Islolated Hepatic Perfusion with Oxaliplatin

描述（由申请人提供）：结肠癌和直肠癌预计将成为2005年美国癌症死亡的第三大原因。肝转移作为唯一或主要的生命限制性疾病的部位发生在大约20 - 50%的这些患者中。切除这些肝转移导致五年生存率接近40%，这表明该疾病的区域控制可导致总生存率的改善。不幸的是，只有一小部分孤立性肝转移的患者适合切除。我们目前正在探索一种新的和非常有前途的方法来治疗不可切除的肝转移瘤，隔离肝灌注。我们的目标是开发一种区域性肝脏治疗，其缓解率接近100%，缓解持续时间长。我们设想将这种成功的局部治疗与有效的抗肿瘤免疫疗法相结合，最终对总生存率产生重大影响。这一目标导致了奥沙利铂隔离肝灌注治疗结直肠转移的I期研究。在这项I期研究中，在6名可评价患者中，我们的客观放射学部分缓解率为50%，完全缓解率为17%，导致总体客观放射学缓解率为67%。虽然这是一个显着的反应率为1期试验，我们不相信，奥沙利铂单独是我们的最佳方案IMP.Given深刻的协同作用之间的5-FU和奥沙利铂，我们建议检查5-FU和奥沙利铂的组合，通过一个隔离的肝脏灌注回路。该联合用药的基本原理基于大量体外和体内数据，这些数据表明这些药物之间具有显著的协同作用且无重叠毒性，以及全身性奥沙利铂的重要早期临床经验，这些经验表明该药物与其他细胞毒性药物联合使用时最有效。

DESCRIPTION (provided by applicant): Cancer of the colon and rectum is expected to be the third leading cause of cancer death in the United States in 2005. Hepatic metastases as the sole or dominant site of life-limiting disease occur in approximately 20-50% of these patients. Resection of these liver metastases results in five year survival approaching 40%, suggesting that regional control of this disease can lead to improved overall survival. Unfortunately, only a small fraction of patients with isolated liver metastases are eligible for resection. We are currently exploring a novel and highly promising approach to treatment of unresectable liver metastases, isolated hepatic perfusion. It is our goal to develop a regional hepatic therapy that has a response rate approaching 100% with a long duration of response. We envision then combining this successful regional treatment with an effective anti-tumor immunotherapy to ultimately have a significant impact on overall survival. This goal led to a phase I study of isolated hepatic perfusion with oxaliplatin for colorectal metastases. In this phase I study, out of six evaluable patients we had an objective radiographic partial response rate of 50%, a complete response rate of 17%, leading to an overall objective radiographic response rate of 67%. While this is a remarkable response rate for a phase 1 trial we do not believe that oxaliplatin alone is our optimal regimen for IMP. Given the profound synergy between 5-FU and oxaliplatin, we propose to examine the combination of 5-FU and oxaliplatin delivered via an isolated hepatic perfusion circuit. The rationale for this combination is rooted on a large body of in vitro and in vivo data suggesting significant synergy and no overlapping toxicity between these agents as well as important early clinical experience with systemic oxaliplatin that suggested that this agent was most effective when combined with other cytotoxic agents.