Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma A Randomized Clinical Trial
Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma A Randomized Clinical Trial
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串联自体干细胞移植与单次移植对高危神经母细胞瘤患者无事件生存期的影响 一项随机临床试验
DOI：
10.1001/jama.2019.11642
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发表时间：
2019-08-27
影响因子：
120.7
通讯作者：
Diller, Lisa
中科院分区：
文献类型：
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作者：
Park, Julie R.;Kreissman, Susan G.;Diller, Lisa
重要性诱导化疗后的高剂量自体干细胞移植和随后的抗二唾液酸神经节苷脂抗体免疫治疗是高危神经母细胞瘤患者的标准治疗，但这些患者的生存率仍然很低。患者于2007年11月至2012年2月在美国，加拿大，瑞士，澳大利亚和新西兰的142个儿童肿瘤组中心参加了这项随机临床试验。共招募了652例符合条件的30岁或以下的方案定义的高风险神经母细胞瘤患者，其中355例随机分配。最终随访日期为2017年6月29日，数据分析截止日期为6月30日，干预患者随机接受噻替派/环磷酰胺的串联移植，随后接受剂量减少的卡铂/依托泊苷/美法仑（n = 176）或卡铂/依托泊苷/美法仑的单次移植（n = 179）主要结果和测量主要结果是从随机化到第一事件（复发、进展、继发性恶性肿瘤或任何原因的死亡）发生的EFS。该研究的目的是测试单侧假设的优越性，双移植相比，单transplant.Results的652名合格的患者中，297没有进行随机化，因为他们是非随机分配（n = 27），不符合随机化（n = 62），没有治疗（n = 1），或因为医生/父母的喜好（n = 207）。在355例随机化患者中（中位诊断年龄为36.1个月; 152例[42.8%]女性），297例患者（83.7%）完成了研究，21例（5.9%）在完成方案治疗后失访。从随机化开始，双次移植组的3年EFS为61.6%（95% CI，54.3%-68.9%），单次移植组为48.4%（95% CI，41.0%-55.7%）（单侧对数秩P = 0.006）。181例无事件患者随机化后的中位（范围）随访持续时间为5.6（0.6-8.9）年。与单次移植相比，双次移植后最常见的显著毒性是粘膜毒性（11.7% vs 15.4%）和感染性毒性（17.9% vs 18.3%）。结论和相关性在30岁或以下的高危神经母细胞瘤患者中，双次移植的EFS显著优于单次移植。然而，由于随机化率低，研究结果可能不能代表所有高危神经母细胞瘤患者。
IMPORTANCE Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low.OBJECTIVE To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant.DESIGN, SETTING, AND PARTICIPANTS Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017.INTERVENTIONS Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179).MAIN OUTCOMES AND MEASURES The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant.RESULTS Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P = .006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%).CONCLUSIONS AND RELEVANCE Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma.