World J. Surg. 15, 562-567, 1991
World Journal of Surgery 9 1991 by the Soci~t~ lnternationale de Chirurgie
Epidemiology of Large Bowel Cancer K e n n e t h E. Levin, M.D., and R o g e r R. Dozois, M.D. Section of Colon and Rectal Surgery, Department of Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A. Results from epidemiologic studies have prodded insights into the etiology of large bowel cancer. Markedly diverse incidences of colorectal cancer exist in various parts of the world and within different regions of a given country. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk. Sedentary lifestyle, cholecystectomy, and ureterosigmoidostomy may also increase the risk of developing large bowel cancer.
Carcinoma of the large bowel is the second leading cause of death from cancer in the United States today. The American Cancer Society predicts 155,000 new cases of colon and rectal cancer and over 60,000 deaths from this cancer in 1990 [1]. The high incidence and mortality rates have made the epidemiology of large bowel cancer a major area of investigation. The aims of this article are to describe the incidence and patterns of large bowel cancer, to identify high risk groups for developing this cancer, and to discuss some of the potential etiologic factors. Incidence of Large Bowel Cancer
Major leads to the etiology of colon and rectal cancer come from observing its distribution in various countries, its possible changing incidence within a given time period, and its differences in incidence between sexes and socioeconomic groups, as well as within a given population itself. For colorectal cancer, available data clearly show major differences in incidence and mortality rates among countries of similar industrial development [2]. The highest incidence rates are found mainly in Western Europe, North America, Australia, and New Zealand; intermediate rates are found in Eastern Europe; the lowest incidence is noted in Africa, Asia, and South America. As a rule, the more industrialized a country, the higher the risk of colorectal cancer. The two notable exceptions are Japan and Finland [2]. In the United States, the present incidence and mortality rates for colorectal cancer are second only to those for lung cancer. In 1989 an estimated 155,000 new cases were diagnosed, 70% in the colon and 30% in the rectum, and an
Reprint requests: Roger R. Dozois, M.D., Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota, 55905, U.S.A.
estimated 61,000 deaths occurred [3]. Colorectal cancer constitutes about 15% of all newly diagnosed cancers (excluding in situ carcinomas and non-melanotic skin cancers) and 13% of all cancer deaths [3, 4]. At present, the probability of a white male in the United States developing colorectal cancer during his lifetime is 6.3%, and his probability of dying from it is 2.9% [5]. The probability of a white female developing colorectal cancer during her lifetime is 6.8%, and her probability of dying from it is 3.1% [5]. Although the incidence of gastric cancer has fallen dramatically and the incidence of pancreatic cancer has leveled off over the past 25 years, the incidence of colorectal cancer is increasing. From 1973 through 1986, the annual incidence rate for colorectal cancer per 100,000 U.S. population increased 9.4% [6]. Statistically significant increases occurred for all races combined, for whites and blacks, and for males and females. In 1986, the incidence rates for blacks and whites were similar (50.7 per 100,000 vs. 50.3 per 100,000, respectively), while the rate for males was higher than for females (61.1 per 100,000 vs. 42.8 per 100,000, respectively) [6]. The time trends in the average annual rates of increase in colorectal cancer mortality show a pattern worldwide. In countries where rates were initially low (South and Central America, Asia, and Central and Eastern Europe), generally large rates of increase have been reported [7]. In countries where the rate was initially at an intermediate level (Canada, United States, Switzerland, Australia, New Zealand, Ireland, the Netherlands, Belgium, France, Sweden, Denmark, and Austria), small increases of less than 1% increase per year or stabilization of the rate have been observed. In countries where mortality rates from colorectal cancer were initially high (England, Wales, Australia, and Scotland), stabilization or decreases have taken place [7].
Migrant Population Studies The incidence and mortality rates for large bowel cancer vary greatly around the world, indicating the importance of environmental factors. Although some of the international variation of colorectal cancer may have a genetic basis, evidence supporting a major role for environmental and lifestyle factors can be found in studies of migrant populations [4]. In general, as groups of people move to a new land, their risk of various cancers shifts
K.E. Levin and R.R. Dozo|s: Epidemioiogy of Colorectai Cancer
away from the pattern prevailing in the country of origin toward that of the host country. Among Japanese in Japan, colorectal cancer, in contrast to gastric cancer, has a very low incidence (about 3 per 100,000 [8]. In Japan, fat intake is low and, although it is rising, it is little more than half of that in Western populations. Dietary fiber intake, once high, is now decreasing. The colon cancer rate is slowly rising. Japanese immigrants to Hawaii and California, however, soon experience considerable increases in colorectal cancer incidence. Indeed, in both these regions first-generation immigrants attain about double the frequency of sigmoid colon and rectal cancer compared With the rates of their white neighbors [8, 9]. At the same time, the risk of stomach cancer decreases in the migrants [10]. Migration of blacks from Africa to the United States has led to a dramatic increase in the incidence of colorectal cancers. According tO Petrakis [11], 75% of American blacks are said to be derived from West Africa, with 40% coming from the region of present-day Nigeria. From 1969 tO 1971, the incidence of colon cancer among U.S. black males far exceeded that among Nigerian black males (11.6 per 100,000 vs. 0.8 per 100,000, resPectively) [12]. Similarly, the U.S. incidence of rectal cancer in black males (6.6 per 100,000) was higher than in Nigeria (0.6 per 100,000). A similar comparison of incidence rates was also present between U.S. black females and Nigerian black females [12]. Colorectal cancer incidence rates among Chinese Americans are 4 to 7 times greater than rates among the general population in the People's Republic of China [13]. The disparity is more pronounced for men than for women, and it increases with age. Rate s among Chinese American men are comparable to those among white American men [13]. In contrast, Chinese American women have rates intermediate between those of white American women and those of women in China [13]. Several conclusions can be made from studies of colorectal cancer in migrating populations [4]. The risk of colon and rectal cancer can change in the migrating population and can closely approach that of the country of destination. The risk of colorectal cancer Seems to change more rapidly in the migrating generation than does the risk of other major cancers. The risk of colorectal cancer c a n be radically altered in the migratory generation, but it need not be. The mortality from colorectal cancer seems to rise more quickly among immigrant men than women. Urban-Rural Gradient and Socioeconomic Status A difference in incidence of cancer has been observed when comparing an urban population to a rural population [t4]. In countries at high, intermediate, and low risk of colorectal cancer, the rates are consistently higher among urban residents [15]. United States mortality data for 1949 to 1951 showed that an excess risk of colorectal cancer in metropolitan versus non-metropolitan counties existed in all regions of the country [16]. The current residence in an urban or rural area was a stronger determinant of risk of colorectal cancer than was the place of birth. However, by 1970, incidence data for Iowa and Colorado indicated that an excess risk in urban areas occurred only for colon cancer among males, with no gradient apparent for female colon cancer or rectal cancer in either sex [17]. Thus,
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urban-rural gradients in incidence and mortality from colorectal cancer appear to have diminished in the U.S. over time [17]. In the United States and other developed countries, socioeconomic status does not Seem to be as Strongly associated with colorectal cancer risk as does urbanization [15]. Only in white males was the risk of colorectal cancer associated with socioeconomic status, and the associations with colon and rectal cancer were in different directions [4]. Significant positive associations with both income and education were apparent for colon cancer in white males; the risks in the highest income and education groups were, respectively, 1.3 and 1.4 times those in the lowest groups. On the other hand, rectal cancer showed a significant inverse association with income in white males, with the highest income category having a risk 0.7 times that o f the lowest.
Race J
There is little difference in colorectal cancer incidence between blacks and whites within each community and region of the United States [12]. The incidence rates for cOlon cancer were similar among males and females for both blacks and whites [6]. The black/white ratio for colon cancers was 0.8 for males and 1.0 for females [12]. While there has been some increase over time in the incidence of colon cancer among whites, there has been a sharp increase among blacks, particularly among black females, On the other hand; for rectal cancer the incidence is lower in both black males and black females. The black/white ratio for rectal cancer was 0.8 in both males and females [12].
Age and Sex Colorectal cancer is primarily a cancer of the older population. From 1982 to 1986, the median age at diagnosis was 71 years for colon cancer and 69 years for rectal cancer [6]. Risk for colorectal cancer increases with age. For example, from 1982 to 1986, the incidence rate for persons 30 to 34 years old was 2.9 per 100,000, compared with 531.6 per i00,000 for persons age 85 or older [6]. The overall sex ratio for colon cancer in most sOcieties is near unity, in contrast with cancer of the rectum, which is predominantly a male disease, especially in the older ages [2, 18]. However, there is a tendency under the age of 50 for the ratio of colon cancer to be slightly higher in women and in the older age groups to be somewhat higher in men [2]. In men, colorectal cancer ranks third behind lung and prostate cancer in the number of new male cancer cases in the United States [3]. Colorectal cancer in males ranks second behind lung cancer for deaths by cancer, accounting for 11% of cancer deaths [3]. In women, colorectal cancer ranks second behind breast canCer in new cancer cases in the United States, and it ranks third behind lung and breast cancer in percentage of cancer deaths (13%) [3]. In the past 25 years, there has been a noticeable decrease in the age-adjusted death rate for women (22%), whereas no such decrease has been noted for men [3, 14].
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Religion Differences exist in the colorectal cancer incidence rates among certain religious groups in the United States. Colorectal cancer is more common in the Jewish population and less common among Seventh-Day Adventists and Mormons [2, 4, 14]. The studies which revealed a higher incidence rate in Jews were completed 20 years or more ago; thus, further studies would be useful to determine if such differences persist. The Adventists abstain from tobacco and alcohol and tend to avoid caffeine, highly refined foods, and sweets; approximately half are lacto-ovo-vegetarians [4]. The Mormon religion prohibits use of tobacco, alcohol, tea, and coffee, and it stresses a balanced diet including grains, vegetables, and fruits; meats are eaten in moderation. They do not, however, consume a diet especially low in total fat. Although the reason for the reduced risk of colorectal cancer in Adventists and Mormons is not clear, these lifestyle traits may be causally related to their 30--40% reduction in incidence of colorectal cancer.
Anatomic Distribution A marked change in the anatomic distribution of colorectal cancers has occurred in the past 40 years. During this period, clinicians have noted an increased incidence of right-sided colonic cancer and a decrease in rectal cancer [19]. It had previously been thought that 75% of colorectal cancers were within reach of the rigid proctosigmoidoscope; more recent data suggest that the figure is closer to 60% [14]. In a study of almost 6,000 resected large bowel specimens removed over a 40 year period [20], the incidence of right colon cancer increased from 7% to 22%. At the same time, the incidence of rectosigmoid, sigmoid, and rectal cancer fell from 80% to 62%. A trend to smaller tumors was also evident with less frequent lymph node involvement of the distal lesions, possibly reflecting an improvement in early detection [20]. High-risk Groups for Large Bowel Cancer A significant proportion of persons developing colorectal cancer come from well recognized high-risk groups. Colorectal cancer is an inherited disease in about 5% of cases. These patients are part of the familial polyposis syndromes and the hereditary nonpolyposis colon cancer (Lynch) syndromes [21]. Persons with inflammatory bowel disease, chronic ulcerative colitis in particular, are also at significantly higher risk for developing colorectal cancer than is the general population. In addition, persons with certain extracolonic carcinomas may also be at increased risk of developing colorectal cancer.
Hereditary Nonpolyposis Colon Cancer Hereditary nonpolyposis colon cancer is defined as a syndrome characterized by the inheritance of colon cancer in an autosoreal dominant pattern [21, 22]. The other cardinal features are: early age of colon cancer onset (mean age of 46 years), proximal colon cancer involvement' with relative rectal sparing (70% located proximal to the splenic flexure of the colon), increased incidence of synchronous (18%) and metachronous (40% by 10 years) colon cancer compared to a 4% incidence of each in
World J. Surg. Vol. 15, No. 5, Sept./Oct. 1991 patients with no hereditary colon cancer, and the presence of a specific extracolonic cancer in some families [22, 23]. Though most of the extracolonic cancers in Lynch Syndrome II (colorectal and extracolonic cancers) are endometrial, others also described are ovarian, gastric, renal, urinary bladder, pancreatic, and breast cancers, Lynch and coworkers [22, 23] have predicted that 5 to 6% of all cases of colorectal cancer fulfill the criteria for hereditary nonpolyposis colon cancer. Mecklin [24] determined in a Finnish study that 4 to 6% of the colorectal cancer patients fell into the hereditary nonpolyposis colorectal cancer syndrome.
Familial Adenomatous Polyposis Familial adenomatous polyposis is an autosomaUy dominant inherited disease occurring in 1 of every 7,000 to 10,000 births. The colon is involved with innumerable adenomatous polyps. Despite the well recognized pattern of inheritance, approximately 20% of patients have no such history [25]. The condition does not seem to skip generations, as was once thought [26]. Therefore, children of an affected patient have a 50% chance of inheriting the defect and thus the adenomas and other extracolonic manifestations. Familial adenomatous polyposis, Gardner's syndrome, and Turcot's syndrome are now all thought to be variations of the same basic genetic defect with varying degrees of genetic expression, as opposed to distinct entities, as had been suggested in the past, The adenomas occur early in life, and it is often possible to see them in children before 10 years of age. The general distribution of polyps in the large bowel is uniform, although there seems to be a slight preponderance of left-sided lesions [26]. Cancers that develop may be multifocal, but again, there is a more common distribution on the left side, presumably associated with the slight increase in the number of adenomas in the left colon and rectum. The progression to cancer is inevitable, and 75% of familial adenomatous polyposis patients develop colorectal cancer by the age of 35 years; almost all die of cancer in their forties unless surgical intervention is performed. Carcinomas occurring in familial adenomatous poiyposis represent about 1% of all colorectal cancer cases [23, 24].
Inflammatory Bowel Disease It is well recognized that patients with chronic ulcerative colitis are at higher risk for the development of colon and rectal cancers, Carcinoma of the colon or rectum begins to appear 5 to 8 years after the onset of ulcerative colitis. By 10 years after disease onset, approximately 5% of patients have developed colorectal cancer, with the cumulative incidence of colorectal cancer increasing progressively with time of disease, reaching 25 to 30% at 25 years [27]. Incidence rates for colorectal cancer in chronic ulcerative colitis are not uniform worldwide, with lower rates reported in Scandinavia and Europe [28, 29]. Extent of colitis appears to also be a factor in the development of colorectal cancer. The cumulative risk of colorectal cancer was significantly higher in patients with pancoiitis than with left-sided disease [30]. The distribution of cancers in patients with ulcerative colitis is more uniform, that is, with a higher proportion of right-sided and transverse colon cancers,
K.E. Levin and R.R. Dozois: Epidemiology of Colorectal Cancer
than in patients with colorectal cancers without ulcerative colitis [27]. The incidence of colorectal cancer is equal in both sexes, reflecting the fact that ulcerative colitis affects both sexes in approximately an equal ratio. However, the colorectal cancers in ulcerative colitis patients tend to be infiltrative and scirrhous, and their fiat nature often goes unrecognized even by careful endoscopic examination. Additionally, a large proportion of the lesions are highly aggressive and poorly differentiated at time of diagnosis. The incidence of colorectal cancer associated with colonic Crohn's disease is much lower than that associated with chronic ulcerative colitis. Actuarial methods suggest that the risk of colorectal cancer complicating long-standing Crohn's colitis is, however, 4 to 20 times the incidence found in the general population [31]. Segments of intestine excluded from the fecal stream, such as an isolated rectal stump or bypassed ileum, are especially vulnerable, perhaps because of bacterial proliferation due to stasis.
Extracolonic Carcinoma A correlation between breast and colorectal cancer is suggested by the occurrence of parallel geographic variations in the incidence of both tumors. The increased risk for colorectal cancer demonstrated in women with breast cancer is supported by the findings in one study of an increased prevalence of adenomatous polyps in the colon and rectum in patients with breast cancer [32]. Another study found that patients with breast cancer have the same risk for developing a colorectal cancer as that for a second primary in the opposite breast [33]. Potential Etiologic Factors
Descriptive epidemiology has played a vital role in formulating hypotheses regarding the causes of large bowel cancer. The worldwide variation in incidence, the changing rates among migrant groups, and the rates among religious groups such as Seventh-Day Adventists and Mormons point to environmental factors being of crucial importance in the etiology of these cancers. Evidence from these studies and substantive support from animal experiments indicate that dietary factors are likely to be responsible for the majority of colorectal cancers. Bacteria are also thought to play a role in the causation of colorectal cancer by their action on ingested fat or metabolites. Occupation and level of physical activity is also believed to influence the incidence of colorectal tumors. Cholecystectomy and ureterosigmoidostomy are also important factors in the incidence of these tumors.
Diet Diet is the epidemiologic area that has received the most attention during the past 20 years, especially since Burkitt's original observations in 1971 [34] and further work by Nigro and others [35]. Burkitt felt that it was reasonable to assume that the conditions prevailing within the lumen of the bowel are the factors most responsible for the environment of bowel mucosa. As has been emphasized, there is a close relationship between large bowel cancer and economic development, and the influ-
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ential factors are probably alterations in dietary patterns [18, 34, 35]. Burkitt observed that the proportions of unabsorbable fiber and refined carbohydrate in ingested food were the most notable differences between the diet of the Western world, where colorectal cancer is most prevalent, and that of less developed communities, where it has its lowest incidence. He felt that the adoption of a refined carbohydrate diet is the most important, though not the only, dietary factor in the causation of colorectal cancers [34]. Presently, the two major dietary risk factors for colorectal cancer are diets high in fat and low in fiber, but the mechanisms appear complex and difficult to unravel [4, 35-39]. Bile acids and neutral sterols are important endogenous compounds related to dietary fat secreted into the gut. The intake of high dietary fat, animal fat in particular, and cholesterol not only changes the composition of bile acids and neutral sterols in the large bowel, but also modifies the large bowel bacteria quantitatively, which in turn may transform these compounds into carcinogenic secondary bile acids and cholesterol metabolites [37, 39]. The evidence for bile acids as colon tumor promoters has been obtained from animal experiments [38, 39]. Overall, the current theory of dietary influence on colorectal cancer incidence is that qualitative and quantitative differences in luminal compounds such as bile acids and cholesterol metabolites play an enhancing role in colon carcinogenesis. These compounds are primarily derived from dietary factors and subsequently modified by the gut bacteria, chiefly in the large bowel. Increased intake of dietary fiber is associated with a decreased risk of colorectal cancer, probably due to several reasons: fiber can decrease transit time, thereby decreasing the contact time between tumor promoters and carcinogens and the colonic mucosa; fiber can influence the composition and metabolic activity of gut bacteria that play a role in the production of colon cancer initiators and promoters; or fiber can affect the absorption and excretion of these carcinogens and promoters in the colon. A number of additional dietary factors have been suspected of playing a role in cancers of the large bowel. Decreased risk may be associated with intake of cruciferous vegetables, vitamin A and vitamin C, and beta-carotene. Increased risk may be associated with intake of protein, alcohol, and cigarette smoking [38, 40]. However, the evidence for most of these factors is largely anecdotal and it is not possible to distinguish associations of etiologic significance from those that are merely coincidental.
Occupational and Physical Activity Recently, studies have shown an increased risk of colon cancer among people in occupations with low physical activity. In a Swedish 14 year follow-up study of 16,477 subjects, the relative risk of colon cancer in subjects with low physical activity was estimated at 3.6 (1,3-9.8, 95% confidence interval) [41]. The association was observed for men and women, but the relative risk for rectal cancer was not elevated. This finding was also noted in a study from Utah which found that intense physical activity was protective against the development of colon cancer in both men and women and that physical activity modifies colon cancer risk associated with diet [42]. Brownson and coworkers [43] similarly noted that an excess risk of colon
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cancer was present in those employed in sedentary jobs, and an inverse linear trend in risk was shown according to the level of occupational physical activity.
World J. Surg. Vol. 15, No. 5, Sept./Oct. 1991
chol6cystectomie et l'ur6t6rosigmoidostomie sont aussi de possibles facteurs favorisants. Resumen
Risk Following Cholecystectomy Following cholecystectomy, the concentration of secondary bile acids in the bile increases, and secondary bile acids have been theorized in the pathogenesis of large bowel cancer. Numerous studies have investigated the hypothesis that the risk of colorectal Cancer is increased following cholecystectomy. Despite the large number of studies, the precise relationship between cholecystectomy and the development of colorectal cancer remains controversial and data are conflicting [44]. Many of the studies have serious limitations in design, size, and make-up of subject groups and controls, and the majority are retrospective in nature. The ultimate answer to this question will only be resolved by careful planning and follow-up of prospective studies.
Risk Following Ureterosigmoidostomy Carcinoma of the colon developing at or about the site of ureterosigm0id0stomy anastomosis is a well recognized delayed complication of urinary diversion [45, 46]. The chances of a carcinoma, usually adenocarcinoma, developing in patients who have a ureterosigmoidostomy have been estimated to be 100 to 550 times greater than that of the general population [47]. These carcinomas develop many years following urinary diversion and tend to do so over the region of ureteral implantation. Urinary carcinogens are felt to be involved in the neoplastic change, and if fecal material is present it can play a promoting role in this carcinogenic process. Because of the increased risk of late development of adenocarcinoma following ureterosigmoidostomy, routine long-term followSup surveillance is mandatory in these patients. Summary
Results from epidemiological investigations have provided clues to etiological factors involved in the development of large bowel cancer. At present, uncertainties as to the identity and significance of genetic and environmental risk factors complicate the goal of seeking to prevent the disease or identify those at particular risk. However, certain risk factors have been dearly identified, and there is promise that future studies will further clarify the interactive aspects of the many factors involved. R6sum6
Un apergu des facteurs 6tiologiques dans le d6veloppement du cancer colorectal a 6t6 d6gag6 grace ~ une 6tude 6pid6mio|ogique. L'incidence du cancer colorectal varie beaucoup dans le monde et au sein d'un m6me pays suivant les r6gions. L'6tude des populations migrantes a d6montr6 le r61e de l'environnement, et en particulier de l'alimentation, dans la g6n~se des cancers colorectaux. Des facteurs g6n6tiques et l'existence d'une maladie inflammatoire de l'intestin ont 6galement ~t6 incrimin6s chez certains individus. La s6dentarit6, la
Los resultados de estudios epidemiol6gicos han provisto nuevos conocimientos sobre los factores etiol6gicos involucrados en el desarrollo del c~incer de colon. Marcadas variaciones en la incidencia de c~incer colorrectal se observan en diversas partes del mundo y entre diferentes regiones dentro de un mismo pals. Estudios sobre poblaciones migrantes han revelado el rol de factores ambientales, en particular los de car~icter dietario, en la etiologia de estos c~lnceres. Factores gen6ticos y la enfermedad inflamatoria del colon tambi6n colocan a ciertos individuos en condici6n de riesgo aumentado. L a vida sedentaria, la colecistectomia y la ureterosigmoidostomia peuden tambi6n incrementar el riesgo de desarrollar c~incer del colon. References
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Second International Symposium on Colorectal Cancer, Washington, 1981 Agarwal, N., Cayten, C.G., Ulahannan, M.J. Pitchumoni, C.S., Mandile, M.A.: Increased risk of colorectal cancer following breast cancer. Ann. Surg. 203:307, 1986 Burkitt, D.P.: Epidemiology of cancer of the colon and rectum. Cancer 28:3, 1971 Nigro, N.D., Singh, D.V., Campbell, R.L., Pak, M.S.: Effect of dietary beef fat on intestinal tumor formation by azoxymethane in rats. J. Natl. Cancer Inst. 54:439, 1975 Nomura, A.: An international search for causative factors of colorectal cancer. J. Natl. Cancer Inst. 82:894, 1990 Wargovich, M.J., Baer, A.R., Hu, P.J., Sumyoshi, H.: Dietary factors and colorectal cancer. Gastroenterol. Clin. North Am. 17:727, 1988 Vogel, V.G., McPherson, R.S.: Dietary epidemiology of colon cancer. Hematol. Oncol. Clin. North Am. 3:35, 1989 Reddy, B.S., Mastromarino, A., Wynder, E.L.: Further leads on metabolic epidemiology of large bowel cancer. Cancer Res. 35: 3403, 1975 Klatzky, A.L., Armstrong, M.A., Friedman, G.D., Hiatt, R.A.: The relation of alcoholic beverage use to colon and rectal cancer. Am. J. Epidemiol. 128:1007, 1988 Gerhardsson, M., Floderus, B., Norell, S.E.: Physical activity and colon cancer risk. Int. J. Epidemiol. 17:743, 1988 Slattery, M.L., Schumacher, M.C., Smith, R.R., West, D.W., Abd-Elgheny, N.: Physical activity, diet, and risk of colon cancer in Utah. Am. J. Epidemiol. 128:989, 1988 Brownson, R.C., Zahm, S.H., Chang, J.C., Blair, A.: Occupational risk of colon cancer: An analysis by anatomic subsite. Am. J. Epidemiol. 130:675, 1989 Moorehead, R.J., McKelvey, S.T.D.: Cholecystectomy and colorectal cancer: Review. Br. J. Surg. 76:250, 1989 Richter, R.M., Ginsberg, S.A.: Late development of colonic carcinoma complicating ureterosigmoidostomy. Am. J. Surg. 113:843, 1967 Metzger, P.P.: Adenocarcinoma developing in a rectosigmoid conduit used for urinary diversion: Report of a case. Dis. Colon Rectum 32:247, 1989 Urdaneta, L.F., Duffell, D., Crevy, C.D., Aust, J.B.: Late development of primary carcinoma of the colon following ureterosigmoidostomy. Ann. Surg. 164:503, 1966
World Journal of Surgery 9 1991 by the Soci~t~ lnternationale de Chirurgie
Epidemiology of Large Bowel Cancer K e n n e t h E. Levin, M.D., and R o g e r R. Dozois, M.D. Section of Colon and Rectal Surgery, Department of Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A. Results from epidemiologic studies have prodded insights into the etiology of large bowel cancer. Markedly diverse incidences of colorectal cancer exist in various parts of the world and within different regions of a given country. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk. Sedentary lifestyle, cholecystectomy, and ureterosigmoidostomy may also increase the risk of developing large bowel cancer.
Carcinoma of the large bowel is the second leading cause of death from cancer in the United States today. The American Cancer Society predicts 155,000 new cases of colon and rectal cancer and over 60,000 deaths from this cancer in 1990 [1]. The high incidence and mortality rates have made the epidemiology of large bowel cancer a major area of investigation. The aims of this article are to describe the incidence and patterns of large bowel cancer, to identify high risk groups for developing this cancer, and to discuss some of the potential etiologic factors. Incidence of Large Bowel Cancer
Major leads to the etiology of colon and rectal cancer come from observing its distribution in various countries, its possible changing incidence within a given time period, and its differences in incidence between sexes and socioeconomic groups, as well as within a given population itself. For colorectal cancer, available data clearly show major differences in incidence and mortality rates among countries of similar industrial development [2]. The highest incidence rates are found mainly in Western Europe, North America, Australia, and New Zealand; intermediate rates are found in Eastern Europe; the lowest incidence is noted in Africa, Asia, and South America. As a rule, the more industrialized a country, the higher the risk of colorectal cancer. The two notable exceptions are Japan and Finland [2]. In the United States, the present incidence and mortality rates for colorectal cancer are second only to those for lung cancer. In 1989 an estimated 155,000 new cases were diagnosed, 70% in the colon and 30% in the rectum, and an
Reprint requests: Roger R. Dozois, M.D., Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota, 55905, U.S.A.
estimated 61,000 deaths occurred [3]. Colorectal cancer constitutes about 15% of all newly diagnosed cancers (excluding in situ carcinomas and non-melanotic skin cancers) and 13% of all cancer deaths [3, 4]. At present, the probability of a white male in the United States developing colorectal cancer during his lifetime is 6.3%, and his probability of dying from it is 2.9% [5]. The probability of a white female developing colorectal cancer during her lifetime is 6.8%, and her probability of dying from it is 3.1% [5]. Although the incidence of gastric cancer has fallen dramatically and the incidence of pancreatic cancer has leveled off over the past 25 years, the incidence of colorectal cancer is increasing. From 1973 through 1986, the annual incidence rate for colorectal cancer per 100,000 U.S. population increased 9.4% [6]. Statistically significant increases occurred for all races combined, for whites and blacks, and for males and females. In 1986, the incidence rates for blacks and whites were similar (50.7 per 100,000 vs. 50.3 per 100,000, respectively), while the rate for males was higher than for females (61.1 per 100,000 vs. 42.8 per 100,000, respectively) [6]. The time trends in the average annual rates of increase in colorectal cancer mortality show a pattern worldwide. In countries where rates were initially low (South and Central America, Asia, and Central and Eastern Europe), generally large rates of increase have been reported [7]. In countries where the rate was initially at an intermediate level (Canada, United States, Switzerland, Australia, New Zealand, Ireland, the Netherlands, Belgium, France, Sweden, Denmark, and Austria), small increases of less than 1% increase per year or stabilization of the rate have been observed. In countries where mortality rates from colorectal cancer were initially high (England, Wales, Australia, and Scotland), stabilization or decreases have taken place [7].
Migrant Population Studies The incidence and mortality rates for large bowel cancer vary greatly around the world, indicating the importance of environmental factors. Although some of the international variation of colorectal cancer may have a genetic basis, evidence supporting a major role for environmental and lifestyle factors can be found in studies of migrant populations [4]. In general, as groups of people move to a new land, their risk of various cancers shifts
K.E. Levin and R.R. Dozo|s: Epidemioiogy of Colorectai Cancer
away from the pattern prevailing in the country of origin toward that of the host country. Among Japanese in Japan, colorectal cancer, in contrast to gastric cancer, has a very low incidence (about 3 per 100,000 [8]. In Japan, fat intake is low and, although it is rising, it is little more than half of that in Western populations. Dietary fiber intake, once high, is now decreasing. The colon cancer rate is slowly rising. Japanese immigrants to Hawaii and California, however, soon experience considerable increases in colorectal cancer incidence. Indeed, in both these regions first-generation immigrants attain about double the frequency of sigmoid colon and rectal cancer compared With the rates of their white neighbors [8, 9]. At the same time, the risk of stomach cancer decreases in the migrants [10]. Migration of blacks from Africa to the United States has led to a dramatic increase in the incidence of colorectal cancers. According tO Petrakis [11], 75% of American blacks are said to be derived from West Africa, with 40% coming from the region of present-day Nigeria. From 1969 tO 1971, the incidence of colon cancer among U.S. black males far exceeded that among Nigerian black males (11.6 per 100,000 vs. 0.8 per 100,000, resPectively) [12]. Similarly, the U.S. incidence of rectal cancer in black males (6.6 per 100,000) was higher than in Nigeria (0.6 per 100,000). A similar comparison of incidence rates was also present between U.S. black females and Nigerian black females [12]. Colorectal cancer incidence rates among Chinese Americans are 4 to 7 times greater than rates among the general population in the People's Republic of China [13]. The disparity is more pronounced for men than for women, and it increases with age. Rate s among Chinese American men are comparable to those among white American men [13]. In contrast, Chinese American women have rates intermediate between those of white American women and those of women in China [13]. Several conclusions can be made from studies of colorectal cancer in migrating populations [4]. The risk of colon and rectal cancer can change in the migrating population and can closely approach that of the country of destination. The risk of colorectal cancer Seems to change more rapidly in the migrating generation than does the risk of other major cancers. The risk of colorectal cancer c a n be radically altered in the migratory generation, but it need not be. The mortality from colorectal cancer seems to rise more quickly among immigrant men than women. Urban-Rural Gradient and Socioeconomic Status A difference in incidence of cancer has been observed when comparing an urban population to a rural population [t4]. In countries at high, intermediate, and low risk of colorectal cancer, the rates are consistently higher among urban residents [15]. United States mortality data for 1949 to 1951 showed that an excess risk of colorectal cancer in metropolitan versus non-metropolitan counties existed in all regions of the country [16]. The current residence in an urban or rural area was a stronger determinant of risk of colorectal cancer than was the place of birth. However, by 1970, incidence data for Iowa and Colorado indicated that an excess risk in urban areas occurred only for colon cancer among males, with no gradient apparent for female colon cancer or rectal cancer in either sex [17]. Thus,
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urban-rural gradients in incidence and mortality from colorectal cancer appear to have diminished in the U.S. over time [17]. In the United States and other developed countries, socioeconomic status does not Seem to be as Strongly associated with colorectal cancer risk as does urbanization [15]. Only in white males was the risk of colorectal cancer associated with socioeconomic status, and the associations with colon and rectal cancer were in different directions [4]. Significant positive associations with both income and education were apparent for colon cancer in white males; the risks in the highest income and education groups were, respectively, 1.3 and 1.4 times those in the lowest groups. On the other hand, rectal cancer showed a significant inverse association with income in white males, with the highest income category having a risk 0.7 times that o f the lowest.
Race J
There is little difference in colorectal cancer incidence between blacks and whites within each community and region of the United States [12]. The incidence rates for cOlon cancer were similar among males and females for both blacks and whites [6]. The black/white ratio for colon cancers was 0.8 for males and 1.0 for females [12]. While there has been some increase over time in the incidence of colon cancer among whites, there has been a sharp increase among blacks, particularly among black females, On the other hand; for rectal cancer the incidence is lower in both black males and black females. The black/white ratio for rectal cancer was 0.8 in both males and females [12].
Age and Sex Colorectal cancer is primarily a cancer of the older population. From 1982 to 1986, the median age at diagnosis was 71 years for colon cancer and 69 years for rectal cancer [6]. Risk for colorectal cancer increases with age. For example, from 1982 to 1986, the incidence rate for persons 30 to 34 years old was 2.9 per 100,000, compared with 531.6 per i00,000 for persons age 85 or older [6]. The overall sex ratio for colon cancer in most sOcieties is near unity, in contrast with cancer of the rectum, which is predominantly a male disease, especially in the older ages [2, 18]. However, there is a tendency under the age of 50 for the ratio of colon cancer to be slightly higher in women and in the older age groups to be somewhat higher in men [2]. In men, colorectal cancer ranks third behind lung and prostate cancer in the number of new male cancer cases in the United States [3]. Colorectal cancer in males ranks second behind lung cancer for deaths by cancer, accounting for 11% of cancer deaths [3]. In women, colorectal cancer ranks second behind breast canCer in new cancer cases in the United States, and it ranks third behind lung and breast cancer in percentage of cancer deaths (13%) [3]. In the past 25 years, there has been a noticeable decrease in the age-adjusted death rate for women (22%), whereas no such decrease has been noted for men [3, 14].
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Religion Differences exist in the colorectal cancer incidence rates among certain religious groups in the United States. Colorectal cancer is more common in the Jewish population and less common among Seventh-Day Adventists and Mormons [2, 4, 14]. The studies which revealed a higher incidence rate in Jews were completed 20 years or more ago; thus, further studies would be useful to determine if such differences persist. The Adventists abstain from tobacco and alcohol and tend to avoid caffeine, highly refined foods, and sweets; approximately half are lacto-ovo-vegetarians [4]. The Mormon religion prohibits use of tobacco, alcohol, tea, and coffee, and it stresses a balanced diet including grains, vegetables, and fruits; meats are eaten in moderation. They do not, however, consume a diet especially low in total fat. Although the reason for the reduced risk of colorectal cancer in Adventists and Mormons is not clear, these lifestyle traits may be causally related to their 30--40% reduction in incidence of colorectal cancer.
Anatomic Distribution A marked change in the anatomic distribution of colorectal cancers has occurred in the past 40 years. During this period, clinicians have noted an increased incidence of right-sided colonic cancer and a decrease in rectal cancer [19]. It had previously been thought that 75% of colorectal cancers were within reach of the rigid proctosigmoidoscope; more recent data suggest that the figure is closer to 60% [14]. In a study of almost 6,000 resected large bowel specimens removed over a 40 year period [20], the incidence of right colon cancer increased from 7% to 22%. At the same time, the incidence of rectosigmoid, sigmoid, and rectal cancer fell from 80% to 62%. A trend to smaller tumors was also evident with less frequent lymph node involvement of the distal lesions, possibly reflecting an improvement in early detection [20]. High-risk Groups for Large Bowel Cancer A significant proportion of persons developing colorectal cancer come from well recognized high-risk groups. Colorectal cancer is an inherited disease in about 5% of cases. These patients are part of the familial polyposis syndromes and the hereditary nonpolyposis colon cancer (Lynch) syndromes [21]. Persons with inflammatory bowel disease, chronic ulcerative colitis in particular, are also at significantly higher risk for developing colorectal cancer than is the general population. In addition, persons with certain extracolonic carcinomas may also be at increased risk of developing colorectal cancer.
Hereditary Nonpolyposis Colon Cancer Hereditary nonpolyposis colon cancer is defined as a syndrome characterized by the inheritance of colon cancer in an autosoreal dominant pattern [21, 22]. The other cardinal features are: early age of colon cancer onset (mean age of 46 years), proximal colon cancer involvement' with relative rectal sparing (70% located proximal to the splenic flexure of the colon), increased incidence of synchronous (18%) and metachronous (40% by 10 years) colon cancer compared to a 4% incidence of each in
World J. Surg. Vol. 15, No. 5, Sept./Oct. 1991 patients with no hereditary colon cancer, and the presence of a specific extracolonic cancer in some families [22, 23]. Though most of the extracolonic cancers in Lynch Syndrome II (colorectal and extracolonic cancers) are endometrial, others also described are ovarian, gastric, renal, urinary bladder, pancreatic, and breast cancers, Lynch and coworkers [22, 23] have predicted that 5 to 6% of all cases of colorectal cancer fulfill the criteria for hereditary nonpolyposis colon cancer. Mecklin [24] determined in a Finnish study that 4 to 6% of the colorectal cancer patients fell into the hereditary nonpolyposis colorectal cancer syndrome.
Familial Adenomatous Polyposis Familial adenomatous polyposis is an autosomaUy dominant inherited disease occurring in 1 of every 7,000 to 10,000 births. The colon is involved with innumerable adenomatous polyps. Despite the well recognized pattern of inheritance, approximately 20% of patients have no such history [25]. The condition does not seem to skip generations, as was once thought [26]. Therefore, children of an affected patient have a 50% chance of inheriting the defect and thus the adenomas and other extracolonic manifestations. Familial adenomatous polyposis, Gardner's syndrome, and Turcot's syndrome are now all thought to be variations of the same basic genetic defect with varying degrees of genetic expression, as opposed to distinct entities, as had been suggested in the past, The adenomas occur early in life, and it is often possible to see them in children before 10 years of age. The general distribution of polyps in the large bowel is uniform, although there seems to be a slight preponderance of left-sided lesions [26]. Cancers that develop may be multifocal, but again, there is a more common distribution on the left side, presumably associated with the slight increase in the number of adenomas in the left colon and rectum. The progression to cancer is inevitable, and 75% of familial adenomatous polyposis patients develop colorectal cancer by the age of 35 years; almost all die of cancer in their forties unless surgical intervention is performed. Carcinomas occurring in familial adenomatous poiyposis represent about 1% of all colorectal cancer cases [23, 24].
Inflammatory Bowel Disease It is well recognized that patients with chronic ulcerative colitis are at higher risk for the development of colon and rectal cancers, Carcinoma of the colon or rectum begins to appear 5 to 8 years after the onset of ulcerative colitis. By 10 years after disease onset, approximately 5% of patients have developed colorectal cancer, with the cumulative incidence of colorectal cancer increasing progressively with time of disease, reaching 25 to 30% at 25 years [27]. Incidence rates for colorectal cancer in chronic ulcerative colitis are not uniform worldwide, with lower rates reported in Scandinavia and Europe [28, 29]. Extent of colitis appears to also be a factor in the development of colorectal cancer. The cumulative risk of colorectal cancer was significantly higher in patients with pancoiitis than with left-sided disease [30]. The distribution of cancers in patients with ulcerative colitis is more uniform, that is, with a higher proportion of right-sided and transverse colon cancers,
K.E. Levin and R.R. Dozois: Epidemiology of Colorectal Cancer
than in patients with colorectal cancers without ulcerative colitis [27]. The incidence of colorectal cancer is equal in both sexes, reflecting the fact that ulcerative colitis affects both sexes in approximately an equal ratio. However, the colorectal cancers in ulcerative colitis patients tend to be infiltrative and scirrhous, and their fiat nature often goes unrecognized even by careful endoscopic examination. Additionally, a large proportion of the lesions are highly aggressive and poorly differentiated at time of diagnosis. The incidence of colorectal cancer associated with colonic Crohn's disease is much lower than that associated with chronic ulcerative colitis. Actuarial methods suggest that the risk of colorectal cancer complicating long-standing Crohn's colitis is, however, 4 to 20 times the incidence found in the general population [31]. Segments of intestine excluded from the fecal stream, such as an isolated rectal stump or bypassed ileum, are especially vulnerable, perhaps because of bacterial proliferation due to stasis.
Extracolonic Carcinoma A correlation between breast and colorectal cancer is suggested by the occurrence of parallel geographic variations in the incidence of both tumors. The increased risk for colorectal cancer demonstrated in women with breast cancer is supported by the findings in one study of an increased prevalence of adenomatous polyps in the colon and rectum in patients with breast cancer [32]. Another study found that patients with breast cancer have the same risk for developing a colorectal cancer as that for a second primary in the opposite breast [33]. Potential Etiologic Factors
Descriptive epidemiology has played a vital role in formulating hypotheses regarding the causes of large bowel cancer. The worldwide variation in incidence, the changing rates among migrant groups, and the rates among religious groups such as Seventh-Day Adventists and Mormons point to environmental factors being of crucial importance in the etiology of these cancers. Evidence from these studies and substantive support from animal experiments indicate that dietary factors are likely to be responsible for the majority of colorectal cancers. Bacteria are also thought to play a role in the causation of colorectal cancer by their action on ingested fat or metabolites. Occupation and level of physical activity is also believed to influence the incidence of colorectal tumors. Cholecystectomy and ureterosigmoidostomy are also important factors in the incidence of these tumors.
Diet Diet is the epidemiologic area that has received the most attention during the past 20 years, especially since Burkitt's original observations in 1971 [34] and further work by Nigro and others [35]. Burkitt felt that it was reasonable to assume that the conditions prevailing within the lumen of the bowel are the factors most responsible for the environment of bowel mucosa. As has been emphasized, there is a close relationship between large bowel cancer and economic development, and the influ-
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ential factors are probably alterations in dietary patterns [18, 34, 35]. Burkitt observed that the proportions of unabsorbable fiber and refined carbohydrate in ingested food were the most notable differences between the diet of the Western world, where colorectal cancer is most prevalent, and that of less developed communities, where it has its lowest incidence. He felt that the adoption of a refined carbohydrate diet is the most important, though not the only, dietary factor in the causation of colorectal cancers [34]. Presently, the two major dietary risk factors for colorectal cancer are diets high in fat and low in fiber, but the mechanisms appear complex and difficult to unravel [4, 35-39]. Bile acids and neutral sterols are important endogenous compounds related to dietary fat secreted into the gut. The intake of high dietary fat, animal fat in particular, and cholesterol not only changes the composition of bile acids and neutral sterols in the large bowel, but also modifies the large bowel bacteria quantitatively, which in turn may transform these compounds into carcinogenic secondary bile acids and cholesterol metabolites [37, 39]. The evidence for bile acids as colon tumor promoters has been obtained from animal experiments [38, 39]. Overall, the current theory of dietary influence on colorectal cancer incidence is that qualitative and quantitative differences in luminal compounds such as bile acids and cholesterol metabolites play an enhancing role in colon carcinogenesis. These compounds are primarily derived from dietary factors and subsequently modified by the gut bacteria, chiefly in the large bowel. Increased intake of dietary fiber is associated with a decreased risk of colorectal cancer, probably due to several reasons: fiber can decrease transit time, thereby decreasing the contact time between tumor promoters and carcinogens and the colonic mucosa; fiber can influence the composition and metabolic activity of gut bacteria that play a role in the production of colon cancer initiators and promoters; or fiber can affect the absorption and excretion of these carcinogens and promoters in the colon. A number of additional dietary factors have been suspected of playing a role in cancers of the large bowel. Decreased risk may be associated with intake of cruciferous vegetables, vitamin A and vitamin C, and beta-carotene. Increased risk may be associated with intake of protein, alcohol, and cigarette smoking [38, 40]. However, the evidence for most of these factors is largely anecdotal and it is not possible to distinguish associations of etiologic significance from those that are merely coincidental.
Occupational and Physical Activity Recently, studies have shown an increased risk of colon cancer among people in occupations with low physical activity. In a Swedish 14 year follow-up study of 16,477 subjects, the relative risk of colon cancer in subjects with low physical activity was estimated at 3.6 (1,3-9.8, 95% confidence interval) [41]. The association was observed for men and women, but the relative risk for rectal cancer was not elevated. This finding was also noted in a study from Utah which found that intense physical activity was protective against the development of colon cancer in both men and women and that physical activity modifies colon cancer risk associated with diet [42]. Brownson and coworkers [43] similarly noted that an excess risk of colon
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cancer was present in those employed in sedentary jobs, and an inverse linear trend in risk was shown according to the level of occupational physical activity.
World J. Surg. Vol. 15, No. 5, Sept./Oct. 1991
chol6cystectomie et l'ur6t6rosigmoidostomie sont aussi de possibles facteurs favorisants. Resumen
Risk Following Cholecystectomy Following cholecystectomy, the concentration of secondary bile acids in the bile increases, and secondary bile acids have been theorized in the pathogenesis of large bowel cancer. Numerous studies have investigated the hypothesis that the risk of colorectal Cancer is increased following cholecystectomy. Despite the large number of studies, the precise relationship between cholecystectomy and the development of colorectal cancer remains controversial and data are conflicting [44]. Many of the studies have serious limitations in design, size, and make-up of subject groups and controls, and the majority are retrospective in nature. The ultimate answer to this question will only be resolved by careful planning and follow-up of prospective studies.
Risk Following Ureterosigmoidostomy Carcinoma of the colon developing at or about the site of ureterosigm0id0stomy anastomosis is a well recognized delayed complication of urinary diversion [45, 46]. The chances of a carcinoma, usually adenocarcinoma, developing in patients who have a ureterosigmoidostomy have been estimated to be 100 to 550 times greater than that of the general population [47]. These carcinomas develop many years following urinary diversion and tend to do so over the region of ureteral implantation. Urinary carcinogens are felt to be involved in the neoplastic change, and if fecal material is present it can play a promoting role in this carcinogenic process. Because of the increased risk of late development of adenocarcinoma following ureterosigmoidostomy, routine long-term followSup surveillance is mandatory in these patients. Summary
Results from epidemiological investigations have provided clues to etiological factors involved in the development of large bowel cancer. At present, uncertainties as to the identity and significance of genetic and environmental risk factors complicate the goal of seeking to prevent the disease or identify those at particular risk. However, certain risk factors have been dearly identified, and there is promise that future studies will further clarify the interactive aspects of the many factors involved. R6sum6
Un apergu des facteurs 6tiologiques dans le d6veloppement du cancer colorectal a 6t6 d6gag6 grace ~ une 6tude 6pid6mio|ogique. L'incidence du cancer colorectal varie beaucoup dans le monde et au sein d'un m6me pays suivant les r6gions. L'6tude des populations migrantes a d6montr6 le r61e de l'environnement, et en particulier de l'alimentation, dans la g6n~se des cancers colorectaux. Des facteurs g6n6tiques et l'existence d'une maladie inflammatoire de l'intestin ont 6galement ~t6 incrimin6s chez certains individus. La s6dentarit6, la
Los resultados de estudios epidemiol6gicos han provisto nuevos conocimientos sobre los factores etiol6gicos involucrados en el desarrollo del c~incer de colon. Marcadas variaciones en la incidencia de c~incer colorrectal se observan en diversas partes del mundo y entre diferentes regiones dentro de un mismo pals. Estudios sobre poblaciones migrantes han revelado el rol de factores ambientales, en particular los de car~icter dietario, en la etiologia de estos c~lnceres. Factores gen6ticos y la enfermedad inflamatoria del colon tambi6n colocan a ciertos individuos en condici6n de riesgo aumentado. L a vida sedentaria, la colecistectomia y la ureterosigmoidostomia peuden tambi6n incrementar el riesgo de desarrollar c~incer del colon. References
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