{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:14:34Z","timestamp":1791231274753,"version":"4.1.0"},"reference-count":43,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2004,8,15]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng\/mL\u00b7h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2004.10.103","type":"journal-article","created":{"date-parts":[[2004,8,14]],"date-time":"2004-08-14T08:37:26Z","timestamp":1092472646000},"page":"3357-3365","source":"Crossref","is-referenced-by-count":66,"title":["Results of a Phase II Upfront Window of Pharmacokinetically Guided Topotecan in High-Risk Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor"],"prefix":"10.1200","volume":"22","author":[{"given":"Clinton F.","family":"Stewart","sequence":"first","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa C.","family":"Iacono","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murali","family":"Chintagumpala","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stewart J.","family":"Kellie","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ashley","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.C.","family":"Zamboni","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.N.","family":"Kirstein","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Fouladi","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis G.","family":"Seele","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Wallace","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Houghton","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amar","family":"Gajjar","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children\u2019s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1999.17.7.2127"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"Tarbell N, Friedman H, Kepner JL: Outcome for children with high stage medulloblastoma: Results of the Pediatric Oncology Group 9031. Int J Radiat Oncol Biol Phys 48:179,2000,  (abstr 134)","DOI":"10.1016\/S0360-3016(00)80151-0"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1002\/mpo.2950250303"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1990.72.4.0572"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19880515)61:10<1992::AID-CNCR2820611011>3.0.CO;2-J"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(90)90017-N"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1016\/S0360-3016(99)00369-7"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1981.55.5.0749"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1227\/00006123-198603000-00014"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19901215)66:12<2465::AID-CNCR2820661204>3.0.CO;2-N"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1990.8.2.330"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1995.13.9.2247"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.05.116"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1996.tb26390.x"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1007\/BF00686188"},{"key":"R16","unstructured":"Blaney SM, Cole DE, Balis FM, et al: Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 53:725,1993-727,"},{"key":"R17","doi-asserted-by":"crossref","unstructured":"Baker SD, Heideman RL, Crom WR, et al: Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 37:195,1996-202,","DOI":"10.1007\/BF00688317"},{"key":"R18","unstructured":"Pawlik CA, Houghton PJ, Stewart CF, et al: Effective schedules of exposure of medulloblastoma and rhabdomyosarcoma xenografts to topotecan correlate with in vitro assays. Clin Cancer Res 4:1995,1998-2002,"},{"key":"R19","unstructured":"Stewart CF, Liu CY, Zamboni WC, et al: Population pharmacokinetics of topotecan in children and adolescents. Proc Am Soc Clin Oncol  ;19:177a,2000 (abstr 687)"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1097\/00043426-199611000-00004"},{"key":"R21","unstructured":"Santana VM, Zamboni WC, Kirstein MN, et al: A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633,2003-640,"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1097\/00000421-198212000-00014"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1007\/BF00166992"},{"key":"R24","unstructured":"Zamboni WC, Gajjar AJ, Mandrell TD, et al: A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: Implications for treatment of children with metastatic medulloblastoma. Clin Cancer Res 4:2537,1998-2544,"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bmt.1703202"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1994.12.3.539"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.7.505"},{"key":"R28","unstructured":"D\u2019Argenio DZ, Schumitzky A: ADAPT II User\u2019s Guide (ed 1) . Los Angeles, CA, Biomedical Simulations Resource, USC, 1990"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.10.2696"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199306173282401"},{"key":"R31","unstructured":"Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032,1993-1036,"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006294102611"},{"key":"R33","unstructured":"Blaney SM, Needle MN, Gillespie A, et al: Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: A collaborative Pediatric Branch, National Cancer Institute, and Children\u2019s Cancer Group Study. Clin Cancer Res 4:357,1998-360,"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1097\/00043426-199807000-00006"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.1.213"},{"key":"R36","doi-asserted-by":"crossref","unstructured":"Zamboni WC, Luftner DI, Egorin MJ, et al: The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid. Ann Oncol 12:119,2001-122,","DOI":"10.1023\/A:1008369615016"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.20.6.1617"},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1007\/BF00173681"},{"key":"R39","unstructured":"Zamboni WC, Gajjar AJ, Heideman RL, et al: Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 4:783,1998-789,"},{"key":"R40","unstructured":"Gajjar A, Kirstein MN, Santana VM, et al: Concomitant dexamethasone (DXM) increases topotecan (TPT) clearance in children. Proc Am Assoc Cancer Res 42:653,2001,  (abstr 3512)"},{"key":"R41","unstructured":"Hale GA, Benaim E, Stewart CF, et al: A phase I study of cyclophosphamide and topotecan in patients with high risk malignancies undergoing autologous hematopoietic stem cell transplantation. Med Pediatr Oncol 37:175,2001,  (abstr O49)"},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1002\/mpo.2950240309"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1016\/0360-3016(88)90363-X"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2004.10.103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T20:55:24Z","timestamp":1653512124000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2004.10.103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,8,15]]},"references-count":43,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2004,8,15]]}},"alternative-id":["10.1200\/JCO.2004.10.103"],"URL":"https:\/\/doi.org\/10.1200\/jco.2004.10.103","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,8,15]]}}}