Phase I /II S tudy o f H epatic A rterial T herapy W ith F loxuridine and D examethasone i n C ombination W ith I ntravenous Irinotecan A s A djuvant T reatment A fter R esection o f H epatic Metastases F rom C olorectal C ancer

Purpose: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. Patients and Methods: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. Results: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m 2 every other week and FUDR at 0.12 mg/kg pump volume pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. Conclusion: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences. J Clin Oncol 21:3303-3309. © 2003 by American Society of Clinical Oncology. N EARLY 129,000 new cases of colorectal cancer are diagnosed each year in the United States. 1 Fifteen percent to 25% of patients have metastatic liver disease when the primary tumor is diagnosed, and an additional 35% to 45% of patients will develop hepatic metastases during the course of their disease. 2 Complete resection of hepatic metastases yields 2- and 5-year survival rates of 65% and 30%, respectively. 3 Approximately 14,300 patients undergo liver resection each year. Seventy-five percent of these patients will have a recurrence, 50% in the liver and 50% in extrahepatic sites. Approximately 65% to 80% of all recurrences appear within the first 2 years. 4 In an effort to decrease recurrence rates, a number of randomized studies have explored the use of combined regional and systemic chemotherapy. The use of hepatic arterial infusion (HAI) exploits the liver’s dual blood supply. Established hepatic metastases greater than 3 cm are supplied almost entirely by the hepatic arterial system, whereas normal liver cells derive most of their blood supply from the portal vein. 5 Thus, HAI offers the possibility of delivering high-dose regional chemotherapy without systemic toxicity. Two large American trials demonstrated a clear reduction in hepatic recurrence with the use of HAI and systemic therapy after liver resection. 6,7 In both trials, floxuridine (FUDR) was used as the regional agent, and fluorouracil (FU) plus or minus leucovorin (LV) was used as the systemic therapy. More recent studies have investigated using newer drugs, such as irinotecan (CPT-11) and oxaliplatin, as the systemic agents. 8,9 A phase I/II trial of patients with unresectable disease demonstrated that the combination of CPT-11 and HAI