Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer

Colorectal cancer (bowel cancer) is the third most commonly diagnosed cancer in the world. Surgery is the primary curative treatment for those with early stage disease. However, a number of patients relapse after primary surgery, presumably due to cancer cells that have spread undetected to other parts of the body. In general, once colorectal cancer has spread it is no longer curable. Hence, adjuvant treatments are given around the time of surgery to eliminate any remnant cells to improve a patient's chance of cure.

Histamine type 2 receptor antagonist drugs (H2RAs) were originally developed as a treatment for peptic ulcers. However, anecdotal reports surfaced of tumour shrinkage with the use of these drugs. This launched a number of trials to see if these medications could be used to improve a patient's chance of cure following surgery for colorectal cancer.

This Cochrane review found six studies that adopted this strategy. There was wide variability amongst the trials in respect to a) the dose used, b) the timing in relation to surgery and c) for how long the H2RA drug was used for. When the results of the trial were analysed together it appeared that there was no survival benefit with the use of these medications. When the studies using cimetidine (a particular H2RA which has a theoretical additional mechanism of action in preventing tumour spread) were analysed, there appeared to be a survival benefit for patients receiving cimetidine.

Given the variability amongst the trials the results can only be considered as speculative, as opposed to strong evidence for this approach. Furthermore, these trials were conducted in a time where the approach to staging and treatment would be considered sub optimal by today's standards. Hence, further trials in the future are warranted.

Authors' conclusions: 

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.

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Background: 

Anecdotal reports of tumour regression with histamine type 2 receptor antagonists (H2RAs) have lead to a series of trials with this class of drug as adjuvant therapy to try and improve outcomes in patients with resected colorectal cancers. There was a plausible scientific rationale suggesting merit in this strategy. This included improved immune surveillance (by way of increasing tumour infiltrating lymphocytes), inhibiting the direct proliferative effect of histamine as a growth factor for colorectal cancer and, in the case of cimetidine, inhibiting endothelial expression of E-selectin (a cell adhesion molecule thought to be critical for metastatic spread).

Objectives: 

To determine if H2RAs improve overall survival when used as pre- and/or postoperative therapy in colorectal cancer patients who have had surgical resection with curative intent. We also stratified the results to see if there was an improvement in overall survival in terms of the specific H2RA used.

Search strategy: 

Randomised controlled trials were identified using a sensitive search strategy in the following databases: MEDLINE (1964 to present), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2009), EMBASE (1980 to present) and Cancerlit (1983 to present).

Selection criteria: 

Criteria for study selection included:
patients with colorectal cancer surgically resected with curative intent;
H2RAs used i) at any dose, ii) for any length of time, iii) with any other treatment modality and iv) in the pre-, peri- or post-operative period. The results were stratified for the H2RA used.

Data collection and analysis: 

The literature search retrieved 142 articles. There were six studies included in the final analysis, published from 1995 to 2007, including a total of 1229 patients. All patients were analysed by intention to treat according to their initial allocation. Log hazard ratios and standard errors of treatment effects (on overall survival) were calculated using the Cochrane statistical package RevMan Version 5. Hazard ratios and standard errors were recorded from trial publications or, if not provided, were estimated from published actuarial survival curves using a spreadsheet designed for this purpose (http://www.biomedcentral.com/content/supplementary/1745-6215-8-16-S1.xls).

Main results: 

Of the six identified trials, five used cimetidine as the experimental H2RA, whereas one used ranitidine. There was a trend towards improved survival when H2RAs were utilised as adjuvant therapy in patients having curative-intent surgery for colorectal cancer (HR 0.70; 95% CI 0.48-1.03, P = 0.07). Analysis of the five cimetidine trials (n = 421) revealed a statistically significant improvement in overall survival (HR 0.53; 95% CI 0.32 to 0.87).

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