title: Upfront window trial of topotecan in previously untreated children and adolescents with poor prognosis metastatic osteosarcoma: children's Cancer Group (CCG) 7943.
abstract: BACKGROUND
  Patients with metastatic osteosarcoma have a poor prognosis. The objectives of the study were to determine the antitumor activity and toxicity of topotecan (daily x5) in newly diagnosed patients with metastatic osteosarcoma followed by chemotherapy (ifosfamide, carboplatin, etoposide [ICE], alternating with cisplatin and doxorubicin [CD]).
  
  
  METHODS
  Newly diagnosed patients (< or =30 years of age) with extensive metastatic disease (primary and > or =5 pulmonary nodules and/or bone metastases) with normal hepatic, renal, and cardiac function were eligible. Patients were eligible to receive further topotecan after standard chemotherapy if they exhibited a response. Twenty-eight patients were enrolled. Seventeen had metastases to the lung only and 11 had metastases to the bone or multiple sites. Of 28 patients enrolled, 27 could be evaluated for response. A limited dose escalation was incorporated.
  
  
  RESULTS
  No responses were seen in the 11 patients treated at 3 mg/m(2)/day. One partial response (PR) and 1 clinical response (CLR) were reported among 15 patients who received topotecan at 3.5 mg/m(2)/day. No dose-limiting toxicity was observed. Principal nondose-limiting toxicities were hematologic and gastrointestinal. The 2- and 5-year event-free survival rates were low, 7% and 4%, respectively, but the 2- and 5-year overall survival rates were 44% and 22%, respectively.
  
  
  CONCLUSIONS
  Topotecan at dose of 3.5 mg/m(2)/day can be safely administered upfront to newly diagnosed patients without excessive toxicity. Insufficient activity was seen with topotecan in this schedule to warrant further studies in osteosarcoma. The combination of ICE and CD was tolerable when delivered after initial topotecan therapy.
authors.affiliation: Hematology-Oncology, Children's National Medical Center, George Washington University School of Medicine, Washington, DC 20010, USA. nseibel@cnmc.org
authors.forename: Nita L
authors.initials: NL
authors.lastname: Seibel
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Healey
authors.forename: Philip P
authors.initials: PP
authors.lastname: Breitfeld
authors.forename: Richard
authors.initials: R
authors.lastname: Drachtman
authors.forename: Brian
authors.initials: B
authors.lastname: Greffe
authors.forename: James
authors.initials: J
authors.lastname: Nachman
authors.forename: Helen
authors.initials: H
authors.lastname: Nadel
authors.forename: Judith K
authors.initials: JK
authors.lastname: Sato
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D020714:Maximum Tolerated Dose; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D011379:Prognosis; D016019:Survival Analysis; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan