Neoadjuvant Denosumab Research Articles

Interest of Denosumab for the Treatment of Giant-cells Tumors and Aneurysmal Bone Cysts of the Spine. About Nine Cases.

A prospective cohort study. 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). 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. 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 osteosynthesis 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. 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 osteosynthesis, one "en bloc" resection, four curettages, and two of them associated with an osteosynthesis. 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. Denosumab allows bone formation and tumor regression with a maximum efficacy after 6 months of treatment without widely substituting surgery. Long-term results are mandatory to confirm the interest of denosumab and to evaluate LR when stopping denosumab. 3.

Disappearance of giant cells and presence of newly formed bone in the pulmonary metastasis of a sacral giant-cell tumor following denosumab treatment: A case report.

A giant-cell tumor of the bone (GCTB) is a benign but locally aggressive bone tumor. Recently, the receptor activator of nuclear factor κB (RANK) ligand inhibitor, denosumab, has demonstrated activity against giant-cell tumors. The current study reports a case of a sacral GCTB with lung metastasis. A 19-year-old male patient presented with right buttock pain and right lower leg pain, and a sacral GCTB was diagnosed based on the histological analysis of a biopsy specimen. The patient was successfully treated with neoadjuvant denosumab therapy, which allowed curettage. In addition, the pulmonary nodule reduced in size following denosumab administration, and surgical resection was performed. Since the operation, the patient has been managed with the continued use of denosumab with no sign of recurrence. Microscopic findings from the surgical specimen following denosumab treatment revealed that the giant cells had disappeared and woven bone had formed. The specimen from the pulmonary nodule exhibited similar findings to the surgical specimen. It was reported that denosumab treatment was able to reduce the number of giant cells and RANK-positive stromal cells, and cause the formation of new bone in the primary lesion. The present study reports the first case to demonstrate the efficiency of denosumab in treating pulmonary metastasis of GCTB.

A Translational Study of the Neoplastic Cells of Giant Cell Tumor of Bone Following Neoadjuvant Denosumab

Giant cell tumor of bone is a primary bone tumor that is treated surgically and is associated with high morbidity in many cases. This tumor consists of giant cells expressing RANK (receptor activator of nuclear factor-κB) and mesenchymal spindle-like stromal cells expressing RANKL (RANK ligand); the interaction of these cells leads to bone resorption. Denosumab is a monoclonal antibody that binds RANKL and directly inhibits osteoclastogenesis. Clinical studies have suggested clinical and histological improvement when denosumab was administered to patients with a giant cell tumor. However, no studies have yet examined the viability and functional characteristics of tumor cells following denosumab treatment. Specimens were obtained from six patients with a histologically confirmed giant cell tumor. Two of the patients had been treated with denosumab for six months. Primary cultures of stromal cells from fresh tumor tissue were established. Cell proliferation was measured over a two-day time course. The expression of RANKL and osteoprotegerin was analyzed with use of real-time PCR (polymerase chain reaction). Histological specimens from both patients who had completed denosumab treatment showed the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. The expression of RANKL in the specimens from the treated patients was almost completely eliminated. Once the giant cell tumor tissue was no longer exposed to denosumab, the stromal cells continued to proliferate in vitro, albeit to a lesser degree. However, they also showed almost complete loss of RANKL expression. It is clear that treatment with denosumab only partially addresses the therapeutic need of patients with a giant cell tumor by wiping out the osteoclasts but leaving the neoplastic stromal cells proliferative.