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

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Colon Cancer
Rectal Cancer
Presenter M. Jameson
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors M. Jameson1, M. Arendse1, M. Findlay2, I. Bissett3, S. Lolohea1, J. Warren1, F. Frizelle4, J. Keating5, G. Jacobson6, C. Romano1, R. van Dalen1
  • 1Waikato Hospital, Hamilton/NZ
  • 2Cancer Trials New Zealand, Auckland/NZ
  • 3University of Auckland, Auckland/NZ
  • 4Canterbury District Health Board, Christchurch/NZ
  • 5Capital & Coast District Health Board, Wellington/NZ
  • 6University of Waikato, Hamilton/NZ

Abstract

Introduction

Cimetidine (CIM) reduces metastatic potential in colorectal cancer (CRC) through preserving perioperative immune function and inhibiting expression of E-selectin, an endothelial cell adhesion molecule (induced by inflammatory cytokines) that binds circulating tumour cells expressing appropriate ligands. In a Cochrane meta-analysis of 5 randomised phase 2 trials using peri- or post-operative CIM in conjunction with curative-intent surgery for CRC, CIM resulted in reduced mortality (HR 0.53, 95% CI 0.32-0.87). The benefit was greatest in patients whose tumours expressed the sialyl Lewis (sLe) antigens a (CA19-9) or x that bind to E-selectin. This randomised phase II trial evaluated issues critical to planning a phase 3 trial.

Methods

Patients with stage 1-3 CRC were randomised to take cimetidine 800mg twice daily or placebo orally for 5 weeks, starting 2-7 days before curative-intent surgery. The primary endpoint was 2-year disease-free survival (DFS) in patients with sLe antigen-positive tumours; secondary endpoints included survival, CIM compliance, recruitment, serum inflammatory cytokine profile and tumour expression of sLe antigens by immunohistochemistry.

Results

128 patients (35% female), median 70 (29-86) years, were recruited in 4 centres over 3.5 years and randomised to CIM (n = 65) or placebo (n = 63); 6 patients took none. 40% of screened CRC patients were eligible of whom 53% were recruited. Of the 45% with a rectal primary, 68% received preoperative chemoradiation (CRT); 15% and 21% of those were downstaged to TNM stage 0 or 1 respectively. Postoperative TNM stage in all patients was 0-1, 2, 3 and 4 in 27%, 38%, 31%, and 2% respectively. 29% of patients had adjuvant chemotherapy. CIM was well-tolerated and feasible to administer orally throughout; in the first 2 postoperative days 77% of patients took >80% of planned study medication orally. At median follow-up of 26 (range 5-56) months, with 18 relapses and 15 deaths, 2-year DFS was 89% and 83% with CIM and placebo respectively (HR 0.76, 95% CI 0.30–1.91, logrank p = 0.56). Serum inflammatory cytokines were elevated up to 2 weeks post-operatively but normalised by 4 weeks (prior to CIM finishing). Expression of sLe antigens in >5% of cells was seen in 90% for CA19-9 and 74% for sLe x; all tumours expressed at least one antigen at that level. In 32% of tumours with high expression (>70% of cells) DFS was similar to the whole group. Tumour IHC score for CA19-9 correlated with baseline serum CA19-9 (r = 0.30, p = 0.014).

Conclusion

Perioperative CIM for 5 weeks is feasible and sufficient to cover the period of greatest risk of disseminating metastases due to elevated inflammatory cytokines. Given the excellent DFS seen in both groups and the small sample size, this study cannot adequately determine whether cimetidine improves DFS and whether its effect is modulated by expression of ligands for E-selectin on tumour cells. Nevertheless the trend to improved DFS is consistent with meta-analysis data. A phase 3 trial appears justified.