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; 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.

项目摘要 /摘要 癌症是15岁以下儿童的第二次最常见的死亡原因，主要中央 神经系统（CNS）肿瘤是癌症相关儿童死亡的最常见原因。髓母细胞瘤 （MB）是最常见的恶性儿童脑肿瘤（每年5.5/百万）。大约40％的案件 发生在<5岁的儿童中，可以通过生物标记将其细分为两组：低风险组， 由无翼/集成（Wnt）或声音刺猬（SHH）激活TP53-WT定义的生物学定义 高风险组由非WNT/非SHH生物学定义。由于Wnt激活的MB在早期极为罕见 童年，只有低风险（SHH激活）MB的年轻患者（<5岁）才有资格 在这项研究中，如果用两个随机臂中的任何一个在两个随机臂中进行治疗，则出色的预后。颅骨脊髓 辐照（CSI）是治疗MB的组成部分；但是，由于造成破坏性的影响 在中枢神经系统（CNS）和神经认知结果上，必须尽可能避免它 考虑到对教育和出版成就的重大干扰。因此，维护或 改善神经认知和QOL功能是可以童年冲浪者的重要机会 现在可以用不包括CSI的治疗方法来治愈。潜在的国际唾液/连接 III期研究以改善低风险髓母细胞瘤的幼儿的神经认知结果 （YCMB-LR）是有史以来的第一项随机研究 治疗方案，Head Start 4和Hit-Skk，将在小儿肿瘤学中心举行 欧洲和北美，是第一个将神经心理学和QOL结果包括在内的人 客观的。目标1）比较Wechsler学前班衡量的整体智能和智商子域 和新诊断患者诊断后2。5年的智力量表和一级尺度 非转移性，SHH激活的TP53-WT MB随机分配给介入臂A（head start 4）或b（hit- Skk）。目标2）比较基线时两个随机组之间的轨迹 诊断的诊断：a）整体智力和智商子域，b）行为发展和c）QOL，以及 诊断后2。5年的分析：d）精细的运动灵量和处理速度，e）视觉运动 集成，f）执行功能和g）社会情感功能。目标3）几个定量成像 关于脑量和白质损伤的指标将成为辅助无创生物标志物 AIM 1中两个介入臂的比较，并将与神经认知统计相关， AIM 2中的QOL和行为结果。影响：我们的工作将定义新的“黄金标准”治疗的“金标准” 儿童早期低风险MB，与更好的神经认知结果有关 并最终在生存方面产生更好的QoL，同时改善和协调国际 诊断和治疗标准不仅用于MB，而且针对其他儿科中枢神经系统肿瘤。