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.
Kelly
M D
MD
Department of Surgery, University of New South Wales St. George Hospital, Sydney, Australia.
King
J
J
Cherian
M
M
Dwerryhouse
S J
SJ
Finlay
I G
IG
Adams
W J
WJ
King
D W
DW
Lubowski
D Z
DZ
Morris
D L
DL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D002927:Cimetidine / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006635:Histamine H2 Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D016130:Immunophenotyping; D015993:Life Tables; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D011292:Premedication; D011300:Preoperative Care; D016019:Survival Analysis; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D006635:Histamine H2 Antagonists; D002927:Cimetidine