Laura CAMPANACCİ, Andrea SAMBRİ, Manuel Ricardo MEDELLİN, Pietro CİMATTİ, Costantino ERRANİ, Davide Maria DONATİ

A new computerized tomography classification to evaluate response to Denosumab in giant cell tumors in the extremities

Objectives: The aim of this study was to describe the cohort of patients who have been treated with Denosumab as neoadjuvant therapy prior to surgery for aggressive giant cell tumor of bone in the extremities, to evaluate the radiological responses to Denosumab comparing Choi criteria and a newly described computerized tomography (CT) classification, and to evaluate the risk of local recurrence after intralesional curettage or radical excision. Methods: We retrospectively evaluated 36 patients (20 females and 16 males; mean age at diagnosis 36 years (range, 18e64)) treated with neoadjuvant Denosumab therapy prior to surgery for aggressive giant cell tumor of bone in the extremities. The radiological responses to Denosumab treatment were analyzed on the preoperative images after the neoadjuvant course with the Choi criteria and with a newly proposed classification based on CT. All these images were independently reviewed by two of the researchers. Surgical intervention methods were noted and local recurrence rates were evaluated. The correlation between radiological response amount and local recurrence were analyzed for both Choi criteria and the new CT classification. Results: Denosumab was administered for a mean of 21 weeks (range 7e133). Five patients also had a short postoperative course. According to Choi criteria there was a radiological response in 32 patients (89%), while the new CT classification identified responses in all the 36 patients (100%). The identification of changes after 7 weeks of treatment was higher using the CT classification compared to Choi criteria (p ¼ 0.043 vs p ¼ 0.462). The surgical interventions after Denosumab comprised curettage in 29 patients (74%) and resection in 7 (26%). Local recurrence was higher in patients managed with intralesional curettage than in those treated with en bloc resection (55.1% vs 0%, p < 0.001). At last follow up 19 patients (53%) required en bloc resections. Good responders to Denosumab (type 2C) had lower risk of local recurrence (p ¼ 0.047) after either resection or curettage. Conclusion: The new CT classification evaluated more accurately the response to Denosumab. Our experience suggests that the requirement for radical bone resection remains high despite the use of Denosumab.

___

1. Skubitz KM. Giant cell tumor of bone: current treatment options. Curr Treat Options Oncol. 2014;15(3):507e518. https://doi.org/10.1007/s11864-014- 0289-1.

2. van der Heijden L, Dijkstra PD, van de Sande MA, et al. The clinical approach toward giant cell tumor of bone. Oncologist. 2014;19(5):550e561. https://doi. org/10.1634/theoncologist.2013-0432.

3. He Y, Zhang J, Ding X. Prognosis of local recurrence in giant cell tumour of bone: what can we do? Radiol Med. 2017;122(7):505e519. https://doi.org/10. 1007/s11547-017-0746-6.

4. Errani C, Ruggieri P, Asenzio MA, et al. Giant cell tumor of the extremity: a review of 349 cases from a single institution. Cancer Treat Rev. 2010;36(1):1e7. https://doi.org/10.1016/j.ctrv.2009.09.002.

5. Errani C, Tsukamoto S, Leone G, et al. Denosumab may increase the risk of local recurrence in patients with giant-cell tumor of bone treated with curettage. J Bone Joint Surg Am. 2018;100(6):496e504. https://doi.org/10.2106/JBJS.17. 00057.

6. Shehadeh A, Noveau J, Malawer M, Henshaw R. Late complications and survival of endoprosthetic reconstruction after resection of bone tumors. Clin Orthop Relat Res. 2010;468(11):2885e2895. https://doi.org/10.1007/s11999-010- 1454-x.

7. Rosario M, Takeuchi A, Yamamoto N, et al. Pathogenesis of osteosclerotic change following treatment with an antibody against rankl for giant cell tumour of the bone. Anticancer Res. 2017;37(2):749e754. https://doi.org/10. 21873/anticanres.11373.

8. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012;18(16):4415e4424. https://doi.org/10.1158/1078-0432.CCR12-0578.

9. Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside: elucidation of the opgrank-rankl pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11(5):401e419. https://doi.org/10.1038/nrd3705.

10. 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 analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14(9):901e908. https://doi.org/10.1016/S1470-2045(13)70277-8.

11. Ueda T, Morioka H, Nishida Y, et al. Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase ii trial. Ann Oncol. 2015;26(10):2149e2154. https://doi.org/10.1093/annonc/mdv307.

12. 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):2860e2868. https://doi.org/10.1245/s10434-015-4634-9.

13. Boye K, Jebsen NL, Zaikova O, et al. Denosumab in patients with giant-cell tumor of bone in Norway: results from a nationwide cohort. Acta Oncol. 2017;56(3):479e483. https://doi.org/10.1080/0284186X.2016.1278305.

14. Gaston CL, Grimer RJ, Parry M, et al. Current status and unanswered questions on the use of denosumab in giant cell tumor of bone. Clin Sarcoma Res. 2016;6(1):15. https://doi.org/10.1186/s13569-016-0056-0.

15. Engellau J, Seeger L, Grimer R, et al. Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone. World J Surg Oncol. 2018;16(1):191. https://doi.org/10.1186/s12957-018-1478-3.

16. Palmerini E, Chawla NS, Ferrari S, et al. Denosumab in advanced/unresectable giant-cell tumour of bone (Gctb): for how long? Eur J Cancer. 2017;76: 118e124. https://doi.org/10.1016/j.ejca.2017.01.028.

17. Choi H, Charnsangavej C, Faria SC, et al. 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(13): 1753e1759. https://doi.org/10.1200/JCO.2006.07.3049.

18. Enneking WF, Dunham WK. Resection and reconstruction for primary neoplasms involving the innominate bone. J Bone Joint Surg Am. 1978;60(6): 731e746.

19. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494e502.

20. Rekhi B, Verma V, Gulia A, et al. Clinicopathological features of a series of 27 cases of post-denosumab treated giant cell tumors of bones: a single institutional experience at a tertiary cancer referral centre, India. Pathol Oncol Res. 2017;23(1):157e164. https://doi.org/10.1007/s12253-016-0123-0.

21. Muller DA, Beltrami G, Scoccianti G, Campanacci DA, Franchi A, Capanna R. Risks and benefits of combining denosumab and surgery in giant cell tumor of bone-a case series. World J Surg Oncol. 2016;14(1):281. https://doi.org/10.1186/ s12957-016-1034-y.

22. Traub F, Singh J, Dickson BC, et al. Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone. Eur J Cancer. 2016;59:1e12. https://doi.org/10.1016/j.ejca.2016.01.006.

23. Costelloe CM, Chuang HH, Madewell JE, Ueno NT. Cancer response criteria and bone metastases: recist 1.1, Mda and percist. J Cancer. 2010;1:80e92.

24. Deveci MA, Paydas S, Gonlusen G, Ozkan C, Bicer OS, Tekin M. Clinical and pathological results of denosumab treatment for giant cell tumors of bone: prospective study of 14 cases. Acta Orthop Traumatol Turc. 2017;51(1):1e6. https://doi.org/10.1016/j.aott.2016.03.004.