OBJECTIVES: To analyze the impact of surgical margins and other clinicopathological data on treatment outcomes on 75 patients treated from 1999 to 2006 by initial potentially curative surgery (+/- intraoperative radiotherapy), followed by high-dose 3-dimensional conformal radiation therapy and concomitant fluoropyrimidine-based chemoradiotherapy. MATERIALS AND METHODS: All clinical and pathologic data on this patient cohort were analyzed by actuarial Kaplan-Meier survival methodology and by univariate and multivariate Cox proportional hazards methods to measure effects on survival and patterns of failure. RESULTS: With a median follow-up of 28 months, the median, 2-year and 5-year overall survival (OS) rates were 18.1 month, 41% and 23.6%, respectively. Disease-free survival (DFS) rates were of 11.4 months, 35% and 20%, respectively. Only 2 clinicopathological features, positive (< or =1 mm) surgical margins (P < 0.05) and a 2-fold (>70 U/mL) elevation of the postoperative serum CA19-9 (P < 0.001) impacted OS and disease-free survival. In patients with negative (>1 mm) surgical margins and a low (< or =70 U/mL) postoperative CA19-9, the projected 2- and 5-year OS were 80% and 65%, respectively, compared with 40% and 10% with positive surgical margins and a low CA19-9 and to 10% and 0% with positive or negative surgical margins and a high (>70 U/mL) CA19-9. Positive surgical margins (P < 0.001) and an elevated postoperative CA19-9 (P < 0.001) also predicted early development of distant metastases, whereas isolated loco-regional failure was less common and not affected by these or other clinicopathological features. CONCLUSIONS: Using this fluoropyrimidine-based chemoradiotherapy regimen after surgical resection (+/- intraoperative radiotherapy), positive surgical margins and an elevated (2-fold) postoperative serum CA19-9 level predicted for reduced survival and early development of distant metastatic disease.