Current regimens of systemic chemotherapy result in only modest lengthening of survival in patients with advanced stage, liver-dominant, metastatic colorectal cancer who have failed first-line chemotherapy. The objective of this study was to investigate the safety and tolerability of NV1020, a replication-competent, attenuated, genetically engineered herpes simplex virus type 1 (HSV-1), in patients with hepatic colorectal metastases refractory to first-line chemotherapy. A phase I, open-label, dose-escalating study of a single 10-min hepatic arterial infusion of NV1020 in four cohorts. Three patients in each cohort received doses of 3 x 10(6), 1 x 10(7), 3 x 10(7), and 1 x 10(8) plaque-forming units. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum y-glutamyltransferase, one diarrhea, and one leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There were no deaths during the study, and there was no evidence of disseminated herpes infection. Viral presence was detected in only one saliva sample and two serum samples from one asymptomatic patient in the highest dose cohort. In the first week after viral administration only rare and minor increases were noted for tumor necrosis factor-alpha (six samples; three patients; peak, 40 pg/ml), interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and interferon-y (four samples; two subjects; peak, 54 pg/ml). No IL-2 was detected. Mild liver enzyme elevations were self-limiting and not associated with clinical symptoms. We conclude that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function.

18 F-FDG PET has proven invaluable in the staging of patients with metastatic colorectal cancer. The aim of the current study was to determine whether this biologic scan would correlate with other cellular characteristics and the clinical behavior of tumors. Methods: Ninety patients with resectable colorectal cancer metastatic to the liver underwent 18 F-FDG PET before hepatectomy. At surgery, tumors were harvested and prepared for assessment by histology and immunohistochemistry. Expression of Ki67 (a marker for cell proliferation), GLUT1 and GLUT3 (markers for glucose transportation), p53 and p27 (markers for cell cycle control), and BCL-2 (a marker for apoptosis) was assessed by a pathologist who was unaware of the PET results and the clinical outcome. Patients were followed to determine outcome. Survival analysis was performed comparing patient outcome in groups segregated according to standardized uptake values (SUVs) greater or less than 5, 7, or 10. Results: Maximum SUV correlated with GLUT1 (P 5 0.03), Ki67 (P 5 0.026), and p53 (P 5 0.024) but did not correlate with p27, BCL-2, or GLUT3. Survival was significantly longer for patients with a low SUV than for patients with a high SUV, with P values of 0.014, 0.025, and 0.0095 for SUV cutoffs of 5, 7, and 10, respectively. Conclusion: 18 F-FDG PET is a biologic scan that predicts prognosis in patients with metastatic colorectal cancer. It is uncertain if this ability is due to cellular glucose metabolism or to a correlation with other cellular characteristics of aggressive tumors. PETusi ng 18 F-FDG has become an indispensable staging modality for many types of cancer, including colorectal cancer (1,2), esophageal cancer (3), melanoma (4), sarcoma (5), and lung cancer (6). This imaging technique detects glucose-avid cancer deposits and can enhance the detection of metastatic deposits, resulting in more complete tumor resections and preventing nontherapeutic laparotomies for patients with unresectable disease (7). The result of the application of this technique is more appropriate and more efficient clinical care, resulting in improved long-term outcome (1). This scanning technique is now standard in the preoperative work-up for many types of cancer.18 F-FDG PET is a biologic scanning technique that measures the glucose metabolism in a tumor. Enhanced glucose metabolism has been related to the aggressiveness of cancer cells. Thus, it is not surprising that in some types of cancer, such as esophageal cancer (8), lung cancer (9), and gastrointestinal stromal tumors (10), the quantity of 18 F-FDG uptake as assessed by PET correlates with outcome. Whether such a correlation exists for patients with colorectal cancer metastatic to the liver has not been reported and was the subject of the current prospective trial. Because this evaluation was prospective, we were able to secure freshly harvested tumors at resection. Molecular analysis of these tissues allowed an analysis of the correlation between 18 F-FDG uptake and those molecular markers thought to be importan...

Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 x 10(6) to 1 x 10(8) particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13-74%; P < 0.02). One of three individuals at the 10(8) level showed a 39% radiologic decrease in tumor size by cross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50-98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into the human bloodstream to produce selective infection of tumor tissues and biologic effects.

Purpose: There currently is no therapy that enhances the survival of patients with distantly metastatic squamous cell carcinoma (SCC). Engineered herpes oncolytic viruses are effective therapeutic agents when delivered directly to tumors in animal models, but their efficacy in treating disseminated disease is poorly defined.Experimental

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