INNOVATIVE APPROACHES TO PATIENTS WITH ADENOCARCINOMA

直到最近，结肠癌和直肠癌患者的非手术治疗选择一直非常有限。氟化嘧啶5-氟尿嘧啶是用于转移性或辅助治疗的化疗方案的基础，与直肠癌患者的盆腔放射结合使用。几种新的化疗药物和新的给药途径，现在可在需要系统的测试。该项目将对晚期直肠癌患者进行四项I/II期试验，对转移性或复发性结直肠癌患者进行五项I/II期试验。这9项试验的统一临床假设是，将氟化嘧啶、喜树碱和铂类药物的口服类似物引入直肠癌的多模式治疗方案和转移性疾病的挽救治疗方案，将改善这些患者的临床结局和治疗比例。本项目将基于项目2和项目3中研究者的基础科学研究，对肿瘤缓解与肿瘤进展的MMR途径（项目3）和肿瘤进展的非整倍体途径（项目2）中涉及的基因表达状态和程度之间的关系进行特定假设检验。如果这些假设得到证实，这些试验中患者的样本肿瘤中hMSH 2、hMSH 6和Hmlh 1（MMR途径）和PLA 2G 2A（非整倍体途径）等基因的状态将作为后续临床试验的合格标准进行检测。这些研究应提供一个坚实的基础，整合分子遗传学分析作为一个重要因素的治疗决策过程中的结肠癌和直肠癌患者。

Until recently non-surgical therapeutic options for patients with cancer of the colon and rectum have been quite limited. The fluorinated pyrimidine 5-fluorouracil has been the basis of chemotherapeutic regimens used for metastatic or adjuvant therapy, in conjunction with pelvic radiation for patients with rectal cancer. Several new classes of chemotherapeutic agents and new routes of administration are now available in need of systematic testing. This project will execute four phase I/II trials for patients with advanced rectal cancer and five phase I/II trials for patients with metastatic or recurrent colorectal cancer. The unifying clinical hypothesis of these nine trials is that the introduction of oral analogues of fluorinated pyrimidine, camptothecin, and platinum agents to multi-modality regimens for rectal cancer and to salvage regimes for metastatic disease will improve clinical outcomes and the therapeutic ration for these patients. This project will test specific hypotheses, based on the basic science studies of investigators in Projects 2 and 3 regarding the relationship between tumor response and the status and degree of expression of genes implicated in the MMR-Pathway of tumor progression (Project 3) and the Aneuploid Pathway of tumor progression (Project 2). If these hypotheses are confirmed, the status of such genes as hMSH2, hMSH6, and Hmlh1 (MMR-pathway) and PLA2G2A (Aneuploid Pathway) in the sampled tumors of patients in these trials will be tested as eligibility criteria for subsequent clinical trials. These studies should provide a firm foundation for the integration of molecular genetic analysis as an important element of the therapeutic decision-making process for patients with cancer of the colon and rectum.