{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:48:16Z","timestamp":1790167696459,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Surgery with neoadjuvant and adjuvant chemotherapy represents the standard of care for extremity osteosarcoma despite a lack of high-quality evidence for its use, and trial evidence that suggests upfront surgery may result in better outcomes. This study estimated the difference in overall survival for the standard of care (neoadjuvant first) vs upfront surgery first followed by adjuvant chemotherapy (surgery first).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using Surveillance, Epidemiology, and End Results data, we identified patients aged 5-29 years diagnosed with a primary cancer of upper or lower extremity osteosarcoma between 2007 and 2019 who received surgery and chemotherapy. Our primary endpoint was the 5-year survival difference between the surgery first and neoadjuvant first groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Adjusted 5-year survival was 74% for surgery first patients and 67% for neoadjuvant first patients, with a survival difference of 6.9% (95% confidence interval [CI] = \u22124.2% to 16.1%). In sensitivity analyses of 5-year survival, the results were consistent, showing a 6.8%-13.7% higher 5-year survival in surgery first patients. Statistically significant mortality risk factors included older age, larger tumor size, the type of resection (salvage vs amputation), and stage III-IV disease (vs stage I-II disease).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The evidence supporting neoadjuvant therapy in osteosarcoma care is weak. However, there is evidence that pausing chemotherapy in the perisurgical period might affect outcomes. Consequently, this study, and its consistency with the results from the only randomized trial to address this question, suggests that there is reason to revisit a prospective, randomized trial of osteosarcoma treatment regarding the timing of surgery and chemotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jnci\/djae229","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T23:27:23Z","timestamp":1726702043000},"page":"611-618","source":"Crossref","is-referenced-by-count":13,"title":["Effect of chemotherapy and surgery timing on mortality in upper and lower extremity osteosarcoma"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7068-9603","authenticated-orcid":false,"given":"Mark D","family":"Danese","sequence":"first","affiliation":[{"name":"Outcomes Insights, Inc , Calabasas, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S","family":"Groundland","sequence":"additional","affiliation":[{"name":"University of Utah , Salt Lake City, UT,","place":["USA"]},{"name":"Huntsman Cancer Institute , Salt Lake City, UT,","place":["USA"]},{"name":"Primary Children\u2019s Hospital , Salt Lake City, UT,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"issue":"113","key":"2025040623582916400_djae229-B1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/00003086-197511000-00016","article-title":"The potential for an improved prognosis with chemotherapy in osteogenic sarcoma","author":"Jaffe","year":"1975","journal-title":"Clin Orthop Relat Res"},{"issue":"111","key":"2025040623582916400_djae229-B2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1097\/00003086-197509000-00013","article-title":"Chemotherapy of osteosarcoma","author":"Sinks","year":"1975","journal-title":"Clin Orthop Relat Res"},{"issue":"2","key":"2025040623582916400_djae229-B3","first-page":"63","article-title":"Tumours of bone and their management","volume":"54","author":"Sweetnam","year":"1974","journal-title":"Ann R Coll Surg Engl"},{"issue":"1","key":"2025040623582916400_djae229-B4","first-page":"38","article-title":"Osteosarcoma","volume":"44","author":"Sweetnam","year":"1969","journal-title":"Ann R Coll Surg Engl"},{"issue":"7","key":"2025040623582916400_djae229-B5","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1002\/1097-0142(19811001)48:7<1569::AID-CNCR2820480717>3.0.CO;2-X","article-title":"The treatment of osteosarcoma of the extremities: twenty year\u2019s experience at the Istituto Ortopedico Rizzoli","volume":"48","author":"Campanacci","year":"1981","journal-title":"Cancer"},{"issue":"1","key":"2025040623582916400_djae229-B6","first-page":"27","article-title":"Improved results in osteogenic sarcoma 1973-79 vs. 1980-86: Analysis of results from a single center","volume":"29","author":"Cohen","year":"1993","journal-title":"Isr J Med Sci"},{"issue":"4","key":"2025040623582916400_djae229-B7","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1097\/00000658-198010000-00001","article-title":"Is amputation necessary for sarcomas? A seven-year experience with limb salvage","volume":"192","author":"Eilber","year":"1980","journal-title":"Ann Surg"},{"issue":"429","key":"2025040623582916400_djae229-B8","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1097\/01.blo.0000145991.65770.e6","article-title":"Survival data for 648 patients with osteosarcoma treated at one institution","author":"Mankin","year":"2004","journal-title":"Clin Orthop Relat Res"},{"issue":"7","key":"2025040623582916400_djae229-B9","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":"2025040623582916400_djae229-B10","first-page":"53","article-title":"Combination chemotherapy preceding surgery in osteogenic sarcoma","volume":"201","author":"van Oosterom","year":"1985","journal-title":"Prog Clin Biol Res"},{"key":"2025040623582916400_djae229-B11","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1002\/1097-0142(19900601)65:11<2539::AID-CNCR2820651125>3.0.CO;2-M","article-title":"Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin","volume":"65","author":"Bacci","year":"1990","journal-title":"Cancer"},{"issue":"5","key":"2025040623582916400_djae229-B12","doi-asserted-by":"crossref","first-page":"659","DOI":"10.3928\/0147-7447-19850501-19","article-title":"Preoperative (neoadjuvant) chemotherapy for osteogenic sarcoma: a ten year experience","volume":"8","author":"Rosen","year":"1985","journal-title":"Orthopedics"},{"key":"2025040623582916400_djae229-B13","doi-asserted-by":"crossref","first-page":"l","DOI":"10.1002\/1097-0142(197601)37:1<1::AID-CNCR2820370102>3.0.CO;2-3","article-title":"Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma","volume":"37","author":"Rosen","year":"1976","journal-title":"Cancer"},{"issue":"9","key":"2025040623582916400_djae229-B14","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.2106\/00004623-198668090-00005","article-title":"Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur","volume":"68","author":"Simon","year":"1986","journal-title":"J Bone Joint Surg Am"},{"issue":"5","key":"2025040623582916400_djae229-B15","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3928\/0147-7447-19850501-15","article-title":"The UCLA Experience in Limb Salvage Surgery for Malignanat Tumors","volume":"8","author":"Eckardt","year":"1985","journal-title":"Orthopedics"},{"issue":"3","key":"2025040623582916400_djae229-B16","first-page":"31","article-title":"The history of bone tumour treatment and the state of the art in Vienna. Macedonian academy of sciences and arts","volume":"38","author":"Kotz","year":"2017","journal-title":"Pril (Makedon Akad Nauk Umet Odd Med Nauki)"},{"issue":"12","key":"2025040623582916400_djae229-B17","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.3928\/0147-7447-19861201-07","article-title":"A modular femur-tibia reconstruction system","volume":"9","author":"Kotz","year":"1986","journal-title":"Orthopedics"},{"key":"2025040623582916400_djae229-B18","first-page":"188","article-title":"Reconstruction of musculoskeletal defects about the knee for tumor","volume":"221","author":"Sim","year":"1987","journal-title":"Clin Orthoped Relat Res"},{"issue":"suppl 5","key":"2025040623582916400_djae229-B19","doi-asserted-by":"crossref","first-page":"v204","DOI":"10.1093\/annonc\/mdq223","article-title":"Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"21","author":"Hogendoorn","year":"2010","journal-title":"Ann Oncol"},{"key":"2025040623582916400_djae229-B20","author":"National Comprehensive Cancer Network","year":"2024"},{"issue":"8","key":"2025040623582916400_djae229-B21","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1200\/JCO.2003.08.165","article-title":"Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651","volume":"21","author":"Goorin","year":"2003","journal-title":"J Clin Oncol"},{"key":"2025040623582916400_djae229-B22","author":"Surveillance, Epidemiology, and End Results (SEER) Program"},{"issue":"9","key":"2025040623582916400_djae229-B23","doi-asserted-by":"publisher","first-page":"e55-64","DOI":"10.1097\/MLR.0000000000000073","article-title":"Comparison of SEER treatment data with medicare claims","volume":"54","author":"Noone","year":"2016","journal-title":"Med Care"},{"issue":"1","key":"2025040623582916400_djae229-B24","doi-asserted-by":"crossref","first-page":"9219","DOI":"10.1038\/s41598-020-65917-x","article-title":"G-computation, propensity score-based methods, and targeted maximum likelihood estimator for causal inference with different covariates sets: A comparative simulation study","volume":"10","author":"Chatton","year":"2020","journal-title":"Sci Rep"},{"key":"2025040623582916400_djae229-B25","volume-title":"Flexible Parametric Survival Analysis Using Stata: Beyond the Cox model.","author":"Royston","year":"2011"},{"issue":"6","key":"2025040623582916400_djae229-B26","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00264-006-0192-x","article-title":"Current Strategies of chemotherapy in osteosarcoma","volume":"30","author":"Carrle","year":"2006","journal-title":"Int Orthop"},{"issue":"15","key":"2025040623582916400_djae229-B27","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.2106\/JBJS.K.00971","article-title":"Effects of neoadjuvant chemotherapy on image-directed planning of surgical resection for distal femoral osteosarcoma","volume":"94","author":"Jones","year":"2012","journal-title":"J Bone Joint Surg Am"},{"key":"2025040623582916400_djae229-B28","first-page":"1","volume-title":"Current Advances in Osteosarcoma","author":"Jaffe","year":"2014"},{"issue":"1","key":"2025040623582916400_djae229-B29","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1007\/s12032-014-0430-9","article-title":"Circulating tumor cells in sarcomas: A brief review","volume":"23","author":"Chang","year":"2015","journal-title":"Medical Oncology"},{"issue":"9","key":"2025040623582916400_djae229-B30","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.20892\/j.issn.2095-3941.2022.0279","article-title":"Detection and surveillance of circulating tumor cells in osteosarcoma for predicting therapy response and prognosis","volume":"19","author":"Mu","year":"2022","journal-title":"Cancer Biol Med"},{"issue":"10","key":"2025040623582916400_djae229-B31","doi-asserted-by":"crossref","first-page":"3333","DOI":"10.2147\/CMAR.S176515","article-title":"Significance of circulating tumor cells in osteosarcoma patient treated by neoadjuvant chemotherapy and surgery","volume":"10","author":"Wu","year":"2018","journal-title":"Cancer Manag Res"},{"issue":"11","key":"2025040623582916400_djae229-B32","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1097\/CORR.0000000000000387","article-title":"Neoadjuvant chemotherapy followed by delayed surgery: is it necessary for all patients with nonmentastatic high-grade pelvic osteosarcoma?","volume":"476","author":"Xu","year":"2018","journal-title":"Clin Orthop Relat Res"},{"issue":"1","key":"2025040623582916400_djae229-B33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1200\/JCO.1992.10.1.5","article-title":"Chemotherapy for nonmetastatic osteogenic sarcoma: the memorial Sloan-Kettering experience","volume":"10","author":"Meyers","year":"1992","journal-title":"J Clin Oncol"},{"issue":"suppl 7","key":"2025040623582916400_djae229-B34","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1093\/annonc\/mdq276","article-title":"Osteosarcoma","volume":"21","author":"Ritter","year":"2010","journal-title":"Ann Oncol"},{"key":"2025040623582916400_djae229-B35","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jbo.2017.11.005","article-title":"Advances in limb salvage treatment of osteosarcoma","volume":"10","author":"Yang","year":"2017","journal-title":"J Bone Oncol"},{"issue":"14","key":"2025040623582916400_djae229-B36","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1016\/j.ejca.2005.03.036","article-title":"Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution","volume":"41","author":"Bacci","year":"2005","journal-title":"Eur J Cancer"},{"issue":"3","key":"2025040623582916400_djae229-B37","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1200\/JCO.2002.20.3.776","article-title":"Prognostic factors in highgrade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols","volume":"20","author":"Bielack","year":"2002","journal-title":"J Clin Oncol"},{"issue":"12","key":"2025040623582916400_djae229-B38","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1007\/s00264-011-1209-7","article-title":"The relation of tumour necrosis and survival in patients with osteosarcoma","volume":"35","author":"Li","year":"2011","journal-title":"Int Orthop"},{"issue":"3","key":"2025040623582916400_djae229-B39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/CORR.0000000000002380","article-title":"Ninety percent or greater tumor necrosis is associated with survival and social determinants of health in patient with osteosarcoma in the National Cancer Database","volume":"481","author":"Richardson","year":"2023","journal-title":"Clin Orthop Relat Res"},{"key":"2025040623582916400_djae229-B40","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1002\/1097-0142(19820315)49:6<1221::AID-CNCR2820490625>3.0.CO;2-E","article-title":"Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy","volume":"49","author":"Rosen","year":"1982","journal-title":"Cancer"},{"issue":"6","key":"2025040623582916400_djae229-B41","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1302\/0301-620X.102B6.BJJ-2019-1307.R1","article-title":"Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma","volume":"102-B","author":"Tsuda","year":"2020","journal-title":"Bone Joint J"},{"issue":"6","key":"2025040623582916400_djae229-B42","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1093\/annonc\/mdr491","article-title":"Survival from high-grade localised extremity osteosarcoma: Combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials","volume":"23","author":"Whelan","year":"2012","journal-title":"Ann Oncol"},{"issue":"10","key":"2025040623582916400_djae229-B43","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1016\/S1470-2045(16)30214-5","article-title":"Comparison of MAP IE versus MAP in patients with a poor response to preopertative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomized controlled trial","volume":"17","author":"Marina","year":"2016","journal-title":"Lancet Oncol"},{"issue":"4","key":"2025040623582916400_djae229-B44","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/S0959-8049(02)00747-5","article-title":"Scandinavian Sarcoma Group Osteosarcoma Study SSG VII: Prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders","volume":"39","author":"Smeland","year":"2003","journal-title":"Eur J Cancer"},{"issue":"2","key":"2025040623582916400_djae229-B45","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1200\/JCO.1988.6.2.329","article-title":"Neoadjuvant chemotherapy of osteosarcoma: Results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response","volume":"6","author":"Winkler","year":"1988","journal-title":"J Clin Oncol"}],"container-title":["JNCI: Journal of the National Cancer Institute"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jnci\/advance-article-pdf\/doi\/10.1093\/jnci\/djae229\/59835288\/djae229.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnci\/article-pdf\/117\/4\/611\/59835288\/djae229.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnci\/article-pdf\/117\/4\/611\/59835288\/djae229.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T19:59:30Z","timestamp":1743969570000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnci\/article\/117\/4\/611\/7762639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,20]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,9,20]]},"published-print":{"date-parts":[[2025,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jnci\/djae229","relation":{},"ISSN":["0027-8874","1460-2105"],"issn-type":[{"value":"0027-8874","type":"print"},{"value":"1460-2105","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2024,9,20]]}}}