Hepatic Arterial Flouridine and IV Bevacizumab for Primary Hepatic Malignancy

描述（由申请人提供）：这项拟议的II期研究将评估系统性血管生成抑制联合局部肝动脉化疗对不可切除的原发性肝恶性肿瘤患者的疗效。具体来说，该方案针对不可切除的肝细胞癌（HCC）或肝内（外周）胆管癌（ICC）患者持续输注氟尿定（FUDR）联合全身贝伐单抗。先前的工作已经确定了局部肝内FUDR在该患者群体中的安全性和有效性。目前的建议是基于原发性肝癌的生长和进展依赖于促血管生成过程的假设，抑制这一过程将增强细胞毒性化疗的递送并提高其疗效。共有45名患者将接受肝动脉输注泵的放置，随后持续肝内FUDR (0.16mg/kg) +地塞米松（1mg/m2/kg/天）联合全身贝伐单抗（5mg/kg），周期为4周。计算的样本量将提供90%的能力来检测与单独肝内化疗的基线治疗相比，进展时间提高50%。本研究还将探讨动态对比增强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发现与肿瘤放射学反应相关联方面的应用。研究设计允许x线摄影检查由于血管生成抑制引起的肿瘤灌注动力学的变化，无论是单独还是与细胞毒性化疗联合使用。对于不可切除的原发性肝癌患者，该建议评估了一种有希望的治疗方法，这种治疗方法的发病率正在增加，与生存率低有关，并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。此外，所提出的治疗方法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。这项研究还将为评估血管生成抑制效果的新兴功能成像技术提供重要数据，其必要性已变得越来越明显。此外，提出的相关研究解决了几个重要的临床问题，其结果将引起临床肿瘤学的广泛兴趣。

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.