The Surgical Metabolism Section of the Surgery Branch conducts clinical trials evaluating regional cancer treatments for patients with a variety of solid tumor malignancies and new imaging techniques such as PET scan for their ability to identify sites of occult disease or gauge response to therapy. The Section actively provides surgical consultation and treatment for patients with endocrine disorders including parathyroid, thyroid, endocrine pancreas, and adrenal neoplasms. We actively participate in developing new diagnostic or imaging techniques for patients with endocrine disorders and have established an active program of advanced therapeutic laparoscopic surgery for such patients including laparoscopic partial pancreatectomy, liver resection, or adrenalectomy. Clinical trials are actively evaluating cancer treatments as outlined below:1.) Isolated organ perfusion of the limb or liver using biological agents, melphalan, and hyperthermia. Isolated hepatic perfusion (IHP) has resulted in substantial and durable regression of locally advanced cancers in the majority of patients treated. In patients with advanced unresectable liver cancers, IHP with TNF and melphalan results in significant regression of tumors (> 50% reduction in size) in 75% of patients. Tumor responses are seen in all histologies treated and occur even in patients with large (>10 cm) lesions, multiple tumors, or those with a significant (>30%) tumor burden in liver. An overall responses rate of 72% has been obtained in patients with ocular melanoma metastatic to liver with a median duration of almost 12 months. Patients with colorectal metastases to liver are being treated with a combination of IHP and melphalan followed by hepatic artery infusion of floxuridine and leucovorin. An overall response rate of 74% and median duration of response of 15 months have been obtained. 2.) A trial evaluating the use of radiofrequency ablation (RFA) for local ablation of hepatic tumors is being conducted. RFA has been shown in preliminary results to be an effective modality for local control of tumors up to 6 cm in diameter. 3.) A random assignment trial evaluating disease-free and overall survival for patients undergoing resection of colorectal metastases (except for bone or brain) followed by adjuvant oral thalidomide versus placebo. 4.) A clinical trial evaluating new imaging techniques such as PET and CEA scans for their ability to detect occult recurrences in patients with a history of colorectal cancer and who have rising CEA values. When appropriate, surgical exploration with resection of identifiable disease is performed and has resulted in normalization of CEA in most patients.5.) A clinical trial using PET scan with new radiopharmaceuticals to quantify changes in tumor viability, metabolism, and blood flow in patients treated with antiangiogenic therapies. Initial results indicate that PET scan is a very sensitive test for detecting occult tumors and may provide valuable insights into the efficacy and mechanisms of action of antiangiogenic therapies.Laboratory research falls into several broad areas that complement the clinical research effort. Adeno- and vaccina viral constructs with reporter or therapeutic genes are being developed to target tumors in experimental models of liver metastases, peritoneal carcinomatosis, and pulmonary metastases. Vaccinia viral (VV) constructs containing a suicide gene (cytosine deaminase, CD) under the control of a synthetic early/late promoter followed by prodrug administration with 5-FC results in a significant survival benefit in mice with established liver metastases with long term cures observed in about 20% of treated animals.The unique phenotype of tumor neovasculature is being characterized and explored as an important potential target for cancer therapy. The laboratory has shown that a tumor derived cytokine, endothelial monocyte activating polypeptide (EMAP), will cause procoagulant effects in tumor microvasculature. EMAP expression in tumors correlates with TNF senstivity in vivo. Retroviral transduction of TNF resistant tumors so that they express higher titers of EMAP renders them sensitive to TNF in experimental models. In addition, using a rat aortic ring assay of angiogenesis, the laboratory has showm that EMAP has potent antiangiogenic effects. In order to better understand the mechanisms of antitumor activity in isolated organ perfusion, we have been investigating the effects of melphalan, hyperthermia, and TNF on endothelial cell viability and permeability in vitro and on tumor microvascular permeability in an experimental model of liver metastases. In patients undergoing isolated hepatic perfusion TNF continues to be critically evaluated to determine its role in this setting.
