Ranitidine as adjuvant treatment in colorectal cancer. Short-course cimetidine and survival with colorectal cancer. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. Cimetidine as an adjuvant treatment in colorectal cancer. A double-blind, randomized pilot study.
Results from short-term studies of histamine type 2 (H2) receptor antagonists on survival of patients with solid tumours are debatable. In this study the efficacy of the H2-receptor antagonist ranitidine on long-term survival of patients with colorectal cancer was evaluated.
                Patients scheduled for elective resection of primary tumours were consecutively included in a randomized double-blind placebo-controlled clinical study designed to evaluate the effect of ranitidine on survival. Before skin incision ranitidine 100 mg or placebo was given intravenously twice daily followed by oral ranitidine 150 mg or placebo twice daily for 5 years. Adjuvant cytotoxic or radiation therapy was not given. An observer-blinded interim analysis performed after 40 months showed that there was no effect of ranitidine on overall survival, and the study was discontinued in accordance with the protocol. The patient cohort has been followed continuously without loss of any patient, and a final statistical analysis was performed on an intention-to-treat basis after more than 5 years; this included a subgroup analysis of perioperative blood transfusion and postoperative infectious complications.
                The median observation period of the 740 patients included was 6.8 (range 5.4-7.9) years. A univariate analysis of all 740 patients and of the subgroup of 560 who underwent curative resection showed no significant effect of ranitidine on survival. Furthermore, ranitidine had no survival benefit in curatively resected patients who received a perioperative blood transfusion (n = 358), but it improved the survival of non-transfused patients (n = 202; hazard ratio (HR) 0.6 (95 per cent confidence interval (c.i.) 0.4 to 0.9), P = 0.02) and of non-transfused patients who did not develop postoperative infectious complications (n = 170; HR 0.6 (95 per cent c.i. 0.4 to 0.9), P = 0.01). In multivariate analysis of patients who had a curative resection, including Dukes' stage, age, gender, tumour location, blood transfusion, postoperative infectious complications and treatment, ranitidine still had an independent, beneficial effect on survival (HR 0.6 (95 per cent c.i. 0.4 to 1.0), P = 0.04) within the subgroup of patients who did not receive perioperative blood transfusion and did not develop postoperative infectious complications.
                Ranitidine may prolong the survival of patients who undergo curative resection of colorectal cancer and who do not receive perioperative blood transfusion and do not develop postoperative infectious complications. nan Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a).
                Copyright 2002 The Cancer Research Campaign To evaluate the influence of a H2 receptor antagonist (cimetidine) on survival in patients with colorectal carcinoma, a randomized, controlled pilot study was performed in three university hospitals in Copenhagen, Denmark.
                A total of 192 patients, who had undergone a resection or an exploratory operation for adenocarcinoma of the colon or rectum between May 1988 and May 1991, were enrolled in the study. After a median observation time of 40 months, outcome was noted for each patient concerning cancer-specific mortality rate.
                In patients operated with curative intent (n = 148), no difference was found in cancer-specific mortality between the two treatments. However, a tendency toward reduction in mortality rate was found in patients with curatively operated Dukes Stage C carcinoma (P = 0.11, log-rank test; difference, 29 percent; 90 percent confidence interval, 2 to 57 percent) in the cimetidine-treated group. In patients with disseminated disease no total difference was found between the two treatment groups.
                Cimetidine does not seem to reduce mortality in patients with colorectal cancer, but there seems to be a tendency toward a survival benefit in patients undergoing surgery for Dukes Stage C carcinoma. Results seem to justify trials in this patient category to reveal a benefit of H2 receptor antagonists in adjuvant therapy of colorectal carcinoma.
Of the H2RAs evaluated cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers. The trial designs were heterogeneous and adjuvant therapy has evolved since these trials were performed. Further prospective randomised studies are warranted.