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

A B S T R A C T PurposeSingle-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. Patients and MethodsChildren 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. (CRϩPR, 11 [19%] of 59; P ϭ .081); toxicity was similar. At 3 years, progression-free survival (PFS) and overall survival (OS) were 4% Ϯ 2% and 15% Ϯ 4%, respectively. PFS was significantly better for TOPO/CTX (P ϭ .029); there was no difference in OS. Older age at diagnosis and lack of MYCN amplification predicted increased OS (P Ͻ .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. Results Seven ConclusionTOPO/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.

Overview and recent advances in the treatment of neuroblastoma

“…Topotecan is primarily used in combination with cyclophosphamide, and the initial phase II study using cycles of this combination (250 mg/m 2 /day cyclophosphamide and 0.75 mg/m 2 /day topotecan for 5 days each) achieved objective responses in 6 of 13 neuroblastoma patients [105]. Further studies have shown increased response rates in patients treated with the cyclophosphamide/topotecan combination compared to topotecan alone (2 mg/m 2 /day for 5 days), although no difference in OS rates were observed [106]. Higher doses of cyclophosphamide and topotecan combined with vincristine have also shown impressive results, including an overall response rate of 19% for patients with primary refractory neuroblastoma and 52% for those with first relapse [107].…”

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

“…The combination of cyclophosphamide plus topotecan has been active in rhabdomyosarcoma, neuroblastoma, and Ewing sarcoma patients with recurrent or refractory disease who have not received topotecan previously (18)(19)(20). The combination of topotecan, cyclophosphamide, and etoposide is tolerable and effective in relapsed and newly diagnosed neuroblastoma in phase II clinical trials and upfront phase III clinical trials (18,21).…”

Assessing causal relationships between treatments and clinical outcomes: always read the fine print

“…Consider a randomized trial of topotecan þ cyclophosphamaide vs topotecan alone in recurrent neuroblastoma. 38 Intent-to-treat analysis indicated no difference in OS. However, some of the patients on study received auto-SCT, with patients responding to the initial chemotherapy regimen more likely having subsequent auto-SCT.…”

“…It is theoretically possible that a suboptimal pattern of auto-SCT administration eliminated the potential OS benefit. To explore this London et al 38 used causal-inference methods to estimate potential OS benefit under two hypothetical scenarios: (1) no auto-SCT was performed and (2) if patients received auto-SCT administration that was optimized for their initial response status. The analyses confirmed lack of benefit for topotecan þ cyclophosphamaide regimen.…”