Denosumab For Giant Cell Tumor Research Articles

Oral management of patients treated with denosumab for giant cell tumor of bone: A retrospective study at the University Hospitals of Strasbourg

ObjectivesGiant cell tumor of bone (GCTB) is defined as a rare intermediate-grade mesenchymal tumor. The first-line treatment was surgery but since the 2010s, denosumab is a medical therapeutic option that can stop progression of GCTBs with a high efficiency. Osteochimionecrosis of the jaw (ONJ) is a well-documented oral complication associated to denosumab implying careful oro-dental follow-up. So far, GCTB patients constitute a particular subgroup of denosumab-treated patients for whom very few studies about orodental care are described. Materials and methodsAll patients diagnosed with GCTB and treated by denosumab therapy and who had oro-dental follow-up were included. Nine patients received denosumab as adjuvant and/or neoadjuvant treatment of surgery and one patient received denosumab as an exclusive therapy. Denosumab was temporary stopped in case of a serious adverse event like ONJ. ResultsOf the 10 patients enrolled in this study, 8 started denosumab after undergoing one or more GCTB resection surgeries, and 1 patient was started on denosumab early on because surgery was considered too harmful. Only one patient benefited from denosumab treatment without tumor resection. All patients except one received an oral examination prior to initiation of denosumab treatment, the mean DMFT index was 9.8 and 4 patients had a poor periodontal status. In 5 of our 10 patients, denosumab therapy have been disturbed in order to manage one ONJ and 7 tooth extraction. ConclusionOro-dental status can strongly influence denosumab therapy in GCTB patients that's why a close collaboration is required between oncologist and oral surgeon.

Denosumab in Giant Cell Tumor of Bone: Multidisciplinary Medical Management Based on Pathophysiological Mechanisms and Real-World Evidence.

Simple SummaryThe widely accepted local therapy in extremity giant cell tumor of bone (GCTB) is surgery, in the form of extended intralesional curettage with adequate disease clearance and retention of the limb, wherever possible. Denosumab is a relevant therapy option for advanced GCTB, to benefit tumor response and surgical down-staging. Most GCTB patients with localized disease can be successfully treated with surgical curettage; patients with primary unresectable lesions or metastases may experience long-term clinical and radiological remission and pain control with denosumab treatment, and in this clinical situation, denosumab is currently the treatment of choice.(1) Despite the benign nature of the giant cell tumor of bone (GCTB), it shows a local recurrence rate of up to 50% and a chance of malignant transformation. The widely accepted local therapy in extremity GCTB is surgery, in the form of extended intralesional curettage with adequate disease clearance and retention of the limb, wherever possible. Denosumab, a human monoclonal antibody directed against the RANKL and associated inhibition of the RANKL pathway, is a relevant therapy option for advanced GCTB, to benefit tumor response and surgical down-staging. (2) The literature review of patients with GCTB treated with denosumab is performed via PubMed, using suitable keywords from January 2009 to January 2021. (3) Current indications for denosumab use are not definitively clear and unambiguous. Most GCTB patients with localized disease can be successfully treated with surgical curettage, and the role of denosumab in preoperative therapy in this patient population remains unclear. (4) However, patients with primary unresectable lesions or metastases may experience long-term clinical and radiological remission and pain control with denosumab treatment, and in this clinical situation, denosumab is currently the treatment of choice.

Study of imaging changes following preoperative denosumab for giant cell tumor of bone

BackgroundThe changes in the characteristics of the tumor blood supply of giant cell tumor of bone over time after treatment with denosumab remain unclear. The purpose of this study was to evaluate the change in the blood supply imaging characteristics of giant cell tumor of bone after preoperative denosumab treatment and to provide evidence for evaluating the reasonable time for preoperative treatment. MethodsA total of 59 patients with giant cell tumor of bone who were treated in our hospital from 2014 to 2019 were enrolled in the study. All patients underwent enhanced CT examination of the tumor site before denosumab treatment and every month after treatment. The plain CT value and enhanced CT value of the tumor were measured, and the CT enhancement rate of the tumor was calculated. The change in the CT enhancement rate of the tumor over time after denosumab treatment was analyzed. ResultsThe average tumor enhancement rates were 2.14 (1.22–4.05), 1.60 (1.12–2.53), 1.38 (1.02–2.24), and 1.25 (1–2.11) before denosumab treatment and one month, three months, and six months after treatment, respectively. After denosumab treatment, the average monthly CT enhancement rate decreased as follows: 0.54 (25.2%) in the first month, 0.11 (5.15%) in the second to third months, and 0.04 (1.87%) in the fourth to sixth months. The tumor enhancement rate was no longer significantly reduced three months post-treatment. There was a significant correlation between the reduction in the CT enhancement rate and the initial CT enhancement rate (P = 0.000). ConclusionThe preoperative application of denosumab can reduce tumor blood supply. The decrease in the blood supply is the most significant in the initial stage of treatment. Following treatment, the decrease in the blood supply gradually reduces over time. Therefore, for the purpose of reducing intra-operative bleeding and facilitating surgery, application of denosumab treatment is not recommended more than three months before surgery.

Results of neoadjuvant denosumab in giant cell tumor of the bone depending of the tumor location and the surgical grade

Background. The standard treatment for giant-cell tumors of the bone includes radical surgery. However, specific anatomical location of the tumor and/or its spread may hinder its complete excision or result in poor functional outcomes. Currently, combination treatment that includes preoperative denosumab and surgery is preferable. It saves patients’ lives and improves their quality of life. Reduction of local recurrence rate by combination therapy for giant-cell tumors of the bone is being actively studied now.Objective – to analyze treatment outcomes of patients with giant-cell tumors of the bone, including those who received combination treatment that included preoperative therapy with denosumab followed by surgery.Materials and methods. This study included 277 patients with giant-cell tumors treated in N.N. Blokhin National Cancer Research Center between 2005 and 2020. The mean duration of follow-up was 56 months. Study participants were divided into two groups. Group 1 included patients who received surgical treatment alone (n = 212), whereas Group 2 comprised patients who received combination treatment (n = 65). Neoadjuvant therapy included subcutaneous denosumab 120 mg on days 1, 8, 15, and 28, then every 4 weeks until stable effect. There were two variants of surgical treatment: radical (removal by a single block or segmental resection with defect replacement, with or without fixation) and non-radical (excochleation or marginal resection with defect replacement, with or without fixation).Results. During treatment, patients in Group 2 had a significantly milder pain syndrome (assessed both using the visual analog scale for pain and Watkins scale) compared to Group 1. In case of radical surgery, the incidence of local recurrence was 12 % and 0 % in Groups 1 and 2, respectively; the difference was significant (р <0.05). Tumor location and volume of surgery played an important role in disease recurrence (р <0.05). The incidence of complications after radical surgery was 36.9 % and 12.5 % in Groups 1 and 2, respectively; the difference was significant (р <0.05). In addition to that, neoadjuvant therapy with denosumab substantially reduced the duration of surgery and blood loss in patients with challenging anatomical location of the tumor (р <0.05).Conclusion. Combination treatment for giant-cell tumors that includes neoadjuvant therapy with denosumab reduces the risk of recurrence, duration of surgery, blood loss, and the risk of postoperative complications. However, it is important to consider tumor location and the volume of surgery. Since the disease is quite rare, further study of long-term efficacy and safety of combination treatment for giant-cell tumors, including rare ones and those with challenging anatomical location, is necessary.

Denosumab in giant cell tumor of bone – science wins over evidence

Denosumab is a relatively new drug and is used in the treatment of giant cell tumor (GCT) of bone. There are hardly any drugs such as denosumab, indication of which changed in a short period of 10 years. The author analyses the cause of this transformation of indication of that drug in the treatment of GCT of bone, based on the scientific ground, review of the literature, and personal experience.

Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls.

Denosumab is a monoclonal antibody against RANK ligand for treatment of giant cell tumor of bone (GCTB). Clinical trials and case series have demonstrated that denosumab is relevant to beneficial tumor response and surgical down-staging in patients of GCTB. However, these trials or case series have limitations with a short follow-up. Recent increasing studies revealed that denosumab probably increased the local recurrence risk in patients treated with curettage. This may be caused by the thicken bone margin of tumor that trapped tumor cells from curettage. The direct bone formation by tumor cells in the margin after denosumab treatment also contributed to the local recurrence. in vitro studies showed denosumab resulted in a cytostatic instead of a true cytotoxic response on neoplastic stromal cells. More importantly, denosumab-treated GCTB exhibited morphologic overlap with malignancy, and a growing number of patients of malignant transformation of GCTB during denosumab treatment have been reported. The optimal duration, long term safety, maintenance dose, and optimum indications remain to be elucidated. With these concerns in mind, this review warns that the denosumab therapy of GCTB should be applied with caution.

The current standing on the use of denosumab in giant cell tumour of the bone.

Giant cell tumour of the bone (GCTB) has been classically treated surgically. With the advent of denosumab, there is potential to use it as a targeted therapy to downstage the tumour and control its progression. Like all new therapies, the dosage, duration, and long-term effects of treatment can only be determined over the time through numerous trials and errors. The current recommendation of use of the monoclonal antibody is 3-4 months of neoadjuvant denosumab in patients with advanced GCTB for cases who were not candidates for primary curettage initially, and prolonged use for surgically unsalvageable GCTB. The use of Denosumab in the adjuvant setting to prevent recurrence is not established.

Denosumab in giant cell tumour of bone in the pelvis and sacrum: Long-term therapy or bone resection?

IntroductionSurgery of GCTB in sacrum and pelvis is challenging, with high rates of complications and local recurrence. Denosumab can consolidate the peripheral rim of the tumour, thus reducing the rate of morbidities of surgery. The aim of this paper is to evaluate the use of denosumab in pelvic/sacrum giant cell tumours of bone (GCTB). Patients and methodsWe retrospectively reviewed a cohort of 26 patients with aggressive GCTB in sacrum or pelvis treated with denosumab at two referral centres. Clinical response and local recurrence were recorded and the radiologic responses were evaluated with the MDA criteria. Results69% of the pelvic GCTB treated with denosumab presented partial or good radiologic responses (type 2A or 2B) after 49 weeks of treatment. Denosumab was administered as adjuvant therapy prior and after surgery in 11 patients (group A), and as the only treatment in 15 patients (group B). In group A, 62% of local recurrence was observed in patients treated with intralesional curettage. No recurrences were identified after en bloc resection. In group B, 9 patients were on continuous bimonthly long term denosumab administration with type 2A and 2B responses. Six patients stopped denosumab and 66% remained stable after 10 months of follow-up. ConclusionsLong-term denosumab therapy can be considered with curative intent for pelvic and sacrum GCTB. If surgical intervention is required wide resection may be advisable to reduce the risk of recurrence.

Challenges of denosumab in giant cell tumor of bone, and other giant cell-rich tumors of bone.

Purpose of reviewGiant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy.Recent findingsNeoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated.SummaryFor the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease.

MHRA Drug Safety Update: denosumab (Xgeva) and rebound hypercalcaemia

Review of: Medical and Healthcare products Regulatory Agency. Denosumab for giant cell tumor of bone: risk of clinically significant hypercalcaemia following discontinuation. Drug Safety Update 2018;11(11);2.

LBA56 - Long-term efficacy of denosumab in giant cell tumor of bone: Results of an open-label phase 2 study

LBA56 - Long-term efficacy of denosumab in giant cell tumor of bone: Results of an open-label phase 2 study

Effect of denosumab in giant cell tumor of bone

Giant cell tumor (GCT) of bone is a benign tumor with locally aggressive nature. The presence of mononuclear stromal cells and multinucleated giant cells is the microscopic characteristic feature of the GCT. It is an osteoclastic tumor with destruction of tumor is mediated by the receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab, a RANKL inhibitor, may reduce or eliminate tumor giant cells, the relative content of proliferative, densely cellular tumor stromal cells, replacing with nonproliferative, differentiated woven new bone. We report a case of GCT of the right distal femur in a 20-year-old female, treated with 6 cycles of denosumab as neoadjuvant therapy, which shows consolidation of the lesion and became amenable for extended curettage with phenol cauterization and cementing without going for any radical surgery shown to have very good functional outcome.

Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone.

Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug.

Oncology

The August 2015 Oncology Roundup360 looks at: Glasgow prognostic score in soft-tissue sarcoma; Denosumab in giant cell tumour; Timing, complications and radiotherapy; Pigmented villonodular synovitis and arthroscopy; PATHFx: estimating survival in pathological cancer; Prosthetic lengthening of short stumps; Chondrosarcoma and pathological fracture

Tibial stress reaction presenting as bilateral shin pain in a man taking denosumab for giant cell tumor of the bone

Prolonged bisphosphonate use has been associated with increased risk of atypical femoral fractures. Very few cases of atypical femoral fractures have been reported with denosumab. We report a case of bilateral tibial stress reactions in a 60-year-old man with no history of osteoporosis who was on prolonged high-dose denosumab for the treatment of giant cell tumor of bone. He presented with a 3-month history of pain in his bilateral shins worsening with activity and improving with rest. Although initial radiographs were unremarkable, he was found to have changes consistent with a stress reaction on magnetic resonance imaging of the distal tibia. To our knowledge, bilateral tibial stress reactions have not been previously reported with anti-resorptive therapies (neither bisphosphonates nor denosumab). Our case is intriguing in terms of the development of stress reactions as a precursor to stress fractures which may also relate to atypical fractures. Our case suggests a possible association between denosumab use and stress reactions. Of note the indication for denosumab in our case was for the treatment of giant cell tumor of bone where the Food and Drug Administration (FDA) approved dose is substantially higher than the FDA approved dose for osteoporosis treatment. Although rare, clinicians should consider the possibility of stress fractures in patients on anti-resorptive medications such as denosumab, especially when a patient presents with new onset thigh pain, hip pain or pain over an area affecting the long bones. Evaluation by imaging of affected areas should be pursued to enable early detection and intervention, as well as prevention of morbidity and associated ongoing risk to the patient.

Denosumab

It is not often that a new drug becomes available that is likely to affect the workload of orthopaedic surgeons, but denosumab has that potential. This edition of 360 carries a summary of a potentially landmark RCT examining the use of denosumab in giant cell tumour of bone. Denosumab is a fully human monoclonal antibody that inhibits RANK-L (Receptor activator of nuclear factor kappa-B ligand). RANK-L drives osteoclast formation, function and survival and an excess of RANK-L causes an increase in bone destruction, thus inhibiting osteoclast mediated bone destruction. To date, denosumab has found a role in three areas of interest in orthopaedics. These include osteoporosis, metastatic bone disease and giant cell tumour of bone. The evidence for its use in osteoporosis has been confirmed by several randomised controlled trials, the largest of which, the FREEDOM study, showed a significant risk reduction of new vertebral fractures in patients taking denosumab, compared with placebo.1 It also demonstrated improved bone mineral density the longer the treatment was continued.2 In October 2010, NICE approved denosumab as an option for post-menopausal women to prevent them suffering either a first osteoporotic fracture or further osteoporotic fracture if they were unable to take bisphosphonates (the …

1480PD - Efficacy and Safety of Denosumab in Giant Cell Tumor of Bone: Updated Results with Independent Radiographic Assessment of Response

ABSTRACT Giant cell tumor of bone (GCTB) is an aggressive osteolytic tumor that causes substantial morbidity. We present data from a second open label phase 2 study of denosumab in GCTB. Patients (pts) with surgically unresectable GCTB (Cohort 1), resectable GCTB with planned surgery (Cohort 2), and pts who transferred from the first phase 2 study (Cohort 3) received SC denosumab (120 mg, Q4W), with additional doses on days 8 and 15 (Cohorts 1–2). Prespecified efficacy and safety analyses included all pts who received denosumab. Radiographic assessments of tumor response included pts with ≥1 evaluable time point response (TPR); assessments included RECIST (lesion size), EORTC (PET Standardized Uptake Value by Body Weight [SUVbw]), and Density/Size (CT Hounsfield units). Pts (N = 282) were 58% women, mean age 36 (SD 13) years; 46% had recurrent unresectable disease. AEs were reported in 236 pts (84%); most frequent were arthralgia 20%; headache 18%; nausea 17%; fatigue 16%; back pain 15%; and extremity pain 15%. Osteonecrosis of the jaw was reported in 3 pts (1%). One pt died of respiratory failure, not denosumab-related. Hypocalcemia was reported in 15 pts (5%): 14, grade 1 or 2; 1, grade 3 not deemed clinically significant by the investigator. Of 100 pts in Cohort 2, 90% had no surgery or less morbid surgery than planned. Radiologic analyses included 190 pts. An objective complete or partial tumor response was observed in 72% of pts based on best response, any criteria. Of pts with ≥1 objective tumor response, response rates were 25% with RECIST, 96% with EORTC, and 76% with Density/Size criteria. Among pts with ≥1 evaluable TPR, the median time to objective tumor response was 3.1 months (95% CI 2.89, 3.65) based on best response using any tumor response criteria. Among pts with ≥2 evaluable TPRs ≥12 weeks apart, 96% had tumor control sustained ≥12 weeks based on the best response using any tumor response criteria. Eleven pts (6%) had disease progression. Conclusion: Denosumab appeared to be well tolerated in pts with GCTB, reduced requirements for morbid surgery, and provided a durable objective radiologic response for the majority of pts. Denosumab continues to be studied as a potential treatment for GCTB. Disclosure J. Blay: JY Blay has served as an advisory board member for Novartis, GSK, Roche, MSD, and Pharmamar. He has conducted corporate-funded research for Novartis, GSK, Roche, MSD, and Pharmamar. S. Chawla: Sant Chawla has been an advisory board member for and has received corporate-sponsored research funding from Amgen, Threshold, Cytrax, Glaxxo, and Berg Pharma. E. Choy: E. Choy has served as an advisory board member for Amgen, Sanofi-Aventis, and Biomed Valley Discoveries. S. Ferrari: S. Ferrari has received funds from: AMGEN, MOLMED, PharmaMar, and Pfizer. He received funds for participation to scientific meetings from Takeda. P. Reichardt: P. Reichardt has received honoraria for lectures from Amgen Inc. P. Rutkowski: P. Rutkowski has served as an advisory board member for Norvartis, BMS, and MSD. He has also received honoraria for lectures and travel grants from Novartis, Pfizer, Roche, BMS, and MSD. D. Thomas: David Thomas conducts corporate-sponsored research with Pfizer and AMGEN. Y. Qian: Y. Qian is an employee and stockholder of Amgen Inc. I. Jacobs: I. Jacobs is an employee and stockholder of Amgen Inc. All other authors have declared no conflicts of interest.

Safety of denosumab in giant-cell tumour of bone

In The Lancet Oncology, Athanassios Kyrgidis and Konstantinos Toulis1 commented on the study of denosumab for the treatment of giant-cell tumour of bone.2 While recognising the potential of denosumab therapy for the treatment of giant-cell tumour, Kyrgidis and Toulis discuss the adequacy of safety follow-up in this study, and make suggestions for the detection of osteonecrosis of the jaw (ONJ). They specifically recommend protocol amendments—which incorporate regular dental assessment—to monitor for either ONJ or implementation of measures to prevent ONJ.

Safety and efficacy of denosumab in giant-cell tumour of bone

In the March, 2010, issue of The Lancet Oncology, Thomas and colleagues1 describe the safety and efficacy of denosumab in patients with recurrent or unresectable giant-cell tumour (GCT) of bone. From a surgeon's point of view, GCT often requires amputating surgery, and recurrences do occur; therefore, denosumab is a promising systemic treatment option for GCT.2 However, the follow-up of patients in the trial by Thomas and colleagues might not have been adequate to document safety.2