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

改善低危髓母细胞瘤幼儿神经认知结果的前瞻性国际 III 期研究 (YCMB-LR)

• 批准号: 10720110
• 负责人: STEPHEN Alan SANDS
• 金额: $ 26.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720110
• 关键词: 15 year old; 2 year old; 5 year old; Adaptive Behaviors; Adjuvant Therapy; Age; Agreement; American; Autologous; Behavioral; Biological; Biological Markers; Biology; Brain; Brain Neoplasms; Cancer Etiology; Cause of Death; Cells; Central Nervous System; Central Nervous System Neoplasms; Cessation of life; Child; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Leukemia; Childhood Malignant Brain Tumor; Childhood Medulloblastomas; Correlation Studies; Data; Development; Diagnosis; Diagnostic; Dose; Education; Eligibility Determination; Europe; European; Excision; Funding; Goals; Guidelines; Head Start Program; Hematopoietic; High Dose Chemotherapy; Incidence; Infant; Intelligence; International; Intravenous; Intraventricular; Language; Late Effects; Longevity; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Medical center; Methotrexate; Molecular Profiling; Motor; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurologic Deficit; Neuropsychological Tests; Neuropsychology; Newly Diagnosed; Nonmetastatic; North America; Nursery Schools; Outcome; Pathogenesis; Pathway Analysis; Patients; Pediatric Oncology; Prognosis; Progression-Free Survivals; Protocols documentation; Quality of life; Randomized; Regimen; Research Project Grants; Risk; SHH gene; Secure; Short-Term Memory; Site; Societies; Standardization; Survival Rate; Survivors; Testing; Therapeutic; Time; Translating; Treatment Protocols; Vocation; Work; arm; behavioral outcome; brain volume; chemotherapy; clinically relevant; dexterity; early childhood; emotional functioning; executive function; functional outcomes; high risk population; improved; irradiation; medulloblastoma; neurocognitive test; neurosurgery; novel therapeutics; phase 3 study; processing speed; prospective; quantitative imaging; research study; risk prediction; social; standard care; standard measure; survivorship; treatment arm; tumor; visual-motor integration; white matter injury

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.

项目总结/摘要 癌症是15岁以下儿童死亡的第二大最常见原因， 神经系统（CNS）肿瘤是与癌症相关的儿童死亡的最常见原因。成神经 (MB)是儿童期最常见的恶性脑肿瘤（发病率为5.5/万/年）。大约40%的病例 发生于<5岁的儿童，按生物学标志物可分为两组：低危组， 生物学上由无翼/整合（WNT）或音速刺猬（SHH）激活TP 53-wt定义，而 高风险组由非WNT/非SHH生物学定义。由于WNT激活的MB在早期非常罕见， 在儿童期，只有患有低风险（SHH激活）MB的年轻患者（<5岁）才有资格参加， 在本研究中，如果用两个随机分组中的任何一个治疗，则预后良好。全脊髓 照射（CSI）是MB治疗中不可或缺的组成部分;然而，由于其破坏性的影响， 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重大干扰。因此，维持或 改善神经认知和生活质量功能是早期儿童幸存者的重要机会， 现在可以通过不包括CSI的治疗来治愈。展望未来的国际SIOPE/ECOECT 改善低风险髓母细胞瘤幼儿神经认知结局的III期研究 （YCMB-LR）是有史以来第一个直接比较两种高效辐射防护的随机研究。 治疗方案，头开始4和HIT-SKK，这将发生在儿科肿瘤中心， 欧洲和北美，是第一个将神经心理学和QoL结局作为主要结局的研究 objective.目的1）比较韦氏幼儿园测量的整体智力和智商子域 在诊断后2.5年， 非转移性、SHH激活、TP 53-wt MB随机分配至介入组A（Head Start 4）或B（HIT-1）。 SKK）。目的2）比较两个随机分组在基线和2.5年时的轨迹 诊断后：a）总体智力和IQ子域，B）行为发育和c）QoL，沿着 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，和g）社会情感功能。目的3）几种定量成像 关于脑体积和白色物质损伤的度量将作为辅助的非侵入性生物标志物， 目标1中两个介入组的比较，并将与神经认知， 目标2中的生活质量和行为结局。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，与更好的神经认知结局相关，晚期效应不严重 并最终在生存率方面产生更好的生活质量，同时改善和协调国际 这不仅是MB的诊断和治疗标准，也是其他儿科CNS肿瘤的诊断和治疗标准。