Pharmacogenomics of Neoadjuvant Gemcitabine-Pemetrexed *

描述（由申请方提供）：美国多家机构正在研究在诊断后最早时间给予化疗（新辅助化疗或诱导化疗），以降低非小细胞肺癌（NSCLC）患者的疾病复发风险，欧洲和日本。这种方法在接受2-3个周期铂类联合吉西他滨、紫杉醇或多西他赛治疗的IB-IIIA期患者中，放射学缓解率为56-70%，完全缓解率为1-8%，部分缓解率为55-64%。化疗前病理证实为N2疾病的患者在50%的病例中切除时N2淋巴结阴性。在6-16%的患者中记录了完全病理缓解（95% CI，0-23%）。在2-10%的患者中观察到治疗期间的疾病进展，并且在70-92%的患者中实现了完全手术切除。重要的是设计毒性较小，但有效的方案，耐受性良好，可以迅速给予，以便及时进行手术。新辅助治疗允许研究可能影响化疗反应和患者生存的分子参数。我们假设与吉西他滨和培美曲塞药物的激活、失活和疗效相关的基因表达将预测对治疗的反应和预后。我们进一步假设，这些基因的表达将在化疗期间改变。我们提出了一项在可切除NSCLC患者中进行吉西他滨和培美曲塞新辅助化疗的II期研究，特别是将分子参数与主要临床研究终点疾病缓解（放射学CR+PR）和次要终点手术时完全病理学缓解、无病生存期和总生存期相关。

DESCRIPTION (provided by applicant): The administration of chemotherapy at the earliest time (neoadjuvant or induction chemotherapy) following diagnosis in an effort to reduce the risk of disease recurrence in patients with non-small cell lung cancer (NSCLC) is under investigation at multiple institutions in the U.S., Europe, and Japan. This approach has resulted in radiographic response rates of 56-70% with complete remission rates of 1-8% and partial remission rates of 55-64% in patients with stage IB-IIIA with 2-3 cycles of platinum plus gemcitabine, paclitaxel, or docetaxel. Patients with pathologically proven N2 disease prior to chemotherapy had negative N2 nodes on resection in 50% of cases. A complete pathologic remission has been documented in 6-16% of patients (95% Cl, 0-23%). Disease progression during treatment has been observed in 2-10% of patients, and a complete surgical resection was achieved in 70-92% of patients. It is important to devise less toxic, yet efficacious regimens that are well tolerated and can be given expeditiously so as to allow surgery to be done in a timely fashion. Neoadjuvant therapy allows for investigations of molecular parameters that may affect response to chemotherapy and patients' survival. It is our hypothesis that the expression of genes associated with activation, inactivation, and efficacy of the drugs gemcitabine and pemetrexed will predict response to therapy and prognosis. We further hypothesize that the expression of these genes will be altered during chemotherapy. We propose a phase II study of neoadjuvant chemotherapy with gemcitabine and pemetrexed in patients with resectable NSCLC, specifically correlating molecular parameters to the primary clinical study endpoint disease response (radiographic CR+PR) and the secondary endpoints complete pathological response at surgery, disease-free survival, and overall survival.