Prospective international phase-III study to improve neurocognitive outcomes in young children with low-risk medulloblastoma (YCMB-LR)

项目摘要/摘要 癌症是15岁以下儿童死亡的第二大常见原因，也是主要的 神经系统肿瘤是与癌症相关的儿童死亡的最常见原因。髓母细胞瘤 (MB)是儿童最常见的恶性脑肿瘤(发病率为5.5/百万/年)。大约40%的案例 发生于5岁以下儿童，按生物学指标可分为两组：低危组， 生物学上由无翼/集成(WNT)或Sonic Hedgehog(SHH)激活TP53-wt定义，而 高危人群由非WNT/非SHH生物学定义。因为WNT激活的MB在早期是极其罕见的 儿童时期，只有患有低风险(SHH激活)MB的年轻患者(&lt；5岁)才符合条件，并有 在这项研究中，如果用两个随机组中的任何一个治疗，预后都很好。颅脑脊髓 照射(CSI)是甲基溴治疗中不可或缺的组成部分；然而，由于其破坏性影响 对中枢神经系统(CNS)和神经认知结果的影响，必须尽可能避免 鉴于对教育和职业成就的严重干扰。因此，维护或 改善神经认知和生活质量功能是早期儿童幸存者的一个重要机会，他们可以 现在可以通过不包括CSI的治疗来治愈。未来的国际SIOPE/CONNECT 改善低危髓母细胞瘤幼儿神经认知结果的III期研究 (YCMB-LR)是有史以来第一项直接比较两种高效放射节省的随机研究 治疗方案，Head Start 4和HIT-SKK，将在全国各地的儿科肿瘤中心进行 欧洲和北美，是第一个将神经心理学和生活质量结果作为主要指标的国家 目标。目的1)比较韦氏学龄前儿童智力和智商总分 初诊患者与初诊患者在确诊后2.5年后进行初级智能评定量表测试， SHH激活的非转移性TP53-wt MB被随机分配到介入臂A(磁头开始4)或B(HIT- SKK)。目的2)比较两个随机组在基线和2.5年时的轨迹 诊断后：a)总体智力和智商亚域，b)行为发展和c)生活质量，以及 诊断后2.5年的分析：d)精细运动灵活性和处理速度，e)视觉运动 整合，f)执行功能，g)社会-情绪功能。目标3)几种定量成像 有关脑体积和脑白质损伤的指标将作为辅助的非侵入性生物标志物 目标1中两个介入性手臂的比较，并将与神经认知， AIM中的生活质量和行为结果2.影响：我们的工作将定义新的治疗“黄金标准” 儿童早期低风险MB与较好的神经认知结果和较不严重的后遗症相关 并最终提高生存质量，同时改善和协调国际 诊断和治疗标准不仅适用于MB，也适用于其他儿童中枢神经系统肿瘤。

PROJECT SUMMARY / ABSTRACT Cancer is the second most frequent cause of death in children under 15 years of age, and primary central nervous system (CNS) tumors are the most frequent cause of cancer-related childhood deaths. Medulloblastoma (MB) is the most frequent malignant childhood brain tumor (incidence of 5.5/million/year). About 40% of cases occur in children <5 years old, which can be sub-divided by biological markers into two groups: low-risk group, biologically defined by either Wingless/Integrated (WNT) or Sonic Hedgehog (SHH) activation TP53-wt, while the high-risk group is defined by non-WNT/non-SHH biology. As WNT-activated MB is extremely rare in early childhood, only young patients (<5 years of age) with low-risk (SHH-activated) MB are eligible and have an excellent prognosis if treated with either of the two randomized arms in this research study. Craniospinal irradiation (CSI) is an integral component in the treatment of MB; however, because of the devastating impact upon the central nervous system (CNS) and neurocognitive outcomes, it must be avoided whenever possible given the significant interference with educational and vocational attainment. Consequently, maintaining or improving neurocognitive and QoL functioning is an essential opportunity for early childhood survivors who can now be cured with treatment that does not include CSI. The Prospective International SIOPE/CONNECT phase-III study to improve neurocognitive outcomes in young children with low-risk medulloblastoma (YCMB-LR) is the first ever randomized study directly comparing two highly effective irradiation-sparing treatment regimens, Head Start 4 and HIT-SKK, which will take place at pediatric oncology centers across Europe and North America and is the first to include neuropsychological and QoL outcome as the primary objective. Aim 1) Compare the overall intelligence and IQ subdomains as measured by the Wechsler Preschool and Primary Scale of Intelligence administered 2.5 years after diagnosis between patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt MB randomized to the interventional arms A (Head Start 4) or B (HIT- SKK). Aim 2) Compare the trajectory between the two randomized groups at baseline and again at 2.5 years post diagnosis for: a) overall intelligence and IQ subdomains, b) behavioral development and c) QoL, along with analyses at 2.5 years post diagnosis for: d) fine motor dexterity and processing speed, e) visual-motor integration, f) executive functioning, and g) social-emotional functioning. Aim 3) Several quantitative imaging metrics with regard to brain volumes and white matter injury will serve as ancillary noninvasive biomarkers for comparison of the two interventional arms in Aim 1, and will be statistically correlated with the neurocognitive, QoL and behavioral outcomes in Aim 2. Impact: Our work will define the new “gold standard” of treatment in early childhood low-risk MB that is associated with better neurocognitive outcomes with less severe late-effects and ultimately yield a better QoL in survivorship, while simultaneously improving and harmonizing international diagnostic and therapeutic standards not only for MB, but also for other pediatric CNS tumors.