Hepatic Arterial Flouridine and IV Bevacizumab for Primary Hepatic Malignancy

描述（由申请方提供）：这项拟定的II期研究将评价全身性血管生成抑制联合区域性肝动脉化疗在不可切除的原发性肝脏恶性肿瘤患者中的疗效。具体而言，该方案针对不可切除的肝细胞癌（HCC）或肝内（外周）胆管细胞癌（ICC）患者，持续输注阿托尿苷（FUDR）联合全身性贝伐单抗。先前的工作已经确定了局部肝内FUDR在该患者人群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性化疗的递送并提高其疗效。共45例患者将接受肝动脉输注泵置入术，随后接受连续肝内FUDR（0.16 mg/kg）+地塞米松（1 mg/m2/kg/天）联合全身性贝伐珠单抗（5 mg/kg）治疗，4周为一个周期。计算的样本量将提供90%的把握度，以检测与基线治疗相比，肝内化疗单独治疗的至进展时间改善50%。本研究还将研究动态对比增强MRI扫描（DCE-MRI）在治疗前评估肿瘤灌注动力学（灌注和渗透性）、在治疗期间监测这些变化以及将这些结果与放射学肿瘤缓解相关联方面的效用。该研究设计允许对由于血管生成抑制（单独使用和与细胞毒性化疗联合使用）引起的肿瘤灌注动力学变化进行放射学检查。该提案评估了一种有前途的治疗方法，用于不可切除的原发性肝癌患者，其发病率正在增加，与生存率低相关，并且有效治疗有限。因此，目前的研究解决了一个重大的公共卫生问题。此外，然而，所提出的治疗代表了抗血管生成治疗的新应用，具有治疗其他恶性肿瘤的潜在应用。这项研究也将产生重要的数据，一个新兴的功能成像技术，用于评估血管生成抑制的疗效，需要已变得越来越清楚。此外，提出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具有广泛的普遍意义。

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.