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。肝转移作为限制生命的疾病的唯一或主要部位发生在大约20-50%的这些患者中。切除这些肝转移瘤的5年生存率接近40%，这表明对这种疾病的局部控制可以提高总生存率。不幸的是，只有一小部分孤立性肝转移患者符合切除条件。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，孤立的肝灌注。我们的目标是开发一种局部肝脏治疗，其有效率接近100%，反应持续时间长。我们设想将这种成功的局部治疗与有效的抗肿瘤免疫治疗相结合，最终对总生存率产生重大影响。这一目标导致了一项奥沙利铂治疗结肠直肠癌转移的分离肝灌注I期研究。在这项I期研究中，在6名可评估的患者中，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%。虽然这是一个显著的1期试验反应率，但我们不认为单独使用奥沙利铂是治疗IMP的最佳方案。鉴于5-FU和奥沙利铂之间的深刻协同作用，我们建议研究5-FU和奥沙利铂通过孤立的肝脏灌注回路联合给药。这种组合的基本原理是基于大量的体外和体内数据，这些数据表明这些药物之间具有显著的协同作用，没有重叠的毒性，以及系统性奥沙利铂的重要早期临床经验，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.