Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone

Jacob Engellau, Leanne Seeger, Robert Grimer, Robert Henshaw, Hans Gelderblom, Edwin Choy, Sant Chawla, Peter Reichardt, Michael O'Neal, Amy Feng, Ira Jacobs, Zachary J Roberts, Ada Braun, Bruce A Bach, Jacob Engellau, Leanne Seeger, Robert Grimer, Robert Henshaw, Hans Gelderblom, Edwin Choy, Sant Chawla, Peter Reichardt, Michael O'Neal, Amy Feng, Ira Jacobs, Zachary J Roberts, Ada Braun, Bruce A Bach

Abstract

Background: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies.

Methods: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only).

Results: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment.

Conclusion: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab.

Trial registration: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Keywords: Denosumab; Giant cell tumor of bone; Objective tumor response; RANKL.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the institutional review board or ethics committee for each site, and all patients provided written informed consent.

Consent for publication

By giving written informed consent, all patients gave their approval for publication of the results of the study. There are no individually identifiable patient-level data.

Competing interests

JE has received fees for lectures on GCTB and participation on scientific advisory boards regarding denosumab for Amgen Inc. He is a member of the board of directors for Genovis Inc. LS has served as consulting radiologist for Amgen, Inc. for this trial. RG has served on the scientific advisory board for Amgen, Inc. for this trial. RH has served as a primary investigator for Amgen, Inc. and Novartis and has served as a board member of the nonprofit Mattie Miracle Cancer Foundation. HG’s institution has received grants and consultancy fees from Amgen, Inc. EC has served as a consultant on advisory boards for Amgen, Inc., EMD Serono, and Bayer. SC has served as an advisor and consultant for Amgen, Inc. PR has served on advisory boards for Novartis; Pfizer; Bayer; PharmaMar; Ariad; Amgen, Inc.; GlaxoSmithKline; AstraZeneca; Clinigen; and Lilly and has received honoraria from Novartis; Pfizer; Bayer; PharmaMar; Amgen, Inc.; GlaxoSmithKline; and Lilly. MO is an employee of CoreLab Partners (now Bioclinica). AF, IJ, ZJR, AB, and BAB were employees of Amgen, Inc. at the time of the study; they are currently employees of Atara Biotherapeutics, Inc.; Pfizer; Kite Pharma, Inc.; Arog Pharmaceuticals, Inc.; and AbbVie, respectively.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
CONSORT diagram
Fig. 2
Fig. 2
Sacral GCTB before and after treatment with denosumab. a Bone window and b soft tissue window pretreatment CT scan from August 14, 2009, through the level of the upper hip joints. There is extensive bone destruction and a large soft tissue mass that displaces the rectum. c Bone window and d soft tissue window CT repeat scan on December 12, 2013 (about 4 years and 4 months later) following treatment with denosumab (about 3 years and 10 months; first dose on January 21, 2010, and last dose on November 21, 2013). The soft tissue mass is now negligible, and the bone is reconstituting. CT computed tomography; GCTB giant cell tumor of bone

References

    1. Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006;37:35–51. doi: 10.1016/j.ocl.2005.08.005.
    1. Futamura N, Urakawa H, Tsukushi S, Arai E, Kozawa E, Ishiguro N, Nishida Y. Giant cell tumor of bone arising in long bones possibly originates from the metaphyseal region. Oncol Lett. 2016;11:2629–2634. doi: 10.3892/ol.2016.4264.
    1. Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res. 1986;209:9–24.
    1. Szendrői Miklós. European Surgical Orthopaedics and Traumatology. Berlin, Heidelberg: Springer Berlin Heidelberg; 2014. Giant-Cell Tumour of Bone (GCT) pp. 4037–4054.
    1. Klenke FM, Wenger DE, Inwards CY, Rose PS, Sim FH. Recurrent giant cell tumor of long bones: analysis of surgical management. Clin Orthop Relat Res. 2011;469:1181–1187. doi: 10.1007/s11999-010-1560-9.
    1. Szendroi M. Giant-cell tumour of bone. J Bone Joint Surg Br. 2004;86:5–12. doi: 10.1302/0301-620X.86B1.14053.
    1. Arbeitsgemeinschaft K, Becker WT, Dohle J, Bernd L, Braun A, Cserhati M, Enderle A, Hovy L, Matejovsky Z, Szendroi M, et al. Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy. J Bone Joint Surg Am. 2008;90:1060–1067. doi: 10.2106/JBJS.D.02771.
    1. Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;69:106–114. doi: 10.2106/00004623-198769010-00018.
    1. Branstetter DG, Nelson SD, Manivel JC, Blay JY, Chawla S, Thomas DM, Jun S, Jacobs I. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012;18:4415–4424. doi: 10.1158/1078-0432.CCR-12-0578.
    1. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010;11:275–280. doi: 10.1016/S1470-2045(10)70010-3.
    1. Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, Kroep J, Grimer R, Reichardt P, Rutkowski P, et al. 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. Lancet Oncol. 2013;14:901–908. doi: 10.1016/S1470-2045(13)70277-8.
    1. Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999;35:1773–1782. doi: 10.1016/S0959-8049(99)00229-4.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–1759. doi: 10.1200/JCO.2006.07.3049.
    1. Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP, Pienkowski A, Vaz G, Wunder JS, Seeger LL, Feng A, 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;22:2860–2868. doi: 10.1245/s10434-015-4634-9.
    1. Wu KK, Ross PM, Mitchell DC, Sprague HH. Evolution of a case of multicentric giant cell tumor over a 23-year period. Clin Orthop Relat Res. 1986;213:279–88.
    1. Sim FH, Dahlin DC, Beabout JW. Multicentric giant-cell tumor of bone. J Bone Joint Surg Am. 1977;59:1052–1060. doi: 10.2106/00004623-197759080-00009.
    1. Tornberg DN, Dick HM, Johnston AD. Multicentric giant-cell tumors in the long bones. A case report. J Bone Joint Surg Am. 1975;57:420–422. doi: 10.2106/00004623-197557030-00026.
    1. Hindman BW, Seeger LL, Stanley P, Forrester DM, Schwinn CP, Tan SZ. Multicentric giant cell tumor: report of five new cases. Skelet Radiol. 1994;23:187–190. doi: 10.1007/BF00197457.
    1. Hoch B, Inwards C, Sundaram M, Rosenberg AE. Multicentric giant cell tumor of bone. Clinicopathologic analysis of thirty cases. J Bone Joint Surg Am. 2006;88:1998–2008.
    1. Wirbel R, Blumler F, Lommel D, Syre G, Krenn V. Multicentric giant cell tumor of bone: synchronous and metachronous presentation. Case Rep Orthop. 2013;2013:756723.
    1. Ueda T, Morioka H, Nishida Y, Kakunaga S, Tsuchiya H, Matsumoto Y, Asami Y, Inoue T, Yoneda T. Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial. Ann Oncol. 2015;26:2149–2154. doi: 10.1093/annonc/mdv307.
    1. Aponte-Tinao LA, Piuzzi NS, Roitman P, Farfalli GL. A high-grade sarcoma arising in a patient with recurrent benign giant cell tumor of the proximal tibia while receiving treatment with denosumab. Clin Orthop Relat Res. 2015;473:3050–3055. doi: 10.1007/s11999-015-4249-2.
    1. Broehm CJ, Garbrecht EL, Wood J, Bocklage T. Two cases of sarcoma arising in giant cell tumor of bone treated with denosumab. Case Rep Med. 2015;2015:767198. doi: 10.1155/2015/767198.
    1. Bertoni F, Bacchini P, Staals EL. Malignancy in giant cell tumor of bone. Cancer. 2003;97:2520–2529. doi: 10.1002/cncr.11359.
    1. Sanerkin NG. Malignancy, aggressiveness, and recurrence in giant cell tumor of bone. Cancer. 1980;46:1641–1649. doi: 10.1002/1097-0142(19801001)46:7<1641::AID-CNCR2820460725>;2-Z.
    1. McGrath PJ. Giant-cell tumour of bone: an analysis of fifty-two cases. J Bone Joint Surg Br. 1972;54:216–229. doi: 10.1302/0301-620X.54B2.216.
    1. Hefti FL, Gachter A, Remagen W, Nidecker A. Recurrent giant-cell tumor with metaplasia and malignant change, not associated with radiotherapy. A case report. J Bone Joint Surg Am. 1992;74:930–934. doi: 10.2106/00004623-199274060-00015.
    1. Turcotte Robert E., Wunder Jay S., Isler Marc H., Bell Robert S., Schachar Norman, Masri Bassam A., Moreau Guy, Davis Aileen M. Giant Cell Tumor of Long Bone: A Canadian Sarcoma Group Study. Clinical Orthopaedics and Related Research. 2002;397:248–258. doi: 10.1097/00003086-200204000-00029.
    1. Sung HW, Kuo DP, Shu WP, Chai YB, Liu CC, Li SM. Giant-cell tumor of bone: analysis of two hundred and eight cases in Chinese patients. J Bone Joint Surg Am. 1982;64:755–761. doi: 10.2106/00004623-198264050-00015.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera