Hepatic Arterial Flouridine and IV Bevacizumab for Primary Hepatic Malignancy

描述(申请人提供)：这项拟议的II期研究将评估全身血管生成抑制结合区域肝动脉化疗对不能切除的原发性肝脏恶性肿瘤患者的疗效。具体地说，该方案针对不能切除的肝细胞癌(HCC)或肝内(周围型)胆管癌(ICC)患者，持续输注氟尿嘧啶(FUDR)联合全身贝伐单抗。先前的工作已经确定了区域性肝内FUDR在这一患者群体中的安全性和有效性。目前的建议是基于这样的假设，即原发性肝癌的生长和进展依赖于促血管生成过程，抑制促血管生成过程将增强细胞毒化疗的输送，并改善其疗效。45例患者先放置肝动脉输注泵，然后持续肝内注射FUDR(0.16 mg/kg)+地塞米松(1 mg/m2/kg/d)，联合全身贝伐单抗(5 mg/kg)，4周为一周期。计算的样本量将提供90%的力量来检测单独使用肝内化疗的基线治疗的进展时间缩短50%。这项研究还将调查动态增强MRI扫描(DCE-MRI)在治疗前评估肿瘤血流动力学(灌注和渗透性)、在治疗期间监测这些变化以及将这些发现与放射学肿瘤反应相关联的实用性。这项研究设计允许对由于血管生成抑制而引起的肿瘤血流动力学变化进行放射学检查，无论是单独的还是与细胞毒性化疗相结合的。这项建议评估了一种有前景的治疗方法，用于治疗不能切除的原发性肝癌患者，这种癌症的发病率正在增加，与低存活率相关，而且有效的治疗方法有限。因此，目前的研究解决了一个重大的公共卫生问题。然而，此外，拟议的治疗代表了抗血管生成治疗的一种新应用，具有治疗其他恶性肿瘤的潜在应用。这项研究还将提供关于一种新兴的功能成像技术的重要数据，该技术用于评估血管生成抑制的有效性，其必要性已变得越来越明显。此外，拟议的相关研究解决了几个重要的临床问题，其结果将在临床肿瘤学中引起广泛的兴趣。

DESCRIPTION (provided by applicant): This proposed phase II study will evaluate the efficacy of systemic angiogenesis inhibition combined with regional, hepatic arterial chemotherapy in patients with unresectable primary hepatic malignancy. Specifically, this protocol targets patients with unresectable hepatocellular carcinoma (HCC) or intrahepatic (peripheral) cholangiocarcinoma (ICC) for continuous infusion of floxuridine (FUDR) combined with systemic bevacizumab. Prior work has established the safety and efficacy of regional intrahepatic FUDR in this patient population. The current proposal is based on the hypothesis that the growth and progression of primary liver cancer are dependent on pro-angiogenic processes, the inhibition of which will enhance delivery of cytotoxic chemotherapy and improve its efficacy. A total of 45 patients will undergo placement of a hepatic artery infusion pump followed by continuous intrahepatic FUDR (0.16mg/kg) + dexamethasone (1mg/m2/kg/day) combined with systemic bevacizumab (5mg/kg) on a 4-week cycle. The calculated sample size will provide 90% power to detect a 50% improvement in time to progression over baseline therapy with intrahepatic chemotherapy alone. This study will also investigate the utility of dynamic contrast enhanced MRI scans (DCE-MRI) for assessing tumor perfusion kinetics (perfusion and permeability) prior to treatment, for monitoring these changes during treatment and for correlating these findings with radiographic tumor response. The study design allows for radiographic examination of the changes in tumor perfusion kinetics due to angiogenesis inhibition, both alone and in combination with cytotoxic chemotherapy. This proposal evaluates a promising treatment approach for patients with unresectable primary liver cancer, which is increasing in incidence, is associated with poor survival and for which effective treatments are limited. The current study therefore addresses a significant public health concern. Additionally, however, the proposed treatment represents a novel application of anti-angiogenic therapy with potential application for treating other malignancies. This study will also yield important data on an emerging functional imaging technique for assessing the efficacy of angiogenesis inhibition, the need for which has become increasingly clear. Furthermore, several important clinical issues are addressed by the proposed correlative studies, the results of which would be of broad general interest in clinical oncology.