Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR
Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR
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DOI：
10.1016/j.annonc.2019.11.011
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发表时间：
2020-03-01
影响因子：
50.5
通讯作者：
Simon, T.
中科院分区：
文献类型：
--
作者：
Berthold, F.;Faldum, A.;Simon, T.
背景：尽管强化多模式治疗，高危神经母细胞瘤患者的长期存活率仍低于50%。这项试验旨在探讨与标准诱导疗法相比，增加两个含拓扑替康的化疗疗程是否能提高这些患者的无事件生存率(EFS)。患者和方法：在德国和瑞士的58家医院进行了一项开放标签、多中心、前瞻性的随机对照试验。年龄1-21岁的4期神经母细胞瘤和6个月-21岁的MYCN扩增的肿瘤患者符合条件。主端点是EFS。患者被随机分配到标准诱导治疗和6个化疗疗程，或试验性诱导化疗，首先是另外两个疗程的拓扑替康、环磷酰胺和依托泊苷，然后是标准诱导化疗(总共8个疗程)。诱导化疗后，所有患者均接受大剂量化疗联合自体造血干细胞挽救和异维甲酸巩固。结果：536例患者中，422例随机分为对照组(n=211)和试验组(n=211)，中位随访时间3.32年(四分位间隔1.65~5.92)。在数据锁定时，试验组和对照组的3年无病生存率分别为34%和32%[95%可信区间(CI)28%~40%和26%~38%；P=0.258]。同样，患者的3年总生存率无差异[分别为54%和48%(95%可信区间分别为46%和62%和40%和56%)；P=0.558]。对诱导化疗的反应在不同的手臂上没有区别。试验组患者人均非致命性毒性反应的中位数较高，而每个化疗疗程的毒性反应中位数无差异。结论：虽然诱导化疗和毒性延长增加了患者的负担，但增加两个含拓扑替康的化疗疗程并不能改善高危神经母细胞瘤患者的EFS，因此不推荐使用。
Background: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients.Patients and methods: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy.Results: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different.Conclusion: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended.