NEUROONCOLOGY

NCCTG神经肿瘤学计划由三个部分组成：癌症治疗试验、神经行为研究和实验室相关性。这些互补成分有助于改善原发性中枢神经系统恶性肿瘤患者的持续时间和生活质量，并增强我们对潜在疾病过程的理解。在上一个资助周期中，我们观察到在低级别胶质瘤患者中，65cGy射线照射不优于50cGy；前卡巴肼、CCNU、级别胶质瘤患者，我们观察到65cGy射线照射不优于50cGy；Procarbazine、CCNU和长春新碱(PCV)是初始治疗的有效方案；1p和19q染色体上的缺失与低级别少突胶质细胞瘤的诊断有关，但与低级别少星形细胞瘤无关。在高级别胶质瘤(多形性胶质母细胞瘤、间变性少星形细胞瘤)患者中，我们证明了重组α干扰素在加入放射治疗和BCNU时并不能提高生存率，但毒性要大得多；在间变性少星形细胞瘤患者中，分级(3级对4级)具有显著的预后价值；并且，从分级来看，间变性少星形细胞瘤患者的生存率比单纯星形细胞瘤患者有统计学意义的改善。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低存活率有关。胶质母细胞瘤和胶质肉瘤患者的临床病程和遗传异常基本相同。在复发的胶质瘤患者中，我们确定了两种有效的治疗方案：MOP(氮芥、长春新碱和丙卡巴肼)和伊立替康。药代动力学研究表明，同时接受伊立替卡和抗惊厥药物治疗的患者CPT-11清除率和可变代谢增加。非胶质母细胞瘤患者比复发的胶质母细胞瘤患者更有可能对治疗有反应。神经行为研究表明，在多因素分析中，基线Folstein和Folstein简易精神状态检查(MMSE)评分好与较好的生存相关。在没有肿瘤进展的情况下，很少有高级别胶质瘤患者在一年零18个月时迷你智力检查分数降低。相反，与年轻患者相比，迷你精神状态检查分数的下降与确诊时的两者都有很强的相关性，而且更有可能出现认知能力下降，并作为治疗的结果出现认知能力下降。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)有很高的有效率，但受益时间很短。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辐射增敏特性的药物，包括顺铂和伊立替康。我们将继续评估新方案对复发性胶质瘤患者的疗效，包括吡唑吖啶加卡铂和雷帕霉素类似物CCI779。NCCTG已经招募了研究人员，他们展示了在肿瘤侵袭抑制剂和基因治疗方面的经验。目前在临床前研究中主要有两种基因治疗方法：融合膜糖蛋白，如麻疹病毒F和H蛋白和截短的长臂猿白血病病毒表面蛋白(GalV)。神经行为研究正在进行中，包括对认知状态受损、抑郁、疲劳和白天过度嗜睡的评估和治疗。将继续进行药代动力学研究，以调查化疗药物和抗惊厥药物之间的相互作用。对胶质瘤基因改变的研究，特别是间变性星形细胞瘤和低级别胶质瘤，将通过与Robert Jenkins博士(Mayo)、David James(Mayo博士)和Bert Feuerstein博士(加州大学旧金山分校)的合作来扩大。

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).