title: Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study.
abstract: OBJECTIVE
  Single-agent topotecan (TOPO) and combination topotecan and cyclophosphamide (TOPO/CTX) were compared in a phase II randomized trial in relapsed/refractory neuroblastoma. Because responders often underwent further therapies, novel statistical methods were required to compare the long-term outcome of the two treatments.
  
  
  METHODS
  Children with refractory/recurrent neuroblastoma (only one prior aggressive chemotherapy regimen) were randomly assigned to daily 5-day topotecan (2 mg/m(2)) or combination topotecan (0.75 mg/m(2)) and cyclophosphamide (250 mg/m(2)). A randomized two-stage group sequential design enrolled 119 eligible patients. Toxicity and response were estimated. Long-term outcome of protocol therapy was assessed using novel methods-causal inference-which allowed adjustment for the confounding effect of off-study therapies.
  
  
  RESULTS
  Seven more responses were observed for TOPO/CTX (complete response [CR] plus partial response [PR], 18 [32%] of 57) than TOPO (CR+PR, 11 [19%] of 59;P = .081); toxicity was similar. At 3 years, progression-free survival (PFS) and overall survival (OS) were 4% +/- 2% and 15% +/- 4%, respectively. PFS was significantly better for TOPO/CTX (P = .029); there was no difference in OS. Older age at diagnosis and lack of MYCN amplification predicted increased OS (P < .05). Adjusting for randomized treatment effect and subsequent autologous stem-cell transplantation, there was no difference between TOPO and TOPO/CTX in terms of the proportion alive at 2 years.
  
  
  CONCLUSIONS
  TOPO/CTX was superior to TOPO in terms of PFS, but there was no OS difference. After adjustment for subsequent therapies, no difference was detected in the proportion alive at 2 years. Causal inference methods for assessing long-term outcomes of phase II therapies after subsequent treatment can elucidate effects of initial therapies.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. wendy@cog.ufl.edu
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Frantz
authors.forename: Laura A
authors.initials: LA
authors.lastname: Campbell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Babette A
authors.initials: BA
authors.lastname: Brumback
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Robert P
authors.initials: RP
authors.lastname: Castleberry
authors.forename: Lisa
authors.initials: L
authors.lastname: Diller
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015984:Causality; D002648:Child; D002675:Child, Preschool; D015986:Confounding Factors, Epidemiologic; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D015233:Models, Statistical; D009447:Neuroblastoma / Q000188:drug therapy*; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors; D019772:Topotecan / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan; D003520:Cyclophosphamide