{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T17:34:28Z","timestamp":1769276068188,"version":"3.49.0"},"reference-count":72,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tokyo Metropolitan Government, Japan","award":["Clinical Research Fund"],"award-info":[{"award-number":["Clinical Research Fund"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one of the major disadvantages of anthracycline use, limits their utility and effectiveness. Hydroxypropyl acrylamide polymer-conjugated pirarubicin (P-THP), which targets tumor tissue highly selectively via the enhanced permeability and retention (EPR) effect, and secondarily releases active pirarubicin molecules quickly into the acidic environment surrounding the tumor. Although, the latter rarely occurs in the non-acidic environment surrounding normal tissue. This mechanism has the potential to minimize acute and chronic toxicities, including cardiotoxicity, as well as maximize the efficacy of chemotherapy through synergy with tumor-targeting accumulation of the active molecules and possible dose-escalation. Simply replacing doxorubicin with P-THP in a given regimen can improve outcomes in anthracycline-sensitive pediatric cancers with little risk of adverse effects, such as cardiotoxicity. As cancer is a dynamic disease showing intra-tumoral heterogeneity during its course, continued parallel development of cytotoxic agents and molecular targeting agents is necessary to find potentially more effective treatments.<\/jats:p>","DOI":"10.3390\/cancers13153698","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T04:29:14Z","timestamp":1627014554000},"page":"3698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Development of a Selective Tumor-Targeted Drug Delivery System: Hydroxypropyl-Acrylamide Polymer-Conjugated Pirarubicin (P-THP) for Pediatric Solid Tumors"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0036-7748","authenticated-orcid":false,"given":"Atsushi","family":"Makimoto","sequence":"first","affiliation":[{"name":"Department of Hematology\/Oncology, Tokyo Metropolitan Children\u2019s Medical Center, Tokyo 183-8561, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Fang","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Science, Sojo University, Kumamoto 860-0082, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-4913","authenticated-orcid":false,"given":"Hiroshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"BioDynamics Research Foundation, Kumamoto 862-0954, Japan"},{"name":"Department of Microbiology, Kumamoto University School of Medicine, Kumamoto 862-0954, Japan"},{"name":"Tohoku University, Miyagi 980-8572, Japan"},{"name":"Faculty of Medicine, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"ref_1","unstructured":"Global Oncology Trends 2019 (2021, April 05). Therapeutics, Clinical Development and Health System Implications. Institute Report (30 May 2019). Available online: https:\/\/www.iqvia.com\/insights\/the-iqvia-institute\/reports\/global-oncology-trends-2019."},{"key":"ref_2","unstructured":"Blaney, S.M., Adamson, P.C., and Helman, L.J. (2020). General principles of chemotherapy. Pizzo and Poplack\u2019s Pediatric Oncology, Wolters Kluwer. [8th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Maeda, H. (2021). The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery\u2014Personal Remarks and Future Prospects. J. Pers. Med., 11.","DOI":"10.3390\/jpm11030229"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jconrel.2013.11.011","article-title":"Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage","volume":"174","author":"Nakamura","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_5","first-page":"6387","article-title":"A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs","volume":"46","author":"Matsumura","year":"1986","journal-title":"Cancer Res."},{"key":"ref_6","first-page":"987","article-title":"Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes","volume":"54","author":"Gabizon","year":"1994","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1349-7006.1998.tb00563.x","article-title":"Early Phase Tumor Accumulation of Macromolecules: A Great Difference in Clearance Rate between Tumor and Normal Tissues","volume":"89","author":"Noguchi","year":"1998","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1002\/1097-0142(19841201)54:11<2367::AID-CNCR2820541111>3.0.CO;2-F","article-title":"Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium","volume":"54","author":"Konno","year":"1984","journal-title":"Cancer"},{"key":"ref_9","first-page":"103","article-title":"Tumor scanning with 67Ga citrate","volume":"10","author":"Edwards","year":"1969","journal-title":"J. Nucl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/S0002-9440(10)64920-6","article-title":"Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors","volume":"160","author":"Morikawa","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_11","first-page":"2411","article-title":"Microvascular architecture of experimental colon tumors in the rat","volume":"50","author":"Skinner","year":"1990","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0002-9440(10)65006-7","article-title":"Openings between Defective Endothelial Cells Explain Tumor Vessel Leakiness","volume":"156","author":"Hashizume","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ejpb.2008.11.010","article-title":"Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect","volume":"71","author":"Maeda","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.2183\/pjab.88.53","article-title":"Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting","volume":"88","author":"Maeda","year":"2012","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0162-3109(99)00104-6","article-title":"Kallikrein\u2013kinin in infection and cancer","volume":"43","author":"Maeda","year":"1999","journal-title":"Immunopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16051","DOI":"10.1016\/S0021-9258(18)37555-0","article-title":"Purification and identification of [hydroxyprolyl-3] bradykinin in ascitic fluid from a patient with gastric cancer","volume":"263","author":"Maeda","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1111\/j.1349-7006.1988.tb01563.x","article-title":"Involvement of the Kinin-generating Cascade in Enhanced Vascular Permeability in Tumor Tissue","volume":"79","author":"Matsumura","year":"1988","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1111\/j.1349-7006.1991.tb01910.x","article-title":"Kinin-generating Cascade in Advanced Cancer Patients and in vitro Study","volume":"82","author":"Matsumura","year":"1991","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1349-7006.1994.tb02362.x","article-title":"Enhanced Vascular Permeability in Solid Tumor Is Mediated by Nitric Oxide and Inhibited by Both New Nitric Oxide Scavenger and Nitric Oxide Synthase Inhibitor","volume":"85","author":"Maeda","year":"1994","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_20","first-page":"159","article-title":"Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger","volume":"58","author":"Wu","year":"1998","journal-title":"Cancer Res."},{"key":"ref_21","first-page":"1592","article-title":"Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function","volume":"59","author":"Grunstein","year":"1999","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1349-7006.2001.tb01114.x","article-title":"Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases","volume":"92","author":"Wu","year":"2001","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0065-2571(00)00013-3","article-title":"The enhanced permeability and retention (EPR) effect in tumor vasculature: The key role of tumor-selective macromolecular drug targeting","volume":"41","author":"Maeda","year":"2001","journal-title":"Adv. Enzym. Regul."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1567-5769(02)00271-0","article-title":"Vascular permeability enhancement in solid tumor: Various factors, mechanisms involved and its implications","volume":"3","author":"Maeda","year":"2003","journal-title":"Int. Immunopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1158\/1535-7163.MCT-18-0696","article-title":"Augmentation of the Enhanced Permeability and Retention Effect with Nitric Oxide\u2013Generating Agents Improves the Therapeutic Effects of Nanomedicines","volume":"17","author":"Islam","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","first-page":"2115","article-title":"Use of oily contrast medium for selective drug targeting to tumor: Enhanced therapeutic effect and X-ray image","volume":"44","author":"Iwai","year":"1984","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jconrel.2020.07.007","article-title":"Delivering the power of nanomedicine to patients today","volume":"326","author":"Germain","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jconrel.2019.05.044","article-title":"The beginning of the end of the nanomedicine hype","volume":"305","author":"Park","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/micc.12228","article-title":"A Retrospective 30 Years after Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next-Generation Chemotherapeutics and Photodynamic Therapy-Problems, Solutions, and Prospects","volume":"23","author":"Maeda","year":"2016","journal-title":"Microcirculation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/0959-8049(94)00514-6","article-title":"Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier","volume":"31","author":"Seymour","year":"1995","journal-title":"Eur. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0168-3659(01)00341-8","article-title":"Development of the polymer micelle carrier system for doxorubicin","volume":"74","author":"Nakanishi","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1038\/sj.bjc.6602204","article-title":"Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin","volume":"91","author":"Matsumura","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0168-3659(01)00281-4","article-title":"New HPMA copolymers containing doxorubicin bound via pH-sensitive linkage: Synthesis and preliminary in vitro and in vivo biological properties","volume":"73","author":"Etrych","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_34","first-page":"6831","article-title":"Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors","volume":"62","author":"Campbell","year":"2002","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1021\/mp800049w","article-title":"Pharmacokinetics and Biodistribution of Nanoparticles","volume":"5","author":"Li","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jconrel.2007.08.016","article-title":"Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells","volume":"124","author":"Malugin","year":"2007","journal-title":"J. Control. Release"},{"key":"ref_37","first-page":"1462","article-title":"4\u2032-O-tetrahydropyranyladriamycin as a potential new antitumor agent","volume":"42","author":"Tsuruo","year":"1982","journal-title":"Cancer Res."},{"key":"ref_38","first-page":"153","article-title":"Comparison of cardiotoxicity of pirarubicin, epirubicin and doxorubicin in the rat","volume":"20","author":"Hirano","year":"1994","journal-title":"Drugs Exp. Clin. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1200\/JCO.1990.8.4.705","article-title":"Chemotherapy of advanced ovarian cancer with 4\u2032-O-tetrahydropyranyl doxorubicin and cisplatin: A randomized phase II trial with an evaluation of circadian timing and dose-intensity","volume":"8","author":"Benavides","year":"1990","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5529","DOI":"10.1007\/s13277-015-3221-9","article-title":"Neoadjuvant chemotherapy of breast cancer with pirarubicin versus epirubicin in combination with cyclophosphamide and docetaxel","volume":"36","author":"Gu","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e27914","DOI":"10.1002\/pbc.27914","article-title":"Results of a prospective clinical trial JN-L-10 using image-defined risk factors to inform surgical decisions for children with low-risk neuroblastoma disease: A report from the Japan Children\u2019s Cancer Group Neuroblastoma Committee","volume":"66","author":"Iehara","year":"2019","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s10147-018-1281-8","article-title":"Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: A report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG)","volume":"23","author":"Hishiki","year":"2018","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1007\/s00383-013-3399-0","article-title":"A cisplatin plus pirarubicin-based JPLT2 chemotherapy for hepatoblastoma: Experience and future of the Japanese Study Group for Pediatric Liver Tumor (JPLT)","volume":"29","author":"Hiyama","year":"2013","journal-title":"Pediatr. Surg. Int."},{"key":"ref_44","first-page":"S260","article-title":"Intensified Induction Chemotherapy Followed by High-Dose Chemotherapy for Children with Group 3 Alveolar Rhabdomyosarcoma and Group 4 Rhabdomyosarcoma","volume":"63","author":"Hara","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1007\/s00280-003-0569-0","article-title":"Pirarubicin is taken up by a uridine-transportable sodium-dependent concentrative nucleoside transporter in Ehrlich ascites carcinoma cells","volume":"51","author":"Nagai","year":"2003","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1124\/dmd.104.001123","article-title":"Tissue distribution of concentrative and equilibrative nucleoside transporters in male and female rats and mice","volume":"32","author":"Lu","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"312","DOI":"10.7164\/antibiotics.36.312","article-title":"Rapid uptake by cultured tumor cells and intracellular behavior of 4\u2032-O-tetrahydropyranyladriamycin","volume":"36","author":"Kunimoto","year":"1983","journal-title":"J. Antibiot."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1111\/j.1349-7006.1999.tb00814.x","article-title":"Membrane Transport and Antitumor Activity of Pirarubicin, and Comparison with Those of Doxorubicin","volume":"90","author":"Sugiyama","year":"1999","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1021\/acs.molpharmaceut.6b00697","article-title":"Pronounced Cellular Uptake of Pirarubicin versus That of Other Anthracyclines: Comparison of HPMA Copolymer Conjugates of Pirarubicin and Doxorubicin","volume":"13","author":"Nakamura","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1007\/s13346-020-00743-2","article-title":"The solid progress of nanomedicine","volume":"10","author":"Martins","year":"2020","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ijpharm.2017.11.011","article-title":"HPMA copolymer conjugate with pirarubicin: In Vitro and ex vivo stability and drug release study","volume":"536","author":"Islam","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1021\/acs.molpharmaceut.9b00248","article-title":"Superior Penetration and Cytotoxicity of HPMA Copolymer Conjugates of Pirarubicin in Tumor Cell Spheroid","volume":"16","author":"Nakamura","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kudl\u00e1\u010dov\u00e1, J., Kotrchov\u00e1, L., Kostka, L., Rand\u00e1rov\u00e1, E., Filipov\u00e1, M., Janou\u0161kov\u00e1, O., Fang, J., and Etrych, T. (2020). Structure-to-Efficacy Relationship of HPMA-Based Nanomedicines: The Tumor Spheroid Penetration Study. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12121242"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jconrel.2016.05.036","article-title":"Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors","volume":"233","author":"Eckschlager","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s11523-015-0379-4","article-title":"HPMA copolymer-conjugated pirarubisin in multimodal treatment of a patient with stage IV prostate cancer and extensive lung and bone metastases","volume":"11","author":"Dozono","year":"2016","journal-title":"Target. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1517\/14656566.8.8.1039","article-title":"Anthracycline-induced cardiotoxicity: Course, pathophysiology, prevention and management","volume":"8","author":"Barry","year":"2007","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_57","unstructured":"Kufe, D.W., Pollock, R.E., Weichselbaum, R.R., Bast, R.C., Gansler, T.S.G., Holland, J.F., and Frei, E. (2021, May 12). Cardiac complications of cancer treatment, Holland-Frei Cancer Medicine, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK12616\/."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/pbc.23012","article-title":"Assessment of late cardiotoxicity of pirarubicin (THP) in children with acute lymphoblastic leukemia","volume":"57","author":"Shimomura","year":"2011","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1200\/JCO.2006.09.7717","article-title":"Phase III Trial of Two Investigational Schedules of Ifosfamide Compared with Standard-Dose Doxorubicin in Advanced or Metastatic Soft Tissue Sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study","volume":"25","author":"Lorigan","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1200\/JCO.18.00313","article-title":"Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes among Children Treated in the AAML0531 Clinical Trial: A Report from the Children\u2019s Oncology Group","volume":"37","author":"Getz","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"djv357","DOI":"10.1093\/jnci\/djv357","article-title":"Cardioprotection and Second Malignant Neoplasms Associated with Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis","volume":"108","author":"Shaikh","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1093\/jnci\/83.20.1460","article-title":"Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing\u2019s sarcoma","volume":"83","author":"Smith","year":"1991","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_63","first-page":"CD006647","article-title":"Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer","volume":"4","author":"Caron","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1200\/JCO.2008.19.1478","article-title":"Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: A Children\u2019s Oncology Group Study","volume":"27","author":"Granowetter","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1200\/JCO.2011.41.5703","article-title":"Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children\u2019s Oncology Group","volume":"30","author":"Womer","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1470-2045(08)70069-X","article-title":"High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: A randomised trial","volume":"9","author":"Pearson","year":"2008","journal-title":"Lancet Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1200\/JCO.1984.2.7.742","article-title":"Advanced neuroblastoma: Improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26","volume":"2","author":"Shafford","year":"1984","journal-title":"J. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/1097-0142(19880115)61:2<209::AID-CNCR2820610202>3.0.CO;2-L","article-title":"The intergroup rhabdomyosarcoma study\u2014I. A final report","volume":"61","author":"Maurer","year":"1988","journal-title":"Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1002\/1097-0142(19930301)71:5<1904::AID-CNCR2820710530>3.0.CO;2-X","article-title":"The intergroup rhabdomyosarcoma study\u2014II","volume":"71","author":"Maurer","year":"1993","journal-title":"Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/S1470-2045(18)30337-1","article-title":"Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): A multicentre, open-label, randomised controlled, phase 3 trial","volume":"19","author":"Bisogno","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1200\/JCO.2015.63.4048","article-title":"Intensive multiagent therapy, including dose-compressed cycles of ifosfamide\/etoposide and vincristine\/doxorubicin\/cyclophosphamide, irinotecan, and radiation, in patients with high-risk rhabdomyosarcoma: A report from the Children\u2019s Oncology Group","volume":"34","author":"Weigel","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Shaw","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/15\/3698\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:42Z","timestamp":1760164422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/15\/3698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,23]]},"references-count":72,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cancers13153698"],"URL":"https:\/\/doi.org\/10.3390\/cancers13153698","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,23]]}}}