Multimodality approach to hepatic colorectal metastases

肝结直肠转移的多学科治疗方法

基本信息

批准号：
8653836
负责人：
DAVID L BARTLETT
金额：
$ 34.28万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8653836
关键词：
Apoptosis Applications Grants Biochemical Blood Vessels Cancer Etiology Cell Death Cessation of life Clinical Trials Colorectal Colorectal Cancer Combined Modality Therapy Development Disease Dose Goals Hepatic Hyperthermia Isolated Hepatic Perfusion Large Intestine Carcinoma Ligands Liver Liver neoplasms Malignant Neoplasms Metastatic Lesion Metastatic Neoplasm to the Liver Methods Modality Modeling Molecular Neoplasm Metastasis Outcome Study Patients Phase I Clinical Trials Rattus Research Project Grants Resectable Safety Survival Rate TNFSF10 gene Techniques Testing Therapeutic Treatment Efficacy Tumor Necrosis Factor-alpha United States Unresectable chemotherapeutic agent mortality multimodality novel strategies outcome forecast oxaliplatin preclinical efficacy preclinical evaluation public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer, which causes approximately 10% of cancer deaths in the United States, is the third leading cause of cancer-related mortality; death usually results from uncontrolled metastatic disease. Approximately 25% of patients with colorectal cancer will develop metastatic disease exclusively or largely confined to the liver. Untreated patients with liver metastases share a poor prognosis with an average survival of 12 months. In contrast, patients whose liver metastatic lesions are surgically treated have an average 5-year survival rate of 40%, but only 10-15% of initial colorectal liver metastases are considered resectable. The unresectable cases of liver metastatic disease can be treated with isolated hepatic perfusion (IHP), which involves a method of complete vascular isolation of the liver to allow treatment of liver tumors with toxic systemic doses of chemotherapeutic agents, biologic agents, and mild hyperthermia. We recently completed a phase I trial defining the safe dose of oxaliplatin delivered with IHP. In this grant proposal, we will apply IHP using the chemotherapeutic agent oxaliplatin, the biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat advanced colorectal liver metastases. The specific aims of this project are to investigate this multimodality approach as to (1) the mechanism of the synergy between the three treatment modalities, and the efficacy of this treatment, (2) preclinical evaluation of multimodality treatment, and (3) clinical trials of multimodality treatment. The proposed studies for the first aim will employ biochemical and molecular techniques to investigate the mechanisms of cell death. For the second aim, we will employ IHP in a syngeneic rat hepatic metastasis model of colorectal carcinoma. The third aim will evaluate the therapeutic advantage of this treatment on patients. We believe that the successful outcome of this study will support the application of this multimodality approach to colorectal hepatic metastases.

描述（由申请人提供）：在美国造成约10％的癌症死亡的大肠癌是与癌症相关死亡率的第三主要原因。死亡通常是由不受控制的转移性疾病引起的。大约25％的结直肠癌患者将仅或很大程度上局限于肝脏发展转移性疾病。未经治疗的肝转移患者的预后较差，平均存活率为12个月。相反，对手术治疗的肝转移病变的患者的平均5年生存率为40％，但只有10-15％的初始结直肠肝转移被认为可切除。不可切除的肝转移疾病病例可以通过孤立的肝灌注（IHP）治疗，该病例涉及一种完全血管分离的肝脏的方法，以允许用有毒的全身性化学治疗剂，生物学剂，生物学剂和温和热疗法治疗肝肿瘤。我们最近完成了一项I期试验，以定义与IHP一起递送的奥沙利铂的安全剂量。在这项赠款建议中，我们将使用化学治疗剂奥沙利铂（生物学剂肿瘤坏死因子相关的凋亡诱导配体（TRAIL/APO-2L）和轻度疗法的生物性剂肿瘤坏死，并使用轻度高温治疗先进的结直肠肝转移。该项目的具体目的是针对（1）三种治疗方式之间的协同作用以及这种治疗的疗效，（2）多模式治疗的临床前评估以及（3）多态性治疗的临床试验。提出的第一个目标研究将采用生化和分子技术来研究细胞死亡的机制。为了第二个目的，我们将使用IHP进行结直肠癌的合成大鼠肝转移模型。第三个目标将评估这种治疗对患者的治疗优势。我们认为，这项研究的成功结果将支持这种多模式方法在结直肠肝转移中的应用。