André O. von Bueren, Katja von Hoff, Carsten Friedrich, Martin Mynarek, and Stefan Rutkowski, University Medical Center Hamburg-Eppendorf, Hamburg; André O. von Bueren, University Medical Center Goettingen, Goettingen; Rolf-Dieter Kortmann and Klaus Müller, University of Leipzig; Carsten Friedrich, University Hospital Leipzig, Leipzig; Katja von Hoff, Nicolas Gerber, Monika Warmuth-Metz, Niels Soerensen, Frank Deinlein, and Joachim Kuehl, University of Wuerzburg, Wuerzburg; Tobias Goschzik, Anja zur Mühlen, and Torsten Pietsch, University of Bonn Medical Center; Udo Bode, University Hospital of Bonn, Bonn; Isabella Zwiener and Andreas Faldum, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz; Robert Kwiecien and Andreas Faldum, University of Muenster, Muenster; Gudrun Fleischhack, University Hospital of Essen, Essen; Volker Hovestadt, Marcel Kool, David Jones, Paul Northcott, and Stefan Pfister, German Cancer Research Center; Marcel Kool, David Jones, Paul Northcott, and Stefan Pfister, German Cancer Consortium; Stefan Pfister, University Hospital and National Center for Tumor Diseases, Heidelberg, Germany; Nicolas Gerber, University Children's Hospital, Zurich, Switzerland; Martin Benesch, Medical University of Graz, Graz, Austria; and Paul Northcott, St Jude Children's Research Hospital, Memphis, TN.
J Clin Oncol. 2016 Dec;34(34):4151-4160. doi: 10.1200/JCO.2016.67.2428. Epub 2016 Oct 31.
Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT '91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher's exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.
目的 评估在转移性成神经管细胞瘤的临床和生物学危险因素背景下的强化治疗。
患者和方法 患者（4 至 21 岁，2001 年至 2007 年诊断）接受诱导化疗、剂量递增超分割颅脊髓放疗和维持化疗。评估亚组状态和其他生物学参数。
结果 在 123 名合格患者（中位年龄 8.2 岁；中位随访时间 5.38 年）中，5 年无事件生存率（EFS）和总生存率（OS）分别为 62%（95%CI，52 至 72）和 74%（95%CI，66 至 82）。OS 优于先前的 HIT '91 试验。5 年 EFS 和 OS 对于促结缔组织增生型/结节型（n = 11）分别为 89%（95%CI，67 至 100），61%（95%CI，51 至 71）和 75%（95%CI，65 至 85）对于经典型（n = 107），20%（95%CI，0 至 55）和 40%（95%CI，0 至 83）对于大细胞/间变型（n = 5）成神经管细胞瘤（EFS 差异有统计学意义；OS 差异有统计学意义）。组织学（危险比，促结缔组织增生型/结节型为 0.19，大细胞/间变型成神经管细胞瘤为 45.97）和对第一化疗周期无反应（危险比，1.97）是独立的危险因素（EFS）。在 81 名（66%）有肿瘤标本的患者中，低危（无翅型 [WNT]，n = 4；均为 100%）、高危（MYCC/MYCN 扩增，n = 5；均为 20%）和中危（既非，n = 72；63%和 73%）患者的 5 年 EFS 和 OS 不同。分子亚组之间的生存率不同（WNT，n = 4；Sonic Hedgehog [SHH]，n = 4；组 4，n = 41；组 3 有[ n = 3]或无 [n = 17]MYCC/MYCN 扩增）（P <.001）。所有病例均为 p53 免疫阴性。诱导化疗后肿瘤无反应的患者与 WNT（P =.143）或 MYCC/MYCN 状态（P =.075）、组织学亚型（P =.814）或分子亚型（P =.383）之间无相关性，Fisher 确切概率检验。
结论 该方案是可行的，并带来了总体良好的生存。我们的数据在一个同质的前瞻性试验人群中证实了亚组状态和生物学参数（WNT/MYCC/MYCN 状态）的相关性，并表明转移性组 3 患者的结局并非普遍不良。生物学亚组、MYCC/MYCN 状态、对诱导化疗的反应和组织学亚型可能有助于改善治疗分层。
