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Etiology

Cholecystectomy was not associated with the overall risk for colorectal cancer

ACP J Club. 1994 Jan-Feb;120:24. doi:10.7326/ACPJC-1994-120-1-024


Source Citation

Ekbom A, Yuen J, Adami H, et al. Cholecystectomy and colorectal cancer. Gastroenterology. 1993 Jul;105:142-7.


Abstract

Objective

To study the long-term association between cholecystectomy and colorectal cancer.

Design

Cohort study of men and women followed for up to 23 years.

Setting

6 counties in central Sweden.

Participants

62 615 patients (28% < 40 y, 14% ≥ 70 y, 67% women) had cholecystectomy alone or combined with 1 or more of the following procedures: choledochotomy, choledocholithotomy, or sphincterotomy. Exclusion criteria were incomplete or inconsistent national registration numbers or diagnosis of cancer before surgery. Patients were classified as having acute cholecystitis, chronic cholecystitis, cholelithiasis, or other disorders.

Assessment of risk factors

Sex, age at operation, operative procedure, diagnosis at operation, time period of operation (1965 to 1969, 1970 to 1974, 1975 to 1979, 1980 to 1983), presence of common bile stones, and length of follow-up were obtained from medical charts and national registries.

Main outcome measures

Cancer detected in the first year after surgery was not included. Actual and expected numbers of colorectal cancers and deaths up to the end of 1987 were used to calculate standardized incidence ratios (SIRs). Data were available from national registries. Colorectal cancer diagnosis was divided into colon and rectum with a separate analysis of right-sided colon (cecum and ascending or appendix) cancer and of left-sided colon (descending or sigmoid) cancer.

Main results

After the first postoperative year, 633 persons were diagnosed with colorectal cancer compared with 638 expected diagnoses (SIR 0.99, 95% CI 0.92 to 1.07). Overall colorectal cancer and colon cancer, right-sided colon cancer, left-sided colon cancer, and rectal cancer were not associated with any risk factors. Women had an increased risk for right-sided colon cancer after cholecystectomy (SIR 1.24, CI 1.03 to 1.48). This risk increased with follow-up ≥ 15 years (SIR 1.54, CI 1.03 to 2.22). Other risk factors for women were not associated with increased right-sided colon cancer. Neither men nor women had increased risks for other colorectal cancers. Multivariate analysis models adjusted for all risk factors showed no factor was associated with overall colorectal cancer or with any type of colorectal cancer.

Conclusion

Excluding colorectal cancer diagnosed in the first year after cholecystectomy, no associations were noted between colorectal cancer and cholecystectomy except among women, who had a small increased risk for right-sided colon cancer.

Source of funding: Not stated.

For article reprint: Dr. A. Ekbom, Cancer Epidemiology Unit, University Hospital, S-751 85, Uppsala, Sweden. FAX 46-18-50-34-31.


Commentary

S ee alsoReview: Meta-analysis shows that cholecystectomy is associated with a small increased risk for colorectal cancer of the proximal colon

Approximately 20% of women and 10% of men have gallstones (1). Although most patients with gallstones are asymptomatic, approximately 600 000 cholecystectomies are done each year in the United States for symptomatic cholelithiasis (1). An association between cholecystectomy and colon cancer was first reported in 1978 (2), and since then more than 60 studies have attempted to confirm whether cholecystectomy increases the risk for colon cancer. The results have been inconsistent.

An association between cholecystectomy and colon cancer is biologically plausible. Without the gallbladder, continuous circulation of bile salts and increased bacterial degradation of primary to secondary bile salts occur (3, 4). Secondary bile salts may be carcinogenic because they can promote colonic epithelial cell proliferation in animal models (5). The key questions still remain: Is there truly an association, and, if a causal link exists, should we screen patients for colon cancer after cholecystectomy?

Ekbom and colleagues have essentially resolved the issue. Other cohort studies that also found no overall excess risk have been criticized for a potential lack of statistical power (6) or for insufficient follow-up (7). Because of the large sample size, a virtually complete ascertainment of patients, and extensive follow-up, bias is unlikely to explain the findings of the study by Ekbom and colleagues, and their estimates are probably precise. They did find that women had a small increased risk for right-sided colon cancer, particularly ≥ 15 years after surgery, but they note that only 23 more cases occurred than were expected in 41 870 women.

Moreover, these results were largely confirmed in the meta-analysis by Giovannucci and colleagues, although women and, to a lesser extent, men were found to be at a small but increased risk. Although studies that are weakest methodologically (hospital case-control studies) provided the strongest evidence for an increased risk for colon cancer after cholecystectomy, unrecognized bias (e.g., greater scrutiny of patients who had cholecystectomy compared with controls or selection of inappropriate controls) is likely to explain that observation. Cohort studies generally provide more convincing evidence than case-control studies. Why women are at a higher risk than men remains unexplained.

Although a small but definite association is now established for some patients with colon cancer, is this cause and effect? Other factors, such as weight, diet, or heredity, could predispose a person to have right-sided colon cancer and gallstones (and thus a cholecystectomy). On the other hand, confounding by lifestyle factors alone seems unlikely to entirely explain the association, in view of a positive association found in other study populations.

An increased risk for right-sided colorectal cancer appears to occur after cholecystectomy, particularly in women ≥ 15 years after surgery. Screening is, however, not justified because of the tiny attributable risk. Cholecystectomy should not be withheld for patients who need it because of any concern about the development of colon cancer.

Nicholas Talley, MD
Mayo ClinicRochester, Minnesota, USA


References

1. National Institutes of Health Consensus Development Conference Statement on Gallstones and Laparoscopic Cholecystectomy. Am J Surg. 1993;165:390-8.

2. Capron JP, Delamarre J, Canarelli JP, Brousse N, Dupas JL. La cholecystectomie favorise-t-elle l'apparition du cancer rectocolique? Gastroenterol Clin Biol. 1978;2:383-9.

3. Sandler RS. Cholecystectomy and colorectal cancer [Editorial]. Gastroenterology. 1993;105:286-8.

4. Malegelada JR, Go VW, Summerskill WH, Gamble WS. Bile acid secretion and biliary bile acid composition altered by cholecystectomy. Am J Dig Dis. 1973;18:455-9.

5. Narisawa T, Magadia NE, Weisburger JH, Wynder EL. Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine in rats. J Natl Cancer Inst. 1974;53:1093-7.

6. Gudmundsson S, Moller TR, Olsson H. Cancer incidence after cholecystectomy—a cohort study with 30 years follow-up. Eur J Surg Oncol. 1989;15:113-7.

7. Maringhini A, Moreau JA, Melton LJ 3d, et al. Gallstones, gallbladder cancer, and other gastrointestinal malignancies. An epidemiologic study in Rochester, Minnesota. Ann Intern Med. 1987;107:30-5.