Phase II Randomized Comparison of Topotecan Plus Cyclophosphamide Versus Topotecan Alone in Children With Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Study
Phase II Randomized Comparison of Topotecan Plus Cyclophosphamide Versus Topotecan Alone in Children With Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Study
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DOI：
10.1200/jco.2009.27.5016
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发表时间：
2010-08-20
影响因子：
45.3
通讯作者：
Diller, Lisa
中科院分区：
文献类型：
--
作者：
London, Wendy B.;Frantz, Christopher N.;Diller, Lisa
目的比较拓扑替康单药（topotecan，TOPO）和拓扑替康与环磷酰胺联合（topotecan/CTX）治疗复发/难治性神经母细胞瘤的II期随机临床试验。由于缓解者经常接受进一步治疗，因此需要新颖的统计方法来比较两种治疗的长期结果。患者和方法患有难治性/复发性神经母细胞瘤的儿童（之前只有一种积极的化疗方案）被随机分配接受每日5天的托泊替康（2 mg/m（2））或托泊替康（0.75 mg/m（2））和环磷酰胺（250 mg/m（2））联合治疗。随机两阶段组序贯设计招募了119名合格患者。毒性和反应进行了估计。协议治疗的长期结果进行了评估，使用新的方法-因果推理-这允许调整的混杂效应off-study therapeutis.Results7个以上的反应，观察到TOPO/CTX（完全反应[CR]加部分反应[PR]，18 [32%]的57）比TOPO（CR + PR，11 [19%]的59; P = 0.081）;毒性是相似的。3年时，无进展生存期（PFS）和总生存期（OS）分别为4% +/- 2%和15% +/-4%。TOPO/CTX组PFS明显更好（P = 0.029）; OS无差异。诊断时年龄较大和MYCN扩增缺乏预示OS增加（P <0.05）。调整随机治疗效果和随后的自体干细胞移植，有没有TOPO和TOPO/CTX之间的比例在2 years.ConclusionTOPO/CTX生存方面的差异是上级TOPO的PFS，但没有OS差异。在调整后续治疗后，2年时存活的比例无差异。用于评估后续治疗后II期治疗的长期结局的因果推断方法可以阐明初始治疗的效果。
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.ResultsSeven 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.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.