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还是相当有限的。氟化嘧啶5-氟尿嘧啶已成为直肠癌患者化疗方案的基础，用于转移或辅助治疗，并与盆腔放疗相结合。现在有几种新的化疗药物和新的给药途径需要进行系统测试。该项目将对晚期直肠癌患者进行4项I/II期试验，对转移性或复发性结直肠癌患者进行5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种治疗方案和转移性疾病的挽救方案中，将改善这些患者的临床结果和治疗比例。本项目将基于项目2和项目3中研究人员关于肿瘤反应与MMR-肿瘤进展途径(项目3)和非整倍体肿瘤进展途径(项目2)中涉及的基因的表达状态和程度之间的关系的基础科学研究，测试特定的假设。如果这些假设得到证实，这些试验中患者的肿瘤样本中hMSH2、hMSH6和Hmlh1(MMR途径)和Pla2g2a(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测试。这些研究应该为整合分子遗传分析作为结肠癌和直肠癌患者治疗决策过程的重要因素提供坚实的基础。

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.