What is the best clinical approach to recurrent/refractory osteosarcoma?

References

• Picci P, Manfrini M, Fabbri N, et al. Classic osteosarcoma. In: Picci P, Manfrini M, Fabbri Neditors. Atlas of muskuloskeletal tumors and tumorlike lesions. Cham: Springer International Publishing Switzerland; 2014. p. 147–152.
   Google Scholar
• Casali PG, Blay JY, Bertuzzi A, et al. Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):113–123.
   Google Scholar
• Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 2010;8:705–718.
   PubMedGoogle Scholar
• Stiller CA, Bielack SS, Jundt G, et al. Bone tumours in European children and adolescents, 1978-1997. Report from the automated childhood cancer information system project. Eur J Cancer. 2006;42:2124–2135.
   PubMed Web of Science ®Google Scholar
• Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999–2007: results of EUROCARE-5-a population-based study. Lancet Oncol. 2014;15(1):35–47.
   PubMed Web of Science ®Google Scholar
• Cotterill SJ, Wright CM, Pearce MS, et al. Stature of young people with malignant bone tumors. Pediatr Blood Cancer. 2004;42(1):59–63.
   PubMed Web of Science ®Google Scholar
• Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.
   PubMedGoogle Scholar
• Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776–790.
   PubMed Web of Science ®Google Scholar
• Luetke A, Meyers PA, Lewis I, et al. Osteosarcoma treatment - Where do we stand? A state of the art review. Cancer Treat Rev. 2014;40(4):523–532.
   PubMed Web of Science ®Google Scholar
• Ta HT, Dass CR, Choong PFM, et al. Osteosarcoma treatment: state of the art. Cancer Metastasis Rev. 2009;28(1–2):247–263.
   PubMed Web of Science ®Google Scholar
• Kempf-Bielack B, Bielack SS, Jürgens H, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005;23:559–568.
   PubMed Web of Science ®Google Scholar
• Strauss SJ, McTiernan A, Whelan JS. Late relapse of osteosarcoma: implications for follow-up and screening. Pediatr Blood Cancer. 2004;43:692–697.
   PubMed Web of Science ®Google Scholar
• 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. 27(4): 557–565. 2009. .
   Web of Science ®Google Scholar
• Martini N, Huvos AG, Miké V, et al. Multiple Pulmonary Resections in the Treatment of Osteogenic Sarcoma. Ann Thorac Surg. 1971;12(3):271–280.
   PubMedGoogle Scholar
• Hawkins DS, Arndt CAS. Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer. 2003;98:2447–2456.
   PubMed Web of Science ®Google Scholar
• Bacci G, Bricoli A, Longhi A, et al. Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol (Madr). 2005;44(7):748–755.
   PubMed Web of Science ®Google Scholar
• Antunes M, Bernardo J, Salete M, et al. Excision of pulmonary metastases of osteogenic sarcoma of the limbs. Eur J Cardiothorac Surg. 1999;15:592–596.
   PubMed Web of Science ®Google Scholar
• Lamoureux F, Trichet V, Chipoy C, et al. Recent advances in the management of osteosarcoma and forthcoming therapeutic strategies. Expert Rev Anticancer Ther. 2007;7:169–181.
   PubMed Web of Science ®Google Scholar
• Saeter G, Høie J, Stenwig AE, et al. Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival. Cancer. 1995;75(5):1084–1093.
   PubMed Web of Science ®Google Scholar
• Giuliano AE, Feig S, Eilber FR. Changing metastatic patterns of osteosarcoma. Cancer. 1984;54(10):2160–2164.
   PubMed Web of Science ®Google Scholar
• Jaffe N, Smith E, Abelson HT, et al. Osteogenic sarcoma: alterations in the pattern of pulmonary metastases with adjuvant chemotherapy. J Clin Oncol. 1983;1(4):251–254.
   PubMed Web of Science ®Google Scholar
• Goorin AM, Shuster JJ, Baker A, et al., Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study. J Clin Oncol. 9(4): 600–605. 1991.
   PubMed Web of Science ®Google Scholar
• Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol. 1998;9(8):893–899.
   PubMed Web of Science ®Google Scholar
• Longhi A, Errani C, De Paolis M, et al. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev. 2006;32(6):423–436.
   PubMed Web of Science ®Google Scholar
• Marina NM, Pratt CB, Rao BN, et al. Improved prognosis of children with osteosarcoma metastatic to the lung(s) at the time of diagnosis. Cancer. 1992;70:2722–2727.
   PubMed Web of Science ®Google Scholar
• Ward WG, Mikaelian K, Dorey F, et al. Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases. J Clin Oncol. 1994;12(9):1849–1858.
   PubMed Web of Science ®Google Scholar
• Ferrari S, Briccoli A, Mercuri M, et al., Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. J Clin Oncol. 21(4): 710–715. 2003. .
   PubMed Web of Science ®Google Scholar
• Goorin AM, Delorey MJ, Lack EE, et al. Prognostic significance of complete surgical resection of pulmonary metastases in patients with osteogenic sarcoma: analysis of 32 patients. J Clin Oncol. 1984;2(5):425–431.
   PubMed Web of Science ®Google Scholar
• Huth JF, Eilber FR. Patterns of recurrence after resection of osteosarcoma of the extremity: strategies for treatment of metastases. Arch Surg. 1989;124(1):122–126.
   PubMedGoogle Scholar
• Bacci G, Ferrari S, Longhi A, et al. Pattern of relapse in patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy. Eur J Cancer. 2001;37(1):32–38.
   PubMed Web of Science ®Google Scholar
• Grimer RJ, Taminiau AM, Cannon SR. Surgical outcomes in osteosarcoma. J Bone Joint Surg Br. 2002;84(3):395–400.
   PubMedGoogle Scholar
• Chi SN, Conklin LS, Qin J, et al. The patterns of relapse in osteosarcoma: the memorial sloan-kettering experience. Pediatr Blood Cancer. 2004;42(1):46–51.
   PubMed Web of Science ®Google Scholar
• Lindner NJ, Ramm O, Hillmann A, et al. Limb salvage and outcome of osteosarcoma: the university of Muenster experience. Clin Orthop Relat Res. 1999; (358):83–89.
   PubMed Web of Science ®Google Scholar
• Sluga M, Windhager R, Lang S, et al. Local and systemic control after ablative and limb sparing surgery in patients with osteosarcoma. Clin Orthop Relat Res. 1999;358:120–127.
   Google Scholar
• Longhi A, Fabbri N, Donati D, et al. Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother. 2001;13:324–330.
   PubMed Web of Science ®Google Scholar
• Leary SES, Wozniak AW, Billups CA, et al. Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children’s Research Hospital experience. Cancer. 2013;119(14):2645–2653.
   PubMed Web of Science ®Google Scholar
• Harting MT, Blakely ML, Jaffe N, et al. Long-term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma. J Pediatr Surg. 2006;41:194–199.
   PubMed Web of Science ®Google Scholar
• Daw NC, Chou AJ, Jaffe N, et al. Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer. 2015;112:278–282.
   PubMed Web of Science ®Google Scholar
• Briccoli A, Rocca M, Salone M, et al. Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer. 2005;104(8):1721–1725.
   PubMed Web of Science ®Google Scholar
• Gelderblom H, Jinks RC, Sydes M, et al. Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer. 2011;47(6):895–902.
   PubMed Web of Science ®Google Scholar
• Tsuchiya H, Kanazawa Y, Abdel-Wanis ME, et al., Effect of timing of pulmonary metastases identification on prognosis of patients with osteosarcoma: the Japanese Musculoskeletal Oncology Group study. J Clin Oncol. 20(16): 3470–3477. 2002.
   PubMed Web of Science ®Google Scholar
• Chou AJ, Merola PB, Wexler LH, et al. Treatment of osteosarcoma at first recurrence after contemporary therapy: the memorial sloan-kettering cancer center experience. Cancer. 2005;104(10):2214–2221.
   PubMed Web of Science ®Google Scholar
• Spraker-Perlman HL, Barkauskas DA, Krailo MD, et al. Factors influencing survival after recurrence in osteosarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2019;66(1):e27444.
   PubMed Web of Science ®Google Scholar
• Janeway KA, Barkauskas DA, Krailo MD, et al. Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2012;118(18):4597–4605.
   PubMed Web of Science ®Google Scholar
• Briccoli A, Rocca M, Salone M, et al. High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985–2005. Surg Oncol. 2010;19:193–199.
   PubMed Web of Science ®Google Scholar
• Pastorino U, Gasparini M, Tavecchio L, et al. The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol. 1991;9(8):1357–1362.
   PubMed Web of Science ®Google Scholar
• Skinner KA, Eilber FR, Holmes EC, et al. Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma. Arch Surg. 1992;127(9):1065–1070.
   PubMedGoogle Scholar
• Fernandez-Pineda I, Daw NC, McCarville B, et al. Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience. J Pediatr Surg. 2012;47:1250–1254.
   PubMed Web of Science ®Google Scholar
• Scanagatta P. Muscle-sparing thoracotomy: a systematic literature review and the “AVE” classification. J Surg Res. 2015;1(3):035–044.
   Google Scholar
• Fell SC, DeCamp MM. Technical aspects of lobectomy. Gen Thorac Surg Seventh Ed. 2011;479–485.
   Google Scholar
• Rolle A, Pereszlenyi A, Koch R, et al. Is surgery for multiple lung metastases reasonable? A total of 328 consecutive patients with multiple-laser metastasectomies with a new 1318-nm Nd: yAGlaser. J Thorac Cardiovasc Surg. 2006;131(6):1236–1242.
   PubMed Web of Science ®Google Scholar
• Meazza C, Scanagatta P, Luksch R, et al. How far can we go with surgery in metastatic osteosarcoma patients?. Med Oncol. 2015;32(9):223.
   PubMed Web of Science ®Google Scholar
• Furia S, Cadenelli P, Andriani F, et al. Autologous fat tissue grafting improves pulmonary healing after laser metastasectomy. Eur J Surg Oncol. 2017;43(12):2315–2323.
   PubMed Web of Science ®Google Scholar
• Anegg U, Lindenmann J, Matzi V, et al. Efficiency of fleece-bound sealing (TachoSil®) of air leaks in lung surgery: a prospective randomised trial. Eur J Cardiothorac Surg. 2007;31:198–202.
   PubMed Web of Science ®Google Scholar
• Pasalic D, Lu Y, Betancourt-Cuellar SL, et al. Stereotactic ablative radiation therapy for pulmonary metastases: improving overall survival and identifying subgroups at high risk of local failure. Radiother Oncol. 2020 Feb;7(145):178–185.
   Google Scholar
• Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314(25):1600–1606.
   PubMed Web of Science ®Google Scholar
• Crompton BD, Goldsby RE, Weinberg VK, et al. Survival after recurrence of osteosarcoma: a 20-year experience at a single institution. Pediatr Blood Cancer. 2006;47(3):255–259.
   PubMed Web of Science ®Google Scholar
• Tabone MD, Kalifa C, Rodary C, et al. Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol. 1994;12(12):2614–2620.
   PubMed Web of Science ®Google Scholar
• Berrak SG, Pearson M, Berberoǧlu S, et al. High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity. Pediatr Blood Cancer. 2005;44(3):215–219.
   PubMed Web of Science ®Google Scholar
• Belli L, Scholl S, Livartowski A, et al. Resection of pulmonary metastases in osteosarcoma. a retrospective analysis of 44 patients. Cancer. 1989;63(12):2546–2550.
   PubMed Web of Science ®Google Scholar
• Duffaud F, Egerer G, Ferrari S, et al. A phase II trial of second-line pemetrexed in adults with advanced/metastatic osteosarcoma. Eur J Cancer. 2012;48(4):564–570.
   PubMed Web of Science ®Google Scholar
• Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian sarcoma group study. Ann Oncol. 2012;23(2):508–516.
   PubMed Web of Science ®Google Scholar
• Grignani G, Palmerini E, Ferraresi V, et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 2015;16(1):98–107.
   PubMed Web of Science ®Google Scholar
• Omer N, Le Deley MC, Piperno-Neumann S, et al. Phase-II trials in osteosarcoma recurrences: a systematic review of past experience. Eur J Cancer. 2017;75:98–108.
   PubMed Web of Science ®Google Scholar
• Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas. J Clin Oncol. 2007;25(19):2755–2763.
   PubMed Web of Science ®Google Scholar
• Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008;113(2):419–425.
   PubMed Web of Science ®Google Scholar
• Song BS, Seo J, Kim DH, et al. Gemcitabine and docetaxel for the treatment of children and adolescents with recurrent or refractory osteosarcoma: korea Cancer Center Hospital experience. Pediatr Blood Cancer. 2014;61(8):1367–1381.
   Web of Science ®Google Scholar
• Palmerini E, Jones RL, Marchesi E, et al. Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone. BMC Cancer. 2016;16(1):280.
   PubMedGoogle Scholar
• Fox E, Patel S, Wathen JK, et al. Phase II study of sequential gemcitabine followed by docetaxel for recurrent ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of sarcoma alliance for research through collaboration study 003. Oncologist. 2012;17(3):321.
   PubMed Web of Science ®Google Scholar
• Lagmay JP, Krailo MD, Kim H, et al. Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children’s Cancer Group, Pediatric Oncology Group, and Children’s Oncology Group: learning From the Past to Move Forward. J Clin Oncol. 2016;34(25):3031–3038.
   PubMed Web of Science ®Google Scholar
• Goryń T, Pieńkowski A, Szostakowski B, et al. Functional outcome of surgical treatment of adults with extremity osteosarcoma after megaprosthetic reconstruction—single-center experience. J Orthop Surg Res. 2019;14(1):346.
   PubMed Web of Science ®Google Scholar
• Weeden S, Grimer RJ, Cannon SR, et al. The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer. 2001;37(1):39–46.
   PubMed Web of Science ®Google Scholar
• Kawai A, Huvos AG, Meyers PA, et al. Osteosarcoma of the pelvis: oncologic results of 40 patients. Clin Orthop Relat Res. 1998;348:196–207.
   Google Scholar
• Picci P, Sangiorgi L, Rougraff BT, et al. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J Clin Oncol. 1994;12(12):2699–2705.
   PubMed Web of Science ®Google Scholar
• Picci P, Sangiorgi L, Bahamonde L, et al. Risk factors for local recurrences after limb-salvage surgery for high-grade osteosarcoma of the extremities. Ann Oncol. 1997;8(9):899–903.
   PubMed Web of Science ®Google Scholar
• Brosjö O. Surgical procedure and local recurrence in 223 patients treated 1982–1997 according to two osteosarcoma chemotherapy protocols. Acta Orthop Scand. 1999;70(sup285):58–61.
   Web of Science ®Google Scholar
• Loh Amos HP, Navid F, Wang C, et al. Management of local recurrence of pediatric osteosarcoma following limb-sparing surgery. Ann Surg Oncol. 2014;21(6):1948–1955.
   PubMed Web of Science ®Google Scholar
• Merimsky O, Kollender Y, Inbar M, et al. Palliative major amputation and quality of life in cancer patients. Acta Oncologica. 1997;36(2):151–157.
   PubMed Web of Science ®Google Scholar
• Bacci G, Forni C, Longhi A, et al. Local recurrence and local control of non-metastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol. 2007;96(2):118–123.
   PubMed Web of Science ®Google Scholar
• Nathan SS, Gorlick R, Bukata S, et al., Treatment algorithm for locally recurrent osteosarcoma based on local disease-free interval and the presence of lung metastasis. Cancer. 107(7): 1607–1616. 2006.
   PubMed Web of Science ®Google Scholar
• Galindo RC, Shah N, McCarville MB, et al. Outcome after local recurrence of osteosarcoma. Cancer. 2004;100(9):1928–1935. Cancer2004.
   PubMed Web of Science ®Google Scholar
• Palmerini E, Torricelli E, Cascinu S, et al. Is there a role for chemotherapy after local relapse in high-grade osteosarcoma?.Ped Blood Cancer. 2019;66(8):e27792.
   PubMed Web of Science ®Google Scholar
• Ferrari S, Bacci G, Picci P, et al. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol. 1997;8(8):765–771.
   PubMed Web of Science ®Google Scholar
• Jaffe N, Pearson P, Yasko AW, et al. Single and multiple metachronous osteosarcoma tumors after therapy. Cancer. 2003;98(11):2457–2466.
   PubMed Web of Science ®Google Scholar
• Bacci G, Longhi A, Bertoni F, et al. Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy The Rizzoli experience in 52 patients. Acta Orthopaedica. 2006;77(6):938–943.
   PubMed Web of Science ®Google Scholar
• Aung AL, Gorlick R, Healey JH, et al. Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma. J Clin Oncol. 2003;21(2):342–348.
   PubMed Web of Science ®Google Scholar
• Ozaki T, Flege S, Kevric M, et al. Osteosarcoma of the pelvis: experience of the cooperative osteosarcoma study group. J Clin Oncol. 2003;21(2):334–341.
   PubMed Web of Science ®Google Scholar
• Labrinidis A, Hay S, Liapis V, et al. Zoledronic acid inhibits both the osteolytic and osteoblastic components of osteosarcoma lesions in a mouse model. Clin Cancer Res. 2009;15(10):3451–3461.
   PubMed Web of Science ®Google Scholar
• Goldsby RE, Fan TM, Villaluna D, et al. Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Eur J Cancer. 2013;49(10):2384–2391.
   PubMed Web of Science ®Google Scholar
• Piperno-Neuman S, Le Deley M-C, Rédini F, et al. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1070–1080.
   PubMed Web of Science ®Google Scholar
• Beristain AG, Narala SR, Di Grappa MA, et al. Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells. J Cell Sci. 2012;125(4):943–955.
   PubMed Web of Science ®Google Scholar
• Chen Y, Di Grappa MA, Molyneux SD, et al. RANKL blockade prevents and treats aggressive osteosarcomas. Sci Transl Med. 2015;7(317):317ra197.
   PubMed Web of Science ®Google Scholar
• Branstetter D, Rohrbach K, Huang L-Y, et al. RANK and RANK ligand expression in primary human osteosarcoma. J Bone Oncol. 2015;4(3):59–68.
   PubMed Web of Science ®Google Scholar
• Janeway KA, Chou AJ, Lee JL, et al. Phase 2 trial of the RANKL antibody, denosumab, in two cohorts of patients with recurrent/refractory osteosarcoma: a report from the Children’s Oncology Group. Poster session presented at: CTOS Annual Meeting; 2019 Nov 13; Tokyo.
   Google Scholar
• Anderson PM, Wiseman GA, Dispenzieri A, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002;20(1):189–196.
   PubMed Web of Science ®Google Scholar
• Anderson PM, Wiseman GA, Erlandson L, et al. Gemcitabine radiosensitization after high-dose Samarium for osteoblastic osteosarcoma. Clin Cancer Res. 2005;11(19):6895–6990.
   PubMed Web of Science ®Google Scholar
• Lee JA, Paik EK, Seo J, et al. Radiotherapy and gemcitabine-docetaxel chemotherapy in children and adolescents with unresectable recurrent or refractory osteosarcoma. Japan J Clin Oncol. 2016;46(2):138–143.
   Web of Science ®Google Scholar
• Machak GN, Tkachev SI, Solovyev YN, et al. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities. Mayo Clin Proc. 2003;78(2):147–155.
   PubMed Web of Science ®Google Scholar
• Oertel S, Blattmann C, Rieken S, et al. Radiotherapy in the treatment of primary osteosarcoma – a single center experience. Tumori J. 2010;96(4):582–588.
   PubMed Web of Science ®Google Scholar
• Ciernik IF, Niemierko A, Harmon DC, et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 2011;117(19):4522–4530.
   PubMed Web of Science ®Google Scholar
• Matsunobu A, Imai R, Kamada T, et al. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Cancer. 2012;118(18):4555–4563.
   PubMed Web of Science ®Google Scholar
• Marec-Berard P, Dalban C, Gaspar N, et al. A multicentric randomized phase II clinical trial evaluating high-dose thiotepa as adjuvant treatment to standard chemotherapy in patients with resectable relapsed osteosarcoma. Eur J Cancer. 2020;125:58–68.
   PubMed Web of Science ®Google Scholar
• Fagioli F, Aglietta M, Tienghi A, et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian Sarcoma Group study. J Clin Oncol. 2002;20(8):2150–2156.
   PubMed Web of Science ®Google Scholar
• Janinis J, McTiernan A, Driver D, et al. A pilot study of short-course intensive multiagent chemotherapy in metastatic and axial skeletal osteosarcoma. Ann Oncol. 2002;13(12):1935–1944.
   PubMed Web of Science ®Google Scholar
• Boye K, Brach Del Prever A, Eriksson M, et al. High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II Study. Pediatr Blood Cancer. 2014;61:840–845.
   PubMed Web of Science ®Google Scholar
• Chen X, Bahrami A, Pappo A, et al., Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7(1): 104–112. 2014. .
   PubMed Web of Science ®Google Scholar
• Kuijjer ML, Hogendoorn Pancras CW, Cleton-Jansen A-M. Genome-wide analyses on high-grade osteosarcoma: making sense of a genomically most unstable tumor.. Int J Cancer. 2013;133(11):2512–2521.
   PubMed Web of Science ®Google Scholar
• Khanna C, Fan TM, Gorlick R, et al. Toward a drug development path that targets metastatic progression in osteosarcoma. Clin Cancer Res. 2014;20(16):4200–4209.
   PubMed Web of Science ®Google Scholar
• Kansara M, Teng MW, Smyth MJ, et al., Translational biology of osteosarcoma. Nat Rev Cancer. 14(11): 722–735. 2014. .
   PubMed Web of Science ®Google Scholar
• Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Ped Blood Cancer. 2008;50(4):799–805.
   PubMed Web of Science ®Google Scholar
• Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol. 2012;30(1):78–84.
   PubMed Web of Science ®Google Scholar
• Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an International Randomized Phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol. 2013;31(19):2485–2492.
   PubMed Web of Science ®Google Scholar
• Moriceau G, Ory B, Mitrofan L, et al. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (everolimus): pivotal role of the prenylation process. Cancer Res. 2010;70(24):10329–10339.
   PubMed Web of Science ®Google Scholar
• Abdeen A, Chou AJ, Healey JH, et al. Correlation between clinical outcome and growth factor pathway expression in osteogenic sarcoma with advanced bone and soft tissue sarcomas. Cancer. 2009;115(22):5243–5250.
   PubMed Web of Science ®Google Scholar
• Pignochino Y, Grignani G, Cavalloni G, et al. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer. 2009;8(1):118.
   PubMedGoogle Scholar
• Pignochino Y, Dell’Aglio C, Basiricò M, et al. The combination of sorafenib and everolimus abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. Clin Cancer Res. 2013;19(8):2117–2131.
   PubMed Web of Science ®Google Scholar
• Keir ST, Morton CL, Wu J, et al. Initial testing of the multitargeted kinase inhibitor pazopanib by the pediatric preclinical testing program. Ped Blood Cancer. 2012;59(3):586–588.
   PubMed Web of Science ®Google Scholar
• Longhi A, Paioli A, Palmerini E, et al. Pazopanib in relapsed osteosarcoma patients: report on 15 cases. Acta Oncologica. 2019;58(1):124–128.
   PubMed Web of Science ®Google Scholar
• Guagnano V, Kauffmann A, Wöhrle S, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective Pan-FGFR inhibitor. Cancer Discov. 2012;2(12):1118–1133.
   Web of Science ®Google Scholar
• Gaspar N, Sirvent FJB, Venkatramani R, et al. Phase I combination dose-finding/phase II expansion cohort of lenvatinib + etopside + ifosfamide in patients aged 2 to 25 years with relapsed/refractory osteosarcoma. Poster session presented at: ESMOAnnual Meeting; 2019 Sep 27 - June1; Barcelona.
   Google Scholar
• Xie L, Xu J, Sun X, et al. Apatinib for advanced osteosarcoma after failure of standard multimodal therapy: an open label Phase II clinical trial. The Oncologist. 2019;24(7):542–550.
   PubMed Web of Science ®Google Scholar
• 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. Lancet Oncol. 2019;20(1):120–133.
   PubMed Web of Science ®Google Scholar
• Davis LE, Bolejack V, Ryan CW, et al. Randomized double-blind phase II study of regorafenib in patients with metastatic osteosarcoma. J Clin Oncol. 2019;37(16):1424–1431.
   PubMed Web of Science ®Google Scholar
• Fioramonti M, Fausti V, Pantano F, et al. Cabozantinib affects osteosarcoma growth through a direct effect on tumor cells and modifications in bone microenvironment. Sci Rep. 2018;8(1):4177.
   PubMedGoogle Scholar
• Park HJ, Bae JS, Kim KM, et al. The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma. J Exp Clin Cancer Res. 2018;37(1):107.
   PubMedGoogle Scholar
• Roth M, Linkowski M, Tarim J, et al. Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer. 2014;120(4):548–554.
   PubMed Web of Science ®Google Scholar
• Poon VI, Roth M, Piperdi S, et al. Ganglioside GD2 expression is maintained upon recurrence in patients with osteosarcoma. Clin Sarcoma Res. 2015;5(1):4.
   PubMedGoogle Scholar
• Onda M, Matsuda S, Higaki S, et al. ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer. 1996;77(1):71–78.
   PubMed Web of Science ®Google Scholar
• Ahmed N, Brawley VS, Hegde M, et al. Human Epidermal Growth Factor Receptor 2 (HER2) –specific chimeric antigen receptor–modified T cells for the Immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33(15):1688–1696.
   PubMed Web of Science ®Google Scholar
• Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18(11):1493–1501.
   PubMed Web of Science ®Google Scholar
• D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19(3):416–426.
   PubMed Web of Science ®Google Scholar
• Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the children’s oncology group. J Clin Oncol. 2008;26(4):633–638.
   PubMed Web of Science ®Google Scholar
• Chou AJ, Kleinerman ES, Krailo MD, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2009;115(22):5339–5348.
   PubMed Web of Science ®Google Scholar