Preoperative Denosumab plus Surgery in the Management of Giant Cell Tumor of Bone: A Comprehensive Narrative...

Giant cell tumor of bone (GCTB) is a biologically benign osteolytic tumor that affects the metaphyseal/epiphyseal portions of bones. Histologically, GCTB is composed of osteoclast-like multinucleated giant cells that express receptor activator of nuclear factor kappa B (RANK), and neoplastic mesenchymal stromal cells that express RANK ligand (RANKL). The pathogenesis of GCTB is primarily attributable to the RANK-RANKL interaction, resulting in the activation of osteoclasts and the resultant osteolytic phenotype. Denosumab is a monoclonal antibody targeted against RANKL. In 2013, it was approved by the United States Food and Drug Administration (FDA) for the treatment of adults and skeletally mature adolescents with GCTB that is inoperable, or initial surgery is expected to culminate in substantial morbidity. The aim of this study is to narratively review the current literature on the role of preoperative denosumab followed by surgery in the management of patients with GCTB. In brief, caution should be exercised in the interpretation of existing data on preoperative denosumab in the management of GCTB patients, owing to some critical limitations, for example, short follow-up and only a minority of patients have undergone intralesional surgery following denosumab therapy. All in all, administration of preoperative denosumab is associated with clinical, radiological, and histopathological therapeutic benefits. It is also associated with tolerability, safety, surgical downstaging and less morbid salvageable procedures. Preoperative denosumab does not seem to reduce the likelihood of local recurrence after intralesional therapy; a planned randomized phase III clinical trial (JCOG 1610) will holistically address this concern. Furthermore, more than ten cases of denosumab-related malignant transformation of GCTB have been reported in literature. Lastly, large-sized phase III randomized clinical trials with long-term follow-up data are warranted to withdraw concrete conclusions and recommendations.