NEUROONCOLOGY

神经肿瘤学

• 批准号: 6563773
• 负责人: JAN C BUCKNER
• 金额: $ 7.89万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-11 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563773
• 关键词: acridines; analog; anticonvulsants; antineoplastics; carboplatin; cisplatin; combination cancer therapy; cooperative study; drug interactions; gene therapy; glioma; human subject; human therapy evaluation; irinotecan; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; patient oriented research; pharmacokinetics; psychological aspect of cancer; sirolimus

The NCCTG Neuro-Oncology Program consists of three components: Cancer Treatment Trials, Neurobehavioral Studies, and Laboratory Correlates. These complementary components contribute to improving duration and quality of life in patients with primary central nervous system malignancies and to enhancing our understanding of the underlying disease process. During the previous grant cycle, in low-grade glioma patients, we observed that 65 cGy radiation is not better than 50 cGy; pro-carbazine, CCNU, grade glioma patients, we observed that 65 cGy radiation is not better than 50 cGy; procarbazine, CCNU, and vincristine (PCV) is an active regimen as initial therapy; and deletions in chromosomes 1p and 19q are associated with the diagnosis of low-grade oligodendrogliona, but not with low-grade oligoastrocytoma. In patients with high-grade glioma (glioblastoma multiforme, anaplastic oligoastrocytoma), we demonstrated that recombinant alpha interferon does not improve survival when added to radiation and BCNU, but is considerably more toxic; than grading (grade 3 versus grade 4) has significant prognostic value in patients with anaplastic oligoastrocytoma; and that, grade for grade, patients with anaplastic oligoastrocytoma have a statistically significant improved survival compared to those with pure astrocytoma. Moreover, tumoral EGFR amplification, absence of p53 mutations, and PTEN deletions are associated with poor survival in anaplastic astrocytoma patients. Glioblastoma and gliosarcoma patients have essentially identical clinical courses and genetic abnormalities. In recurrent glioma patients, we identified two active regimens: MOP (nitrogen mustard, vincristine, and procarbazine) and irinotecan. Ph. Pharmacokinetic studies demonstrated increase in CPT-11 clearance and variable metabolism in patients receiving irinotecal and anti-convulsants concurrently. Non-glioblastoma patients were more likely to respond to treatment than those with recurrent glioblastoma. Neurobehavioral studies indicated that good baseline Folstein and Folstein mini-mental status examination (MMSE) score is associated with better survival on multi-variate analyses. Few patients with high-grade glioma had diminished mini-mental examination scores at one year and 18 months in the absence of tumor progression. Conversely, reduction in mini-mental status examination scores correlated strongly with both at diagnosis, and were more likely to have cognitive decline to have cognitive decline as a consequence of treatment compared with younger patients. In patients with primary CNS lymphoma, we found a high response rate with CHOP (cyclophosphamide, doxorubicin, vincristine, and dexamethasone), but the duration of benefit was very short. As in patients with high-grade glioma, MMSE scores declined in close association with tumor progression. Future plans include continued evaluation of agents with radiosensitizing properties including cisplatin and irinotecan. We will continue to evaluate the efficacy of new regimens in recurrent glioma patients, including pyrazoloacridine plus carboplatin and the rapamycin analog, CCI 779. NCCTG has recruited investigators demonstrating experience with inhibitors of tumor invasion, as well as gene therapy. There are two main gene therapy approaches current in preclinical investigation: fusogenic membrane glycoproteins such as the measles virus F and H proteins and the truncated Gibbon Ape Leukemia virus surface protein (GALV). Neurobehavioral studies, including evaluation and treatment of impaired cognitive status, depression, fatigue, and excessive daytime somnolence, are in process. Pharmacokinetic studies to investigate interactions among chemotherapeutic agents and anti-convulsants will continue. Studies of genetic alterations in glioma, especially anaplastic astrocytoma and low- grade glioma, will be expanded through collaborations with Drs. Robert Jenkins (Mayo) David James (Mayo), and Bert Feuerstein (UCSF).

NCCTG神经肿瘤学项目由三个部分组成：癌症治疗试验，神经行为研究和实验室相关性。这些补充成分有助于改善原发性中枢神经系统恶性肿瘤患者的生存时间和生活质量，并增强我们对潜在疾病过程的理解。在前一个研究周期中，低级别胶质瘤患者65 cGy放疗不优于50 cGy，丙卡巴肼、环己亚硝脲、级别胶质瘤患者65 cGy放疗不优于50 cGy，丙卡巴肼、环己亚硝脲、长春新碱（PCV）是一个积极的初始治疗方案;染色体1 p和19 q缺失与低级别少突胶质细胞瘤的诊断相关，但与低级别少突星形细胞瘤无关。高级别胶质瘤患者（多形性胶质母细胞瘤，间变性少突星形细胞瘤），我们证明，重组α干扰素并没有改善生存时，加入放疗和BCNU，但毒性大大高于分级（3级对4级）对间变性少突星形细胞瘤患者有显著的预后价值;并且，与单纯星形细胞瘤相比，间变性少突星形细胞瘤患者的生存率在统计学上显著提高。此外，肿瘤EGFR扩增、p53突变缺失和PTEN缺失与间变性星形细胞瘤患者的生存率差相关。胶质母细胞瘤和胶质肉瘤患者具有基本相同的临床病程和遗传异常。在复发性胶质瘤患者中，我们确定了两种活性治疗方案：MOP（氮芥、长春新碱和甲基苄肼）和伊立替康。Ph.药代动力学研究表明，在同时接受伊立替康和抗惊厥药的患者中，CPT-11清除率和可变代谢增加。非胶质母细胞瘤患者比复发性胶质母细胞瘤患者更可能对治疗有反应。神经行为研究表明，良好的基线Folstein和Folstein简易精神状态检查（MMSE）评分与多变量分析的生存率相关。在没有肿瘤进展的情况下，少数高级别胶质瘤患者在1年和18个月时的简易精神检查评分降低。相反，简易精神状态检查评分的降低与诊断时的两者密切相关，并且与年轻患者相比，更有可能因治疗而出现认知下降。在原发性中枢神经系统淋巴瘤患者中，我们发现CHOP（环磷酰胺、阿霉素、长春新碱和地塞米松）的反应率较高，但获益持续时间很短。与高级别胶质瘤患者一样，MMSE评分下降与肿瘤进展密切相关。未来的计划包括继续评估具有放射增敏特性的药物，包括顺铂和伊立替康。我们将继续评估新的治疗方案在复发性胶质瘤患者中的疗效，包括吡唑并吖啶加卡铂和雷帕霉素类似物CCI 779。NCCTG招募了具有肿瘤侵袭抑制剂和基因治疗经验的研究人员。目前在临床前研究中有两种主要的基因治疗方法：融合膜糖蛋白，如麻疹病毒F和H蛋白和截短的巨猿白血病病毒表面蛋白（GALV）。神经行为研究，包括评估和治疗受损的认知状态，抑郁症，疲劳和过度的白天嗜睡，正在进行中。将继续进行药代动力学研究，以研究化疗药物和抗惊厥药物之间的相互作用。通过与罗伯特·詹金斯（马约）、大卫·詹姆斯（马约）和伯特·福伊尔斯坦（加州大学旧金山分校）博士的合作，将扩大对神经胶质瘤，特别是间变性星形细胞瘤和低级别神经胶质瘤遗传变异的研究。