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Cyclooxygenase 2 Expression in Rectal Cancer Is of Prognostic Significance in Patients Receiving Preoperative Radiotherapy

Authors' Affiliations: Departments of ¹ Surgery, ² Clinical Oncology, and ³ Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands; ⁴ Department of Surgery, Catharina Hospital; ⁵ Department of Pathology, PAMM Laboratories, Eindhoven, the Netherlands; ⁶ Department of Radiotherapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands; and ⁷ Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Requests for reprints: Cornelis J.H. van de Velde, Department of Surgery, K6-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, the Netherlands 2515LK. Phone: 31-71-5262309; Fax: 31-71-5266750; E-mail: C.J.H.van_de_Velde{at}lumc.nl.

Purpose: To determine the effect of cyclooxygenase (COX)-2 expression on clinical behavior in irradiated and nonirradiated rectal carcinomas.

Experimental Design: Tumor samples were collected from 1,231 patients of the Dutch TME trial, in which rectal cancer patients were treated with standardized surgery and randomized for preoperative short-term (5 x 5 Gy) radiotherapy or no preoperative radiotherapy. Tissue microarrays were constructed from primary tumor material, and COX-2 expression was assessed by immunohistochemistry. Tumor cell apoptosis was determined by M30 immunostaining.

Results: A high level of COX-2 expression after radiotherapy was associated with low levels of tumor cell apoptosis (P = 0.001). COX-2 expression had no significant effect on patient survival or tumor recurrence in nonirradiated tumors. However, in patients receiving preoperative radiotherapy, high level of COX-2 expression was associated with higher incidence of distant recurrences [P = 0.003; hazard ratio (HR), 1.7; 95% confidence interval (95% CI), 1.2-2.5] and shorter disease-free survival (P = 0.002; HR, 1.8; 95% CI, 1.2-2.5) and overall survival (P = 0.009; HR, 1.5; 95% CI, 1.1-2.0), independent of patient age, tumor stage, tumor location, or the presence of tumor cells in the circumferential resection margin.

Conclusions: A high level of COX-2 expression after preoperative radiotherapy in resection specimens is associated with apoptosis resistance, high distant recurrence rates, and a poor prognosis in rectal cancer.

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