Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor‐associated lymphocytes

BACKGROUND Previous studies have suggested that cimetidine, a histamine‐2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo‐controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS One hundred and twenty‐five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan‐Meier method was performed. RESULTS A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi‐square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action. Cancer 1999;85:1658–63. © 1999 American Cancer Society. A randomized, placebo‐controlled trial was performed using preoperative cimetidine treatment in patients with colorectal carcinoma. There was a trend toward a survival advantage and a trend toward an increase in the number of peritumoral lymphocytic infiltrates as assessed by histopathology. The effect of cimetidine on patient survival was marked in replication error negative tumors (P = 0.04). However, it was not possible to detect an increase in the number of peritumoral lymphocyte numbers by image analysis of immunohistochemically stained section