Thymidylate S ynthase E xpression i n H epatic T umors I s a Predictor o f S urvival a nd P rogression i n P atients W ith Resectable M etastatic C olorectal C ancer

Purpose: To investigate the role of thymidylate synthase (TS), p53, and epidermal growth factor receptor (EGF-R) expressions in hepatic tumors in predicting overall survival (OS), progression-free survival (PFS), and hepatic progression-free survival (HPFS) in patients with resectable metastatic colorectal cancer who were randomly assigned to receive either systemic chemotherapy (SYS) alone or systemic and hepatic arterial infusion (HAISYS) chemotherapy following liver surgery. Patients and Methods: Tissues from metastatic tumors were collected during liver resection from 156 patients, and marker expressions were determined using immunohistochemistry on frozen samples. Univariate associations between marker expressions and baseline variables with OS, PFS, and HPFS were examined. Independent predictors of outcome were determined using a multivariate Cox model. Results: In multivariate analyses, TS overexpression was found to be an independent factor of poor prognosis in OS (P < .01), PFS (P .06), and HPFS (P < .01). In addition, resection margin was a significant independent factor for all three outcomes. Patients who received HAISYS experienced delayed progression in general, and in the liver, specifically. Increased levels of serum alkaline phosphatase correlated with hepatic progression. We also found a significant TS-treatment interaction for OS (P .01) in multivariate analysis. In particular, TS patients receiving HAISYS had significantly higher survival than those receiving SYS (64 months v 21 months; P .01). Conclusion: TS levels in hepatic tumors and resection margin are independent predictors of survival and progression in patients with metastatic colorectal cancer, whereas p53 and EGFR are not independent predictors. Treatment with HAISYS significantly improved the survival profile of TS patients. J Clin Oncol 21:406-412. © 2003 by American Society of Clinical Oncology. C OLORECTAL CANCER is the fourth most commonly diagnosed cancer and ranks second among cancer deaths in the United States. Although it is a highly treatable and often curable disease when localized, the prognosis of metastatic patients is considerably worse. The liver is the most common site of colorectal metastases, and it is often the only organ affected. Fifteen percent of patients present with synchronous disease, and 60% of all metastatic patients will have liver-only or liverdominant disease. The only potentially curative option for liver metastases is surgery, but even after resection, liver is the most common site of relapse. Regional hepatic arterial infusion chemotherapy along with systemic chemotherapy (HAISYS) has been shown to improve 2-year survival when compared with systemic (SYS) chemotherapy alone. 1 Stage of primary tumor, number of liver metastases, disease-free interval, preoperative carcino embryonic antigen, tumor size, positive resection margin, and presence of extrahepatic disease are reported to be independent prognostic factors of survival in this patient popu