{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:44:00Z","timestamp":1793072640679,"version":"4.5.0"},"reference-count":105,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T00:00:00Z","timestamp":1617753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and\/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.<\/jats:p>","DOI":"10.3390\/cancers13081757","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T11:31:59Z","timestamp":1617795119000},"page":"1757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Systematic Review of Recurrent Osteosarcoma Systemic Therapy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8774-136X","authenticated-orcid":false,"given":"Ioanna","family":"Gazouli","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasios","family":"Kyriazoglou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Kotsantis","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0047-8090","authenticated-orcid":false,"given":"Maria","family":"Anastasiou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9052-3416","authenticated-orcid":false,"given":"Anastasios","family":"Pantazopoulos","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Prevezanou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Chatzidakis","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Kavourakis","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-3264","authenticated-orcid":false,"given":"Panagiota","family":"Economopoulou","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6356-4346","authenticated-orcid":false,"given":"Vasileios","family":"Kontogeorgakos","sequence":"additional","affiliation":[{"name":"First Department of Orthopaedic Surgery, Attikon University General Hospital, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panayiotis","family":"Papagelopoulos","sequence":"additional","affiliation":[{"name":"First Department of Orthopaedic Surgery, Attikon University General Hospital, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Psyrri","sequence":"additional","affiliation":[{"name":"Second Propaedeutic Department of Medicine, Attikon University Hospital, 1 Rimini Street, Chaidari, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/cncr.24121","article-title":"Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program","volume":"115","author":"Mirabello","year":"2009","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4419-0284-9_1","article-title":"The epidemiology of osteosarcoma","volume":"152","author":"Ottaviani","year":"2009","journal-title":"Cancer Treat Res."},{"key":"ref_3","unstructured":"Fletcher, C.D.M., Unni, K.K., and Mertens, F. 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