P-255 A randomized, placebo-controlled, double-blind phase II trial of peri-operative cimetidine in early colorectal cancer

Abstract

Background: A Cochrane meta-analysis of randomised trials using histamine-type 2 receptor antagonists with surgery for colorectal cancer (CRC) demonstrated a hazard ratio of 0.53 for mortality if patients used cimetidine. The benefit is likely to be specific to patients whose tumours express the antigens that allow circulating cells to bind to endothelial selectin (E-selectin), the expression of which is induced by inflammatory cytokines perioperatively and inhibited by cimetidine. This trial sought to evaluate several key issues critical to informing the conduct of a phase 3 trial. Methods: Patients with non-metastatic CRC planned for curative-intent surgery were randomised to receive cimetidine 800mg BID or placebo orally for 5 weeks, starting 2-7 days preoperatively. A subset of patients had serial blood sampling for inflammatory cytokines. In addition to DFS and OS, endpoints assessed include treatment compliance and toxicity, recruitment issues, post-operative stay and complications, and tumour characteristics including expression of sialyl Lewis antigens and COX-2. Results: 123 patients (36% female) have been recruited in 4 centres over 3.5 years; another 4 are required to complete the planned 120 treated patients. The primary tumour was rectal in 45% and pathological postoperative tumour stage was 0-I, II, III, and IV in 29%, 33%, 35%, and 2% respectively. About 50% of CRC patients were eligible and fewer than half of those were recruited. Patient compliance was excellent with 89% of patients taking their medication orally in the first 2 days postoperatively. Inflammatory cytokines were commonly elevated postoperatively for up to 2 weeks but normalised by 4 weeks. Immunostaining for tumour antigens is in progress and will be presented. DFS and OS data are immature. Conclusions: Oral administration of cimetidine for 5 weeks is well-tolerated and feasible over the perioperative period, and covers the duration of elevated inflammatory cytokines. Correlative immunostaining studies will be presented. Clinical trial information: 12609000769280.