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    A Solution for Reducing Tumor Size in Giant Cell Tumor of the Bone

    A recently published paper asserts that medical therapy with the monoclonal antibody denosumab should be part of a multimodal treatment strategy for complicated giant cell tumor of the bone.

    Authors

    Timothy Rapp, MD, and Vinay K. Aggarwal, MD

    Article

    van der Heijden L, Dijkstra PD, Blay JY, Gelderblom H. Giant cell tumour of the bone in the denosumab era. Eur J Cancer. 2017 Mar 30; 77: 75-83.

    Summary

    Giant cell tumor of the bone (GCTB) is a primary bone lesion that is locally aggressive and rarely metastasizes. Historically, it has been treated with surgery. This is especially true of tumors in the meta-epiphyseal region of long bones, where surgical excision and curettage with local adjuvants has proven to be successful.

    Depending on the location of the tumor and the effect of adjuvant treatments, local recurrence rates are reported to be 20% to 30%. The goals of treating GCTB are control of tumor locally and avoidance of recurrence while maintaining a functional native joint and high quality of life.

    This is often not possible, however, for more-invasive tumors or those in difficult anatomic locations such as the sacrum. In those cases, treatment typically involves en-bloc resection resulting in severe joint destruction or even amputation of limbs.

    Systemic therapy for GCTB is based in research that shows overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) is responsible for bone resorption in this disease. Denosumab, a monoclonal antibody active against RANKL, aims to decrease tumor size, thereby facilitating surgical treatment of GCTB. In addition, denosumab has been shown to reduce progression of disease.

    Clinical Relevance

    GCTB typically presents in patients ages 30 to 50 years and has an incidence of 1.3 per million per year. Initial workup includes standard radiographs, which will typically show a non-sclerotic, sharply defined, lytic lesion eccentrically positioned in the metaphysis of long bones (Figure 1). Further imaging with CT, MRI, or PET scans can demonstrate the extent of tumor involvement, including soft tissue components.

    Figure 1. Giant cell tumor of bone shown in a typical location at the distal femur.

    Histologically, GCTB shows multinucleated osteoclast-like giant cells expressing receptor activator of nuclear factor kappa-B (RANK) and neoplastic mononuclear stromal cells expressing RANKL (Figure 2).

    Figure 2. Histology demonstrating giant cells with rasinoid nuclei cells appearing nearly identical to those of the surrounding background stroma.

    The difficulty with GCTB in the past has been the locally aggressive tumor, where en-bloc resection or amputation constituted the only treatment options for unsalvageable disease. Denosumab treatment has shown promise in creating operable situations and achieving immediate local tumor control.

    European studies have shown that after 3- to 4-month treatment with denosumab, tumor size decreased and calcified rim formation occurred, thus making local curettage more feasible. [1]

    No current studies examine the effect of denosumab on GCTB recurrence rates after surgical intervention. However, a Phase II study in 2010 by Thomas et al [2] showed decreased progression of disease based on greater than 90% elimination of giant cells on histology, as well as stable radiographic size of lesion.

    A second clinically relevant study showed reduction of surgical invasiveness in 222 patients with resectable GCTB treated with denosumab: 86% reported a clinical benefit, 48% were able to avoid surgery, and 38% reportedly had less morbid surgery than they would have had without medical therapy. [3]

    Currently, recommendations for denosumab treatment include neoadjuvant therapy for 3 to 4 months in patients who cannot undergo primary curettage their lesions. Although questions exist regarding the exact treatment algorithm and its effect on tumor recurrence, denosumab should be a medical treatment considered in managing disease progression and facilitating surgical intervention in GCTB.

    Author Information

    Timothy Rapp, MD, is an Associate Professor of Orthopaedic Surgery and Chief of the Division of Orthopaedic Oncology, at NYU Langone Medical Center – Hospital for Joint Diseases, New York, New York. Vinay K. Aggarwal, MD, is an orthopaedic surgery resident, NYU Langone Medical Center – Hospital for Joint Diseases, New York, New York.

    References

    1. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim anal- ysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 2013;14(9):901e8.

    2.Thomas D , Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study.Lancet Oncol. 2010 Mar;11(3):275-80. doi: 10.1016/S1470-2045(10)70010-3. Epub 2010 Feb 10.

    3. Rutkowski P, Ferrari S, Grimer RJ, et al. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann Surg Oncol 2015;22(9):2860e8.