{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:26:59Z","timestamp":1792520819305,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Children and adolescents with recurrent and metastatic solid tumors have a poor outcome. A previous phase 1 study (ANGIO1) targeting angiogenesis with bevacizumab, sorafenib, and cyclophosphamide, demonstrated a signal of activity in a subset of patients. Here we report the results of a cohort of pediatric and young adult patients treated at the recommended phase 2 doses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Electronic medical records of patients with refractory or recurrent solid tumors who received ANGIO1 therapy were reviewed. Treatment cycles lasted 21 days and included bevacizumab, sorafenib, and cyclophosphamide. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v5.0. Responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST1.1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-nine patients (22 male, 17 female; median age 15 years; range 1-22 years) received the treatment regimen. The most common diagnoses included bone sarcomas (n=21; 14 Ewing sarcoma, 7 osteosarcoma) and soft tissue sarcomas (n=9; 2 rhabdomyosarcoma, 3 synovial sarcoma, 2 desmoplastic small round cell tumors, and 2 high-grade sarcoma). The most common Grade 3 non-hematologic toxicities included hypertension (2, 5.4%) and hematuria (2, 5.4%). Five patients (13.5%) had a pneumothorax (3 at progressive disease, 1 post lung biopsy, and 1 spontaneous). Common Grade 3\/4 hematologic toxicities were lymphopenia (19, 51%) and leukopenia (13, 35%). Sixteen patients (43.2%) developed palmar-plantar erythrodysesthesia Grade 2 or less. A total of 297 cycles were administered. Twenty-three patients required a dose reduction of cyclophosphamide, sorafenib or bevacizumab during therapy, all of whom continued to have clinical benefit following dose modification. One patient (Ewing sarcoma) achieved a complete response after 11 cycles; 2 patients (Ewing sarcoma, high grade sarcoma) achieved a partial response following cycles 2 and 4, respectively and 20 patients had stable disease as a best response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Intravenous bevacizumab combined with oral sorafenib and metronomic cyclophosphamide was tolerated and required minimal supportive care or additional clinic visits. Disease stabilization for prolonged time periods was observed in greater than half of the treated patients. Patients with bone sarcoma demonstrated a signal of activity suggesting possible benefit from incorporation of the therapy as a maintenance regimen in upfront setting, or as a palliative regimen.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2022.864790","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T05:40:07Z","timestamp":1653457207000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Bevacizumab, With Sorafenib and Cyclophosphamide Provides Clinical Benefit for Recurrent or Refractory Osseous Sarcomas in Children and Young Adults"],"prefix":"10.3389","volume":"12","author":[{"given":"Jessica","family":"Bodea","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Caldwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Federico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28748","article-title":"Declining Childhood and Adolescent Cancer Mortality","volume":"120","author":"Smith","year":"2014","journal-title":"Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100396","article-title":"Outcome for Children With Metastatic Solid Tumors Over the Last Four Decades","volume":"9","author":"Perkins","year":"2014","journal-title":"PloS One"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021491","article-title":"A Randomized Trial of Bevacizumab, an Anti-Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer","volume":"349","author":"Yang","year":"2003","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.51.4489","article-title":"Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial","volume":"32","author":"Pujade-Lauraine","year":"2014","journal-title":"J Clin Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032691","article-title":"Bevacizumab Plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer","volume":"350","author":"Hurwitz","year":"2004","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13020253","article-title":"Use of Antiangiogenic Therapies in Pediatric Solid Tumors","volume":"13","author":"Ollauri-Ib\u00e1\u00f1ez","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1200\/JCO.2007.11.9230","article-title":"Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study","volume":"26","author":"Glade Bender","year":"2008","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-3284","article-title":"A Phase I Trial And Pharmacokinetic Study of Sorafenib In Children With Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report","volume":"18","author":"Widemann","year":"2012","journal-title":"Clin Cancer Res."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/BF00254034","article-title":"Low-Dose Cyclophosphamide Versus Adriamycin Plus Cyclophosphamide in Advanced Ovarian Cancer. A Randomized Clinical Study","volume":"4","author":"Bolis","year":"1980","journal-title":"Cancer Chemother Pharmacol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.20544","article-title":"Vinorelbine and Low Dose Cyclophosphamide in the Treatment of Pediatric Sarcomas: Pilot Study for the Upcoming European Rhabdomyosarcoma Protocol","volume":"101","author":"Casanova","year":"2004","journal-title":"Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/01.mph.0000183863.10792.d4","article-title":"A Feasibility Trial of Antiangiogenic (Metronomic) Chemotherapy in Pediatric Patients With Recurrent or Progressive Cancer","volume":"27","author":"Kieran","year":"2005","journal-title":"J Pediatr Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1897","article-title":"Phase I and Clinical Pharmacology Study of Bevacizumab, Sorafenib, and Low-Dose Cyclophosphamide in Children and Young Adults With Refractory\/Recurrent Solid Tumors","volume":"19","author":"Navid","year":"2013","journal-title":"Clin Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.ejca.2020.03.010","article-title":"Phase I Expansion Cohort to Evaluate the Combination of Bevacizumab, Sorafenib and Low-Dose Cyclophosphamide in Children and Young Adults With Refractory or Recurrent Solid Tumours","volume":"132","author":"Federico","year":"2020","journal-title":"Eur J Cancer (Oxf Engl 1990)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20153751","article-title":"New Insights About the Wnt\/\u03b2-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies","volume":"20","author":"Danieau","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.26265","article-title":"Docetaxel, Bevacizumab, and Gemcitabine for Very High Risk Sarcomas in Adolescents and Young Adults: A Single-Center Experience","volume":"64","author":"Kuo","year":"2017","journal-title":"Pediatr Blood Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0068416","article-title":"A Phase I Study of Vincristine, Irinotecan, Temozolomide and Bevacizumab (Vitb) in Pediatric Patients With Relapsed Solid Tumors","volume":"8","author":"Venkatramani","year":"2013","journal-title":"PloS One"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5841","article-title":"Personalized Comprehensive Molecular Profiling of High-Risk Osteosarcoma: Implications and Limitations for Precision Medicine","volume":"6","author":"Subbiah","year":"2015","journal-title":"Oncotarget"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-8-118","article-title":"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","volume":"8","author":"Pignochino","year":"2009","journal-title":"Mol Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr151","article-title":"A Phase II Trial of Sorafenib in Relapsed and Unresectable High-Grade Osteosarcoma After Failure of Standard Multimodal Therapy: An Italian Sarcoma Group Study","volume":"23","author":"Grignani","year":"2012","journal-title":"Ann Oncol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1007\/s12032-018-1180-x","article-title":"Sorafenib in Patients With Progressed and Refractory Bone Tumors","volume":"35","author":"Raciborska","year":"2018","journal-title":"Med Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1186\/s12885-015-1894-5","article-title":"Off-Label Use of Targeted Therapies in Osteosarcomas: Data From the French Registry OUTC\u2019s (Observatoire De L\u2019Utilisation Des Th\u00e9rapies Cibl\u00e9es Dans Les Sarcomes)","volume":"15","author":"Penel-Page","year":"2015","journal-title":"BMC Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/ped.13307","article-title":"Pazopanib for Second Recurrence of Osteosarcoma in Pediatric Patients","volume":"59","author":"Umeda","year":"2017","journal-title":"Pediatr Int"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082130","article-title":". Molecular Biology of Osteosarcoma","volume":"12","author":"Czarnecka","year":"2020","journal-title":"Cancers"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30742-3","article-title":"Efficacy and Safety of Regorafenib in Adult Patients With Metastatic Osteosarcoma: A Non-Comparative, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Study","volume":"20","author":"Duffaud","year":"2019","journal-title":"Lancet Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.02374","article-title":"Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma","volume":"37","author":"Davis","year":"2019","journal-title":"J Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30825-3","article-title":"Cabozantinib in Patients With Advanced Ewing Sarcoma or Osteosarcoma (CABONE): A Multicentre, Single-Arm, Phase 2 Trial","volume":"21","author":"Italiano","year":"2020","journal-title":"Lancet Oncol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/S1470-2045(14)71136-2","article-title":"Sorafenib and Everolimus for Patients With Unresectable High-Grade Osteosarcoma Progressing After Standard Treatment: A Non-Randomised Phase 2 Clinical Trial","volume":"16","author":"Grignani","year":"2015","journal-title":"Lancet Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24547","article-title":"Pilot Study of Vincristine, Oral Irinotecan, and Temozolomide (VOIT Regimen) Combined With Bevacizumab in Pediatric Patients With Recurrent Solid Tumors or Brain Tumors","volume":"60","author":"Wagner","year":"2013","journal-title":"Pediatr Blood Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2010.02.007","article-title":"Targets for Cancer Therapy in Childhood Sarcomas","volume":"36","author":"Wachtel","year":"2010","journal-title":"Cancer Treat Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21132","article-title":"A Phase II Study of Imatinib Mesylate in Children With Refractory or Relapsed Solid Tumors: A Children\u2019s Oncology Group Study","volume":"50","author":"Bond","year":"2007","journal-title":"Pediatr Blood Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31725","article-title":"A Study of Axitinib, a VEGF Receptor Tyrosine Kinase Inhibitor, in Children and Adolescents With Recurrent or Refractory Solid Tumors: A Children\u2019s Oncology Group Phase 1 and Pilot Consortium Trial (ADVL1315)","volume":"124","author":"Geller","year":"2018","journal-title":"Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s13691-019-00362-w","article-title":"Pazopanib Maintenance Therapy After Tandem High-Dose Chemotherapy for Disseminated Ewing Sarcoma","volume":"8","author":"Tamura","year":"2019","journal-title":"Int Cancer Conf J"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.5301\/tj.5000548","article-title":"Response to Pazopanib in Two Pediatric Patients With Pretreated Relapsing Synovial Sarcoma","volume":"103","author":"Casanova","year":"2017","journal-title":"Tumor"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2017-0408","article-title":"Clinical Activity of Pazopanib in Patients With Advanced Desmoplastic Small Round Cell Tumor","volume":"23","author":"Menegaz","year":"2018","journal-title":"Oncology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01228","article-title":"A Chart Review on the Feasibility and Safety of the Vincristine Irinotecan Pazopanib (VIPaz) Association in Children and Adolescents With Resistant or Relapsed Sarcomas","volume":"10","author":"Russo","year":"2020","journal-title":"Front Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1254","article-title":"The Role of Angiogenesis in Hepatocellular Carcinoma","volume":"25","author":"Morse","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in Advanced Hepatocellular Carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N Engl J Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.47.0914","article-title":"Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children\u2019s Oncology Group Phase I Consortium Report","volume":"31","author":"Bender","year":"2013","journal-title":"J Clin Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.784","article-title":"Sorafenib Treatment in Children With Relapsed and Refractory Neuroblastoma: An Experience of Four Cases","volume":"5","author":"Okada","year":"2016","journal-title":"Cancer Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2015.01.005","article-title":"Pneumothorax as a Complication of Combination Antiangiogenic Therapy in Children and Young Adults With Refractory\/Recurrent Solid Tumors","volume":"50","author":"Interiano","year":"2015","journal-title":"J Pediatr Surg"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30617-5","article-title":"Vinorelbine and Continuous Low-Dose Cyclophosphamide as Maintenance Chemotherapy in Patients With High-Risk Rhabdomyosarcoma (RMS 2005): A Multicentre, Open-Label, Randomised, Phase 3 Trial","volume":"20","author":"Bisogno","year":"2019","journal-title":"Lancet Oncol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.2146\/ajhp160228","article-title":"Dinutuximab for Maintenance Therapy in Pediatric Neuroblastoma","volume":"74","author":"McGinty","year":"2017","journal-title":"Am J Health Syst Pharm"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.864790\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T05:40:09Z","timestamp":1653457209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.864790\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,25]]},"references-count":42,"alternative-id":["10.3389\/fonc.2022.864790"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.864790","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,25]]},"article-number":"864790"}}