from a phase II study
Background Surgical resection with curative intent for giant cell tumor of bone ( GCTB ) may be associated with severe morbidity . This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB . Methods Patients with primary or recurrent GCTB , for whom the initially planned surgery was associated with functional compromise or morbidity , received denosumab 120 mg subcutaneously every 4 weeks ( additional doses on days 8 and 15 of the first cycle ) . Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported . Patients were followed for surgical outcome , adverse events , and recurrence following resection . Results Overall , 222 patients were evaluable for surgical downstaging ( 54 % were women ; median age 34 years ) . Lesions ( 67 % primary and 33 % recurrent ) were located in the axial ( 15 % ) and appendicular skeleton ( 85 % ) . At the data cutoff date , most patients had not yet undergone surgery ( n = 106 ; 48 % ) or had a less morbid procedure ( n = 84 ; 38 % ) than originally planned . Median ( interquartile range ) time on denosumab was 19.5 ( 12.4–28.6 ) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab . Native joint preservation was 96 % ( n = 24/25 ) for patients with planned joint/prosthesis replacement and 86 % ( n = 30/35 ) for patients with planned joint resection/fusion . Of the 116 patients who had surgery ( median postsurgical follow-up 13.0 [ 8.5–17.9 ] months ) , local recurrence occurred in 17 ( 15 % ) patients . Conclusion For patients with resectable GCTB , neoadjuvant denosumab therapy result ed in beneficial surgical downstaging , including either no surgery or a less morbid surgical procedure Background : Recent clinical studies have suggested that denosumab is associated with tumor response and reduced surgical morbidity in patients with giant-cell tumor of bone ( GCTB ) . We therefore evaluated the recurrence-free survival rate of patients who had GCTB in an extremity and were treated with surgery and denosumab  , to determine the influence of denosumab and clinical factors on the risk of local recurrence . Methods : We retrospectively review ed the medical records of 408 patients treated for GCTB in an extremity in a single institution from 1990 through 2013 . Two hundred and forty-seven patients underwent curettage ( intralesional surgery ) with a high-speed burr , and 161 underwent resection . Phenol adjuvant was used in 221 of the 247 patients who had  curettage . We also review ed the medical records of 30 patients treated surgically ( 25 with curettage and 5 with resection ) and with denosumab from 2010 through 2013 and compared their clinical results with 378 historical control subjects . The overall minimum duration of follow-up was 24 months . Results : The local recurrence rates were 60 % ( 15 ) of 25 patients treated with curettage and denosumab and 16 % ( 36 ) of 222 patients treated with curettage alone . The joint preservation rates were 80 % ( 20 ) of 25 patients treated with curettage and denosumab and 94 % ( 209 ) of 222 patients treated with curettage alone . Univariate and multivariable analyses showed that denosumab was the only independent factor associated with a poor prognosis when recurrence-free survival and joint preservation were considered . The overall median duration of follow-up was 85.6 months ( interquartile range , 54.3 to 125.1 months ) . Viable tumor was present in all 30 specimens from patients treated with denosumab . Conclusions : There was a higher rate of recurrence in the cohort exposed to denosumab . Because there were substantial differences in the cohorts and r and omization was not applied , however , causation could not be evaluated . Level of Evidence : Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence Study Design . A prospect i ve cohort study . Objective . The aim of this study was to evaluate the interest of denosumab in the treatment of spinal giant-cells tumors ( GCTs ) and aneurysmal bone cysts ( ABCs ) . Summary of Background Data . To treat GCTs and ABCs , surgical resection remains the best treatment to limit local recurrence ( LR ) but constitutes an aggressive treatment with potential morbidity . Denosumab , a human antibody anti-RankL , inhibiting the differentiation of osteoclasts , could be an alternative treatment to avoid aggressive surgery . Methods . Patients suffering from GCTs and ABCs of the spine were included . Patients received a monthly subcutaneous injection of denosumab ( 120 mg ) during a minimum of 6 months either as a neoadjuvant or as an adjuvant therapy . In association with denosumab , an osteo synthesis was added in case of vertebral fracture and a laminectomy in case of spinal cord compression . Clinical and computed tomography (CT)-scan outcomes were analyzed . Results . Eight GCTs and one ABC were included . The mean age was 35 years ( range : 22–55 yr ) . Five patients had neurologic deficit . All patients were operated : six osteo synthesis , one “ en bloc ” resection , four curettages , and two of them associated with an osteo synthesis . Average duration of denosumab therapy was 12.9 months ( range : 3.2–24 months ) . Among them , four patients began denosumab 6 months at least before the surgery . With a mean follow-up of 19.3 months ( range : 3.2–52.4 months ) , back pain and neurologic deficit improved for all patients . Systematic CT-scan at 6 months showed decrease of tumor size and bone consolidation . Regarding patients treated by neoadjuvant denosumab treatment , intraoperative histologic analysis showed an absence of giant cells and a maximum of 10 % of alive tumor cells . Conclusion . Denosumab allows bone formation and tumor regression with a maximum efficacy after 6 months of treatment without widely substituting surgery . Long-term results are m and atory to confirm the interest of denosumab and to evaluate LR when stopping denosumab . Level of Evidence : OBJECT Giant cell tumors ( GCTs ) of the spine are rare and complex to treat . They have a propensity for local recurrence and the potential to metastasize . Treatment is currently surgical and presents unique challenges due to the proximity of neural structures and the need for reconstruction . Denosumab has been shown in clinical trials to be an effective treatment for GCT , but has not yet been studied specifically in GCT of the spine or as a surgical adjunct . To the authors ' knowledge this is the first such reported series . METHODS A multicenter , prospect i ve series of 5 patients with GCT of the spine treated with denosumab were included . Patient demographic data , oncological history , neurological status , tumor staging , treatment details and adverse events , surgical procedure , complications , radiological and histological responses , and patient outcome were analyzed . RESULTS All patients were women , with a mean age of 38 years , and presented with pain ; 2 patients had additional neurological signs and symptoms .  The mean  duration of symptoms was 62 weeks . No patient had a prior tumor or metastatic disease at presentation . All patients had Enneking Stage III tumors and were treated with monthly cycles of 120 mg of denosumab , with initial additional loading doses on Days 8 and 15 . Patients were given daily supplements of calcium ( 500 mg ) and vitamin D ( 400 IU ) . There were no  denosumab-related adverse events . All patients had a radiological response to denosumab . One patient failed to have a histological response to denosumab , with > 90 % of tumor cells found to be viable on histological investigation . CONCLUSIONS This study reports the early experience of using denosumab in the treatment of spinal GCT . The results demonstrate a clinical ly beneficial radiological response and an impressive histological response in most but not all patients . Further experience with denosumab and longer patient follow-up is required . Denosumab has the potential to change the treatment paradigm for spinal GCT BACKGROUND Giant cell tumour of bone ( GCTB ) is a very rare , aggressive , and progressive osteolytic tumour for which no st and ard medicinal treatment or chemotherapy exists . We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB . METHODS We did an international , open-label , parallel-group , phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease . Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg . We divided patients into three cohorts -- those with surgically unsalvageable GCTB ( cohort 1 ) , those with salvageable GCTB whose surgery was associated with severe morbidity ( cohort 2 ) , and those who transferred from a previous study of denosumab for GCTB ( cohort 3 ) . Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle ; those in cohort 3 continued the regimen from the previous study . Investigator-determined disease status and clinical benefit were assessed every 4 weeks . Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities . Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2 . Safety analyses included all patients who received at least one dose of denosumab . Efficacy analyses included all eligible patients who received at least one dose of denosumab . This study is registered with Clinical Trials.gov , identifier NCT00680992 . FINDINGS 282 patients , including ten adolescents , were included between Sept 9 , 2008 , and March 25 , 2011 . Of the 281 patients analysable for safety , three ( 1 % ) had osteonecrosis of the jaw and 15 ( 5 % ) hypocalcaemia . The most common grade 3 - 4 adverse events were hypophosphataemia , which occurred in nine ( 3 % ) patients , and anaemia , back pain , and pain in extremities , each of which occurred in three patients ( 1 % ) . Serious adverse events were reported in 25 ( 9 % ) patients . No treatment-related deaths were reported . On the basis of investigators ' assessment of disease status , 163 of 169 ( 96 % ) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months ( IQR 5·8 - 21·0 ) . In cohort 2 , 74 of 100 ( 74 % ) analysable patients had no surgery and 16 of 26 ( 62 % ) patients who had surgery underwent a less morbid procedure than planned . Median follow-up in cohort 2 was 9·2 months ( IQR 4·2 - 12·9 ) . INTERPRETATION Adverse events were consistent with the known safety profile of denosumab . Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB . Denosumab represents a new treatment option for patients with GCTB . FUNDING Amgen A RANK lig and -specific inhibitor , denosumab , was predicted to reduce osteolysis and control disease progression in patients with giant cell tumor of bone ( GCTB ) . We report , for the first time , the results of the response of GCTB to denosumab obtained from a prospect i ve independent imaging assessment . The findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB BACKGROUND Giant-cell tumour ( GCT ) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity . GCT is rich in osteoclast-like giant cells and contains mononuclear ( stromal ) cells that express RANK lig and ( RANKL ) , a key mediator of osteoclast activation . We investigated the potential therapeutic effect of denosumab , a fully human monoclonal antibody against RANKL , on tumour-cell survival and growth in patients with GCT . METHODS In this open-label , single-group study , 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous denosumab 120 mg monthly ( every 28 days ) , with loading doses on days 8 and 15 of month 1 . The primary endpoint was tumour response , defined as elimination of at least 90 % of giant cells or no radiological progression of the target lesion up to week 25 . Study recruitment is closed ; patient treatment and follow-up are ongoing . The study is registered with Clinical Trials.gov , NCT00396279 . FINDINGS Two patients had insufficient histology or radiology data for efficacy assessment . 30 of 35 ( 86 % ; 95 % CI 70 - 95 ) of evaluable patients had a tumour response : 20 of 20 assessed by histology and 10 of 15 assessed by radiology . Adverse events were reported in 33 of 37 patients ; the most common being pain in an extremity ( n=7 ) , back pain ( n=4 ) , and headache ( n=4 ) . Five patients had grade 3 - 5 adverse events , only one of which ( grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy ) was deemed to be possibly treatment related . Five serious adverse events were reported although none were deemed treatment related . INTERPRETATION Further investigation of denosumab as a therapy for GCT is warranted . FUNDING Amgen , BACKGROUND Giant cell tumour of the bone ( GCTB ) is an aggressive osteolytic primary tumour . GCTB is rich in osteoclast-like giant cells and contains mononuclear cells that express RANK lig and ( RANKL ) , a key mediator of osteoclast activation . The potential therapeutic effect of denosumab was investigated with special reference to its role in joint preservation . METHODS In this prospect i ve non-r and omised study patients with GCTB received denosumab for 6 - 11 months preoperatively . Serial radiographs and biopsy and resection tumour specimens were used to monitor response to denosumab . RESULTS All 20 patients experienced  pain relief in the first month of treatment . All patients demonstrated a positive radiographic response with improved subchondral and cortical bone which allowed intralesional tumour resection and preservation of the joint and articular surface in 18 cases . Histological examination following denosumab revealed rarely detectable osteoclast-like giant cells . There was an obvious increase in osteoid matrix and woven bone which showed rare RANK staining amongst the mononuclear cells and only focal RANKL positivity . At median 30 months follow-up after resection , local tumour recurrence occurred in three patients . CONCLUSION Denosumab provides favourable and consistent clinical , radiographic and pathologic responses which facilitates less aggressive surgical treatment , especially joint preservation . However , the local recurrence rate for GCTB following resection does not seem to be affected by denosumab and remains a concern Purpose : Giant-cell tumor of bone ( GCTB ) is a locally aggressive , benign osteolytic tumor in which bone destruction is mediated by RANK lig and ( RANKL ) . The RANKL inhibitor denosumab is being investigated for treatment of GCTB . We describe histologic analyses of GCTB tumor sample s from a phase II study of denosumab in GCTB . Experimental Design : Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks ( with additional doses on days 8 and 15 ) . The primary histologic efficacy endpoint was the proportion of patients who had a 90 % or more elimination of giant cells from their tumor . Baseline and on- study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL . Results : Baseline tumor sample s were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells , RANK-positive rounded mononuclear cells , abundant RANK-positive tumor giant cells , and areas of scant de novo osteoid matrix and woven bone . In on- study sample s from 20 of 20 patients ( 100 % ) , a decrease of 90 % or more in tumor giant cells and a reduction in tumor stromal cells were observed . In these analyses , thirteen patients ( 65 % ) had an increased proportion of dense fibro-osseous tissue and /or new woven bone , replacing areas of proliferative RANKL-positive stromal cells . Conclusions : Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells .  Denosumab also reduced the relative content of proliferative , densely cellular tumor stromal cells , replacing them with nonproliferative , differentiated , densely woven new bone . Denosumab continues to be studied as a potential treatment for GCTB . Clin Cancer Res ; 18(16 ) ; 4415–24 . © 2012 AACR In a retrospective survey , 487 research projects approved by the Central Oxford Research Ethics Committee between 1984 and 1987 , were studied for evidence of publication bias . As of May , 1990 , 285 of the studies had been analysed by the investigators , and 52 % of these had been published . Studies with statistically significant results were more likely to be published than those finding no difference between the study groups ( adjusted odds ratio [ OR ] 2.32 ; 95 % confidence interval [ Cl ] 1.25 - 4.28 ) . Studies with significant results were also more likely to lead to a greater number of publications and presentations and to be published in journals with a high citation impact factor . An increased likelihood of publication was also associated with a high rating by the investigator of the importance of the study results , and with increasing sample size . The tendency towards publication bias was greater with observational and laboratory-based experimental studies ( OR = 3.79 ; 95 % Cl = 1.47 - 9.76 ) than with r and omised clinical trials ( OR = 0.84 ; 95 % Cl = 0.34 - 2.09 ) . We have confirmed the presence of publication bias in a cohort of clinical research studies . These findings suggest that conclusions based only on a review of published data should be interpreted cautiously , especially for observational studies . Improved strategies are needed to identify the results of unpublished as well as published studies Abstract Denosumab is a fully human monoclonal antibody with high affinity and specificity for human receptor activator of nuclear factor kappa B lig and ( RANKL ) , the principal regulator of osteoclastic bone resorption . By binding to RANKL , denosumab prevents it from binding to its receptor on the cell surface of pre-osteoclasts and mature osteoclasts , thereby reducing the formation , activity , and survival of osteoclasts and inhibiting osteoclastic bone resorption . In a large , r and omized , placebo-controlled clinical trial in postmenopausal women with osteoporosis , denosumab 60 mg administered subcutaneously every 6 months reduced levels of bone turnover markers , increased bone mineral density , and reduced the risk of vertebral fractures , hip fractures , and non-vertebral fractures . There was no significant difference between denosumab and placebo in the overall risk of adverse events or serious adverse events .  Denosumab was associated with a significant increase in the risk of eczema and cellulitis , and a significant decrease in the risk of falling and concussions .  Denosumab recently received regulatory approval for the treatment of postmenopausal women with osteoporosis at high risk for fracture , with no dose adjustment in patients with renal impairment .  Denosumab is a new therapeutic option to reduce fracture risk in women with postmenopausal osteoporosis , especially for those with impaired renal function or with intolerance or poor response to oral therapy Giant cell tumor ( GCT ) is a rare , usually benign but locally aggressive neoplasm . Recent studies suggest new approaches in light of the elucidation of molecular pathways in bone . The osteolytic nature of GCT is caused by the receptor for activating nuclear factor-kB lig and ( RANKL ) associated osteoclasts . Denosumab is a monoclonal antibody that affects GCT through RANKL and it prevents normal and neoplastic osteolysis . The aim of this study is to evaluate the histopathologic alterations due to denosumab treatment and the efficiency of this drug in GCT therapy . Ten patients had been treated with denosumab and were included in the study . Pretreatment biopsies were interpreted as conventional GCTs and posttreatment biopsies of the ten patients ' GCTs were classified in accordance with the grading system . Only one patient had tumor remaining after treatment . There is limited data on histopathologic alterations that follow denosumab treatment . The bone pathologist should keep these changes in mind because they mimic different types of bone tumors . Furthermore , there is no widely accepted grading system to evaluate the effect of denosumab in GCT . Our study suggested a scheme that would be helpful to evaluate the efficiency of denosumab treatment in GCT Abstract Background . Giant cell tumor of bone ( GCTB ) is an aggressive primary osteolytic tumor . GCTB often involves the epiphysis , usually causing substantial pain and functional disability .  Denosumab , a fully human monoclonal antibody against receptor activator of nuclear factor κΒ lig and ( RANKL ) , is an effective treatment option for patients with advanced GCTB . This analysis of data from an ongoing , open-label study describes denosumab 's effects on pain and analgesic use in patients with GCTB . Material and methods . Patients with unresectable disease ( e.g. sacral or spinal GCTB , or multiple lesions including pulmonary metastases ) were enrolled into Cohort 1 ( N = 170 ) , and patients with resectable disease whose planned surgery was associated with severe morbidity ( e.g. joint resection , limb amputation , or hemipelvectomy ) were enrolled into Cohort 2 ( N = 101 ) . Patients received denosumab ( 120 mg ) subcutaneously every four weeks , with additional doses on study days 8 and 15 . Patients assessed worst pain severity with the Brief Pain Inventory – Short Form ( BPI-SF ) at baseline , at each visit for the first six months , and every three months thereafter . Results . Clinical ly relevant pain improvement was reported by 29 % of patients in Cohort 1 and 35 % in Cohort 2 during week 1 and by ≥ 50 % of patients in each cohort at each study visit from months 2–30 . Median time to clinical ly relevant improvement was 30 ( 95 % CI 16 , 57 ) days in Cohort 1 and 15 ( 95 % CI 15 , 29 ) days in Cohort 2 . Results in patients with moderate/severe pain at baseline were similar . Fewer than 30 % of patients in Cohort 1 and 10 % in Cohort 2 experienced clinical ly relevant pain worsening at any visit through 27 months . Most patients had no/low analgesic use during the study . Conclusion . Most patients treated with denosumab experienced clinical ly relevant decreases in pain within two months
Background Denosumab is a human monoclonal antibody ( mAb ) that specifically inhibits tumor-associated bone lysis through the RANKL pathway and has been used as neoadjuvant therapy for giant-cell tumor of bone ( GCTB ) in surgical as well as non-surgical cases .
The purpose of this systematic review of the literature , therefore , is to investigate : ( 1 ) demographic characteristics of patients affected by GCTBs treated with denosumab  and the clinical impact , as well as , possible complications associated with its use ( 2 ) oncological outcomes in terms of local recurrence rate ( LRR ) and development of lung metastasis , and ( 3 ) characteristics of its treatment effect in terms of clinical , radiological , and histological response .