Multimodality approach to hepatic colorectal metastases

肝结直肠转移的多学科治疗方法

• 批准号: 8457992
• 负责人: DAVID L BARTLETT
• 金额: $ 33.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457992
• 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

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(申请人提供)：结直肠癌在美国约占癌症死亡的10%，是癌症相关死亡的第三大原因；死亡通常是由不受控制的转移疾病引起的。大约25%的结直肠癌患者将完全或主要局限于肝脏发生转移性疾病。未经治疗的肝转移患者预后较差，平均生存期为12个月。相比之下，接受手术治疗的肝转移灶患者的平均5年存活率为40%，但只有10%-15%的初始结直肠肝转移被认为是可切除的。不能切除的肝转移疾病可以用隔离肝灌流(IHP)治疗，IHP涉及一种完全隔离肝脏血管的方法，允许使用全身毒性剂量的化疗药物、生物药物和轻度热疗治疗肝肿瘤。我们最近完成了一项I期试验，确定了国际水文计划提供的奥沙利铂的安全剂量。在这份赠款提案中，我们将使用化疗药物奥沙利铂、生物药物肿瘤坏死因子相关凋亡诱导配体(TRAIL/Apo-2L)和亚高温来应用IHP治疗晚期结直肠癌肝转移。本项目的具体目标是研究这一多模式方法：(1)三种治疗模式之间协同作用的机制，以及这种治疗的有效性；(2)多模式治疗的临床前评估；(3)多模式治疗的临床试验。针对第一个目标的拟议研究将使用生化和分子技术来研究细胞死亡的机制。对于第二个目的，我们将在结直肠癌同基因大鼠肝转移模型中应用IHP。第三个目标是评估这种治疗方法在患者身上的治疗优势。我们相信，这项研究的成功结果将支持这种多模式方法在结直肠癌肝转移中的应用。