Interpretation of National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Bone Cancer (Version 2.2026): Updates in diagnosis and treatment strategies for giant cell tumor of bone, osteosarcoma, and Ewing sarcoma_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LI Ruoyu ¹ , HE Mincong ² , ZHENG Jiaqian ¹ , WANG Zhen ³ ,  FANG Bin ¹

1. Department of Bone and Soft Tissue Oncology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou Guangdong, 510405, P. R. China;
2. Department of Orthopedics, the Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou Guangdong, 510378, P. R. China;
3. Department of Orthopedics, Xijing Hospital, the Air Force Medical University, Xi’an Shaanxi, 710032, P. R. China;

Corresponding?author：

FANG Bin, Email: 2352199836@qq.com

Keywords：

Bone neoplasms; National Comprehensive Cancer Network guidelines; giant cell tumor of bone; osteosarcoma; Ewing sarcoma; interpretation of guidelines

DOI：

10.7507/1002-1892.202603049

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Giant cell tumor of bone (GCTB), osteosarcoma, and Ewing sarcoma represent the most characteristic primary bone neoplasms, and optimization of their diagnostic and therapeutic strategies remains a research priority in the field of bone and soft tissue oncology. The National Comprehensive Cancer Network (NCCN) released the Clinical Practice Guidelines in Bone Cancer (Version 2.2026), introducing key evidence-based updates spanning equivalent biological therapy alternatives, perioperative chemotherapy conceptual restructuring, expanded management strategies for recurrent/progressive disease, refined molecular diagnostic protocols, fertility preservation, and standardization of rare subtype treatment. This article systematically interprets the revision highlights of this guideline, integrates recent high-level clinical research evidence, analyzes its evidence-based foundation and clinical translation pathway, and compares it with relevant domestic diagnostic and therapeutic standards to provide academic reference for multidisciplinary standardized management of bone tumors in China.

Citation： LI Ruoyu, HE Mincong, ZHENG Jiaqian, WANG Zhen, FANG Bin. Interpretation of National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Bone Cancer (Version 2.2026): Updates in diagnosis and treatment strategies for giant cell tumor of bone, osteosarcoma, and Ewing sarcoma. Chinese Journal of Reparative and Reconstructive Surgery, 2026, 40(6): 860-866. doi: 10.7507/1002-1892.202603049 Copy

1.	Calvert GT, Randall RL, Jones KB, et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma, 2012, 2012: 152382. doi: 10.1155/2012/152382.
2.	Mirabello L, Zhu B, Koster R, et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol, 2020, 6(5): 724-734.
3.	Ottaviani G, Jaffe N. The etiology of osteosarcoma. Cancer Treat Res, 2009, 152: 15-32.
4.	Bielack SS, Baumhoer D, Hecker-Nolting S, et al. Osteosarcomas in retinoblastoma-survivors: a report of 28 affected patients from the Cooperative Osteosarcoma Study Group (COSS). EJC Paediatric Oncology, 2024, 3: 100158. doi: 10.1016/j.ejcped.2024.100158.
5.	Aoude A, Nikomarov D, Perera JR, et al. Giant cell tumour of bone: analysis of risk factors for recurrence in 354 patients. The Bone & Joint Journal, 2023, 105-B(5): 559-567.
6.	Chawla S, Blay J, Rutkowski P, et al. Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol, 2019, 20(12): 1719-1729.
7.	Zhao M, Hu X, Zhuang P, et al. A multicenter, randomized, double-blind trial comparing LY01011, a biosimilar, with denosumab (Xgeva^?) in patients with bone metastasis from solid tumors. J Bone Oncol, 2025, 51: 100661. doi: 10.1016/j.jbo.2025.100661.
8.	Li N, Chu N, Zhu L, et al. Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase Ⅰ study. Clinical and Translational Science, 2024, 17(12): 1-12.
9.	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): 496-504.
10.	Aponte-Tinao LA, Piuzzi NS, Roitman P, et al. 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(9): 3050-3055.
11.	中華人民共和國國家衛生健康委員會. 骨肉瘤診療指南(2025年版). 中國修復重建外科雜志, 2026, 40(1): 161-163.
12.	Kager L, Zoubek A, P?tschger U, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol, 2003, 21(10): 2011-2018.
13.	Bacci G, Longhi A, Ferrari S, et al. Prognostic factors in non-metastatic Ewing’s sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol, 2006, 45(4): 469-475.
14.	Staals EL, Bacchini P, Bertoni F. High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer, 2008, 112(7): 1592-1599.
15.	Adewuyi E, Chorya H, Muili A, et al. Chemotherapy, immunotherapy, and targeted therapy for osteosarcoma: Recent advancements. Crit Rev Oncol Hematol, 2025, 206: 104575. doi: 10.1016/j.critrevonc.2024.104575.
16.	Palmerini E, Meazza C, Tamburini A, et al. Is there a role for mifamurtide in nonmetastatic high-grade osteosarcoma? results from the Italian sarcoma group (ISG/OS-2) and Spanish sarcoma group (GEIS-33) trials. J Clin Oncol, 2025, 43(28): 3113-3122.
17.	Hiraga H, Machida R, Kawai A, et al. Methotrexate, doxorubicin, and cisplatin versus methotrexate, doxorubicin, and cisplatin+ifosfamide in poor responders to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (JCOG0905): a multicenter, open-label, randomized trial. J Clin Oncol, 2025, 43(16): 1886-1897.
18.	Bacci G, Longhi A, Ferrari S, et al. Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity: experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori, 2004, 90(5): 478-84.
19.	Endara SA, De la Torre JS, Terán FJ, et al. Multidisciplinary management of recurrent synovial sarcoma of the chest wall. N Am Spine Soc J, 2023, 15: 100243. doi: 10.1016/j.xnsj.2023.100243.
20.	Daw NC, Chou AJ, Jaffe N, et al. Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer, 2015, 112(2): 278-282.
21.	Bielack SS, Kempf-Bielack B, Branscheid D, et al. Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. J Clin Oncol, 2009, 27(4): 557-565.
22.	Bacci G, Ferrari S, Lari S, et al. Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg (Br), 2002, 84(1): 88-92.
23.	Aksnes LH, Bauer HC, Jebsen NL, et al. Limb-sparing surgery preserves more function than amputation: a Scandinavian Sarcoma Group study of 118 patients. J Bone Joint Surg (Br), 2008, 90(6): 786-794.
24.	Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors—A subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med, 1994, 331(5): 294-299.
25.	Riggi N, Suvà ML, Stamenkovic I. Ewing’s sarcoma. New Engl J, 2021, 384(2): 154-164.
26.	Treglia G, Salsano M, Stefanelli A, et al. Diagnostic accuracy of ¹⁸F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiology, 2012, 41(3): 249-256.
27.	Italiano A, Di Mauro I, Rapp J, et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol, 2016, 17(4): 532-538.
28.	Glaubiger DL, Makuch R, Schwarz J, et al. Determination of prognostic factors and their influence on therapeutic results in patients with Ewing’s sarcoma. Cancer, 1980, 45(8): 2213-2219.
29.	Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med, 2003, 348(8): 694-701.
30.	Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol, 2012, 30(33): 4148-4154.
31.	Brennan B, Kirton L, Marec-Bérard P, et al. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. The Lancet, 2022, 400(10362): 1513-1521.
32.	Whelan J, Le Deley MC, Dirksen U, et al. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-E. W. I. N. G. 99 and Ewing-2008. J Clin Oncol, 2018, 36(31): JCO2018782516. doi: 10.1200/JCO.2018.78.2516.
33.	Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys, 2003, 55(1): 168-177.
34.	郭衛, 王臻, 郭征, 等. 尤文肉瘤腫瘤家族(ESFT)臨床循證診療指南. 中華骨與關節外科雜志, 2018, 11(4): 260-275.
35.	Italiano A, Mir O, Mathoulin-Pelissier S, et al. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. The Lancet. Oncology, 2020, 21(3): 446-455.
36.	Duffaud F, Mir O, Boudou-Rouquette P, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. The Lancet. Oncology, 2019, 20(1): 120-133.
37.	Beinse G, Boudou-Rouquette P, de Percin S, et al. Fertility preservation in women with sarcoma: a real-world experience. Int J Cancer, 2026, 158(5): 1178-1183.
38.	Burns K, Loren AW. Fertility preservation in adolescents and young adults with cancer: a case-based review. J Clin Oncol, 2024, 42(6): 725-734.
39.	Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg (Am), 1993, 75(9): 1276-1281.
40.	Liu PT, Valadez SD, Chivers FS, et al. Anatomically based guidelines for core needle biopsy of bone tumors: implications for limb-sparing surgery. Radiographics : a review publication of the Radiological Society of North America, Inc. 2007, 27(1): 189-206.
41.	Skrzynski MC, Biermann JS, Montag A, et al. Diagnostic accuracy and charge-savings of outpatient core needle biopsy compared with open biopsy of musculoskeletal tumors. J Bone Joint Surg (Am), 1996, 78(5): 644-649.
42.	Ashford RU, McCarthy SW, Scolyer RA, et al. Surgical biopsy with intra-operative frozen section. An accurate and cost-effective method for diagnosis of musculoskeletal sarcomas. J Bone Joint Surg (Br), 2006, 88(9): 1207-1211.
43.	Connolly E, Boye K, Bonvalot S, et al. Genetic predisposition in sarcomas: clinical implications and management. eClinicalMedicine, 2025, 83: 103203. doi: 10.1016/j.eclinm.2025.103203.

1. Calvert GT, Randall RL, Jones KB, et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma, 2012, 2012: 152382. doi: 10.1155/2012/152382.
2. Mirabello L, Zhu B, Koster R, et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol, 2020, 6(5): 724-734.
3. Ottaviani G, Jaffe N. The etiology of osteosarcoma. Cancer Treat Res, 2009, 152: 15-32.
4. Bielack SS, Baumhoer D, Hecker-Nolting S, et al. Osteosarcomas in retinoblastoma-survivors: a report of 28 affected patients from the Cooperative Osteosarcoma Study Group (COSS). EJC Paediatric Oncology, 2024, 3: 100158. doi: 10.1016/j.ejcped.2024.100158.
5. Aoude A, Nikomarov D, Perera JR, et al. Giant cell tumour of bone: analysis of risk factors for recurrence in 354 patients. The Bone & Joint Journal, 2023, 105-B(5): 559-567.
6. Chawla S, Blay J, Rutkowski P, et al. Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol, 2019, 20(12): 1719-1729.
7. Zhao M, Hu X, Zhuang P, et al. A multicenter, randomized, double-blind trial comparing LY01011, a biosimilar, with denosumab (Xgeva^?) in patients with bone metastasis from solid tumors. J Bone Oncol, 2025, 51: 100661. doi: 10.1016/j.jbo.2025.100661.
8. Li N, Chu N, Zhu L, et al. Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase Ⅰ study. Clinical and Translational Science, 2024, 17(12): 1-12.
9. 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): 496-504.
10. Aponte-Tinao LA, Piuzzi NS, Roitman P, et al. 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(9): 3050-3055.
11. 中華人民共和國國家衛生健康委員會. 骨肉瘤診療指南(2025年版). 中國修復重建外科雜志, 2026, 40(1): 161-163.
12. Kager L, Zoubek A, P?tschger U, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol, 2003, 21(10): 2011-2018.
13. Bacci G, Longhi A, Ferrari S, et al. Prognostic factors in non-metastatic Ewing’s sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol, 2006, 45(4): 469-475.
14. Staals EL, Bacchini P, Bertoni F. High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer, 2008, 112(7): 1592-1599.
15. Adewuyi E, Chorya H, Muili A, et al. Chemotherapy, immunotherapy, and targeted therapy for osteosarcoma: Recent advancements. Crit Rev Oncol Hematol, 2025, 206: 104575. doi: 10.1016/j.critrevonc.2024.104575.
16. Palmerini E, Meazza C, Tamburini A, et al. Is there a role for mifamurtide in nonmetastatic high-grade osteosarcoma? results from the Italian sarcoma group (ISG/OS-2) and Spanish sarcoma group (GEIS-33) trials. J Clin Oncol, 2025, 43(28): 3113-3122.
17. Hiraga H, Machida R, Kawai A, et al. Methotrexate, doxorubicin, and cisplatin versus methotrexate, doxorubicin, and cisplatin+ifosfamide in poor responders to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (JCOG0905): a multicenter, open-label, randomized trial. J Clin Oncol, 2025, 43(16): 1886-1897.
18. Bacci G, Longhi A, Ferrari S, et al. Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity: experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori, 2004, 90(5): 478-84.
19. Endara SA, De la Torre JS, Terán FJ, et al. Multidisciplinary management of recurrent synovial sarcoma of the chest wall. N Am Spine Soc J, 2023, 15: 100243. doi: 10.1016/j.xnsj.2023.100243.
20. Daw NC, Chou AJ, Jaffe N, et al. Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer, 2015, 112(2): 278-282.
21. Bielack SS, Kempf-Bielack B, Branscheid D, et al. Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. J Clin Oncol, 2009, 27(4): 557-565.
22. Bacci G, Ferrari S, Lari S, et al. Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg (Br), 2002, 84(1): 88-92.
23. Aksnes LH, Bauer HC, Jebsen NL, et al. Limb-sparing surgery preserves more function than amputation: a Scandinavian Sarcoma Group study of 118 patients. J Bone Joint Surg (Br), 2008, 90(6): 786-794.
24. Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors—A subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med, 1994, 331(5): 294-299.
25. Riggi N, Suvà ML, Stamenkovic I. Ewing’s sarcoma. New Engl J, 2021, 384(2): 154-164.
26. Treglia G, Salsano M, Stefanelli A, et al. Diagnostic accuracy of ¹⁸F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiology, 2012, 41(3): 249-256.
27. Italiano A, Di Mauro I, Rapp J, et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol, 2016, 17(4): 532-538.
28. Glaubiger DL, Makuch R, Schwarz J, et al. Determination of prognostic factors and their influence on therapeutic results in patients with Ewing’s sarcoma. Cancer, 1980, 45(8): 2213-2219.
29. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med, 2003, 348(8): 694-701.
30. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol, 2012, 30(33): 4148-4154.
31. Brennan B, Kirton L, Marec-Bérard P, et al. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. The Lancet, 2022, 400(10362): 1513-1521.
32. Whelan J, Le Deley MC, Dirksen U, et al. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-E. W. I. N. G. 99 and Ewing-2008. J Clin Oncol, 2018, 36(31): JCO2018782516. doi: 10.1200/JCO.2018.78.2516.
33. Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys, 2003, 55(1): 168-177.
34. 郭衛, 王臻, 郭征, 等. 尤文肉瘤腫瘤家族(ESFT)臨床循證診療指南. 中華骨與關節外科雜志, 2018, 11(4): 260-275.
35. Italiano A, Mir O, Mathoulin-Pelissier S, et al. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. The Lancet. Oncology, 2020, 21(3): 446-455.
36. Duffaud F, Mir O, Boudou-Rouquette P, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. The Lancet. Oncology, 2019, 20(1): 120-133.
37. Beinse G, Boudou-Rouquette P, de Percin S, et al. Fertility preservation in women with sarcoma: a real-world experience. Int J Cancer, 2026, 158(5): 1178-1183.
38. Burns K, Loren AW. Fertility preservation in adolescents and young adults with cancer: a case-based review. J Clin Oncol, 2024, 42(6): 725-734.
39. Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg (Am), 1993, 75(9): 1276-1281.
40. Liu PT, Valadez SD, Chivers FS, et al. Anatomically based guidelines for core needle biopsy of bone tumors: implications for limb-sparing surgery. Radiographics : a review publication of the Radiological Society of North America, Inc. 2007, 27(1): 189-206.
41. Skrzynski MC, Biermann JS, Montag A, et al. Diagnostic accuracy and charge-savings of outpatient core needle biopsy compared with open biopsy of musculoskeletal tumors. J Bone Joint Surg (Am), 1996, 78(5): 644-649.
42. Ashford RU, McCarthy SW, Scolyer RA, et al. Surgical biopsy with intra-operative frozen section. An accurate and cost-effective method for diagnosis of musculoskeletal sarcomas. J Bone Joint Surg (Br), 2006, 88(9): 1207-1211.
43. Connolly E, Boye K, Bonvalot S, et al. Genetic predisposition in sarcomas: clinical implications and management. eClinicalMedicine, 2025, 83: 103203. doi: 10.1016/j.eclinm.2025.103203.

Chinese Journal of Reparative and Reconstructive Surgery

Interpretation of National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Bone Cancer (Version 2.2026): Updates in diagnosis and treatment strategies for giant cell tumor of bone, osteosarcoma, and Ewing sarcoma

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content