Colon Cancer An Epidemio|ogical Survey EDWARD KASSIRA, MD, PhD, LINDA PARENT, BS, and GEORGE VAHOUNY, PhD
Cancer of the colon is currently a leading cause of cancer-related death in the United States. Statistics indicate that mortality from cancer of the colon in males is second only to lung cancer; a similar situation exists among females for whom colonic cancer ranks second after cancer of the breast (Figure 1). Carcinoma of the colon has been characterized by alterations in bowel habits, rectal bleeding, loss of weight and diffuse abdominal pain. These tumors which develop slowly are nevertheless persistent, resulting in the functional derangement of the large intestine. The assumption that the etiology of cancer is multifactorial has been the rationale for application of a wide variety of research techniques. Epidemiological studies have been particularly useful since they emphasize the compilation and integration of a great deal of diverse data, facilitate the formulation of hypotheses based upon discernible trends and patterns, and hopefully contribute to more direct biochemical and clinical experimentation. Many epidemiologists are at present engaged in the study of colonic cancer distribution data in an attempt to determine what factors integral to man's internal and external environment may contribute to site-specific carcinogenesis. Observation of disparate incidence and/or mortality rates for colonic cancer among geographically distinct populations has led a number of researchers to postulate environmental, and therefore exogenous, factors as the primary etiological determinants (4, 5, 11, 27, 30, 33-35). A possible causational role has persistently been assigned to dietary patterns which fluctuate From the Department o f Epidemiology and Environmental Health and Department of Biochemistry The George Washington University Medical Center Washington, D.C. Address for reprint requests: Dr. G.V. Vahouny, Professor of Biochemistry, The George Washington University Medical Center, Ross Hall, 2300 I Street N.W. Washington, D.C. 20037.
Digestive Diseases, Vol. 21, No. 3 (March 1976)
profoundly according to geographic location and standard of living. In the following report, an attempt has been made to compile available data in order to better assess the potential role of nutritional components in the primary etiology of colon-rectum cancer. SECULAR TRENDS A number of researchers contend that the frequency of colon-rectum cancer is greater among contemporary (as differentiated from historical) populations (4, 33, 34). This is difficult to substantiate since most cancer registries (with the exception of the state of Connecticut and the country of Norway) have not been functioning long enough to determine the incidence and mortality due to colonic cancer over historically significant periods of time. Data published by the American Cancer Society, however, have provided a useful basis for determining more recent chronological trends in incidence and mortality from various types of cancer. Gross statistics indicate that cancer of the colon has risen since the early decades of the twentieth century. Careful scrutiny of the available data, however, reveals an equivocal and variable situation with mortality rates due to colon cancer increasing within certain segments of the population while decreasing or remaining unchanged among others. MacDonald (16) has taken these same data and computed yearly percent changes in mortality rates from colon cancer during the 20-year period 19401959. To facilitate regional comparisons, all states in the continental United States have been grouped according to geographic locale (Table 1). The highest yearly regional increase occurred in the south Atlantic states (5.4%) followed by the east south central states (4.3%). However, a number of regions reported downward trends in mortality rates for colonic cancer. For example, mortality rates for 205
KASSIRA ET AL Cancer Deaths by Site and Sex
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Fig 1. D i s t r i b u t i o n of c a n c e r i n c i d e n c e and d e a t h s . T a k e n f r o m C a ( A m e r i c a n C a n c e r S o c i e t y Publication) 24 (1): 8, 1974.
the New England states fell (on the average) 4.8% per year. This may be due to better diagnosis and quality of care. Individual states within each specific regional unit reflected the same mortality trends (ie, overall increase or decrease) as were noted for the entire region. In other words, there was an apparent intraregional consistency. Although a general increase in colonic cancer mortality rates in the United States from 1930-1960 can be statistically varified, geographical differences should not be ignored. Worldwide cancer mortality data compiled and published by Tohoku University of Medicine (23) indicate that colonic cancer mortality rates for the United States rose from 11.9 per 100,000 in 1960-61 to 12.6 per 100,000 in 1966-67. Further corroboration of the upward trend in colonic cancer mortality rates is found in the WHO Statistical Annex (32) which reports a U.S. mortality rate of 17.5 per 100,000 in 1970. A regional analysis of recent mortality and incidence rates is strongly suggested. GEOGRAPHIC DISTRIBUTION
Data contained in the 1973 United Nations Statistical Annex (32) denote definite differences in the distribution of colonic cancer on a worldwide basis, as shown in Figure 2. Very high colonic cancer mortality rates (13.0-25.0 per 100,000) are characteristic of European, North American, and Australian populations; moderate rates (5.0-12.0 per 100,000) are found in eastern Europe, Israel, and the Iberian peninsula, while very low rates (0.2-4.0 per 100,000) are reported for a number of Asian, Central American, and South American countries.
206
Differences in geographic distribution of colonic cancer are strongly supported by data generated from cancer research studies in Africa. Although standardized cancer incidence and mortality rates are not available for most of continental Africa, various small-scale studies overwhelmingly suggest the absence of colonic cancer among indigenous Africans (2, 3, 8, 9, 18, 20, 26). Furthermore the incidence of colonic cancer relative to all other to all other forms of cancer experienced by African populations is extremely low and can be regarded as the worldwide minimum incidence of this specific cancer (25). SEX DIFFERENCES
A gross comparison of sex-specific mortality rates throughout the world reveals a small yet fairly consistent female predisposition (Figure 3). However when male/female rates are adjusted for age a different picture emerges. Wynder and Shigamatsu (33) report that sex rates computed for successive age groups reveal what is known as a "bimodal" distribution. Bimodality (the occurrence of two separate peaks in age-specific incidence or mortality data) suggests that causal differences (eg, two distinct sets of ancillary experiences) may be operating. For example, data drawn from the Connecticut Cancer Registry indicate that males younger than age 30 are at greater risk of developing colon cancer than are females of the same age. After 30, the trend shifts markedly, with a predominant female risk from age 30-60. After age 60, the male/female difference is no longer apparent (33). When certain attenuating factors such as overall Digestive Diseases, Vol. 21, No. 3 (March 1976)
COLON CANCER 1. Endemic Phase (low overall risk). This is characterized by low male/female risk ratios (ie, a higher incidence among females) and by a preponderance of tumors localized in the cecum and ascending colon. The maximum incidence of the disease appears to peak at age 50-55.
TABLE 1. AVERAGE YEARLY (1940--1959) PERCENTAGE CHANGES IN MORTALITY FROM COLONIC CANCER (16)
Geographic area
Percentage change~year
Pacific Rock y mountains West north central East north central Middle Atlantic N e w England West south central East south central South Atlantic
+ + + +
0.9 5.0 0.4 1.0 1.3 4.8 3.6 4.3 5.4
2. Transitional Phase (intermediate risk). This is characterized by a rise in sigmoid cancers among males in all age groups over 55, followed (somewhat later) by a rise in sigmoid cancers among females but at consistently older ages than is observed in males. 3. Epidemic Phase (high-risk population). This is characterized by male/female risk ratios which approach unity; this pattern can be attributed to the concomittant rise in the incidence of cecum and ascending colon cancer among males (12). To account for the apparent epidemic properties of colon cancer, Haenszel and Correa (12) postulate that in intermediate and high-risk populations exposure to an etiologic factor may become progressively more intense and/or prolonged and that males may respond with greater "volatility" to such exposure.
level of risk in a given population and the anatomical location of the tumor are considered, the sex-related risk profile becomes more complex. Haenszel and Correa (12) have plotted separate age-sex incidence curves for countries, have divided these into high-, intermediate-, and low-risk categories, and argue that the interrelationship of these factors may be a key element in the epidemiology of colon cancer. The thrust of their argument can be summarized as follows:
25
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Digestive Diseases, Vol. 21, No. 3 (March 1976)
207
KASSIRA ET AL
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These observations might prove useful in evaluating some of the biochemical hypotheses which are currently being advanced. In any event it is clear that future colon cancer research should emphasize both age-sex differentials and precise tumor location. GENETIC FACTORS The unequal distribution of colonic cancer mortality rates among geographically distinct populations suggests that racially determined (ie, genetic) factors may be etiologically operative. However, numerous studies (12, 24, 25, 34) indicate that immigrant populations rapidly assume tlae colonic cancer risk profile characteristic of their adopted locale. For example, statistics indicate that second-generation Japanese living in California and Hawaii exhibit colonic cancer rates (clearly in excess of their country of origin) which equal those of the wider (Caucasian) population (24, 33, 34). Similarly, Chinese immigrating from Singapore to Hawaii show increases in colonic cancer incidence over Chinese in Singapore by as much as 14-fold (25).
208
Black Americans, traditionally far less prone to cancer of the colon than the Caucasian population, are now reported to have incidence rates comparable to standard U.S. levels (23). In 1967 the mortality rate for black American males was 11.3 per 100,000 while the corresponding rate for white American males was 13,7 per 100,000 (24). Furthermore, presem colonic cancer mortality rates reported for black Americans are significantly higher than rates computed for African blacks who, as previously mentioned, demonstrate a lesser predisposition to colonic cancer than any other racially distinguishable group. Similar changes in colonic mortality rates have been documented for a number of ethnic groups immigrating to the United States from European countries of moderate to low colonic cancer incidence. For example, second-generation Po!ish and Norwegian Americans reveal colonic cancer mortality rates which approximate standard American rates (12). Therefore, acculturation and/or duration of residence in the U.S, can be correlated with a rise in susceptibility to colonic cancer. Digestive Diseases, Vol. 21, No. 3 (March 1976)
COLON CANCER SOCIOECONOMIC STATUS Since a worldwide comparison of colonic cancer mortality rates reveals distinct differences between Western and non-Western societies and s~nce one of the obvious differences between these societies is standard of living, a connection between predisposition to colonic cancer and socioeconomic status is suggested. A comparison of per capita gross national product (a fairly reliable indicator of relative standards of living) and mortality rates for cancer of the colon among Western and non-Western countries indicates that, on the whole, countries characterized by a high standard of living report "moderatelyhigh" or "high" mortality rates from colon cancer while those countries regarded as economically "underdeveloped" display " l o w " to "extremely low" rates. However, there are a number of significant exceptions which discourage facile conclusions, For example, Japan and Venezuela (with low mortality rates of 3.9 per 100,000 and 1.9 per 100,000, respectively) have relatively high per capita GNPs ($2,i30 and $1,060 per year). An examination of data presented in Table 2 reveals a similar (yet reversed) situation for Malta and Portugal and, to a lesser degree, Ireland. Additional studies regarding standard of living (that is, factors contributing to, or resulting from, economic prosperity, or lack thereof) and predisposition to colonic cancer is clearly indicated. DIET AND NUTRITION
One essential difference between Western and non-Western societies is reflected in dietary habits. A gross statistical comparison of gram per day consumption of the major nutritional components reveals widely dissimilar patterns. Western diets are characterized by high intakes of animal fats and protein, processed sugar, and refined carbohydrates with a low fiber content. Non-Western societies consume much less meat or meat products, relying on vegetables for the bulk of their protein; their diets also contain relatively large amounts of unrefined cereals as well as other foods with high fiber Content such as legumes and tubers. The data in Figures 4 and 5 emphasize the significant differences in food consumption among populations exhibiting varying predispositions to colonic cancer. Various assumptions concerning the etiology of colonic cancer can be made on the basis of epidemiologir evidence presented thus far. The first is Digestive Diseases, VoL 21, No. 3 (March 1976)
TABLE 2. A COMPARISONOF GROSSNATIONALPRODUCTAND MORTALITYFROMCOLON CANCER
Countries
United Kingdom Ireland Austria Denmark Germany France Sweden New Zealand U.S.A. Canada Australia Switzerland Norway Hungary Italy Portugal Czechoslovakia Spain Malta Israel Finland Greece Poland Barbados Japan Romania Singapore Yugoslavia Mauritius Venezuela Panama Mexico Costa Rica Thailand Egypt E1 Salvador Honduras
1971 1970 colonic cancer per capita GNP* mortality rate/lO0,O00
$2,430 1,510 2,200 3,430 3,210 3,360 4,240 2,470 5,160 4,140 2,870 2,640 3,130 1,200 1,860 730 2,120 1,100 694 2,190 2,550 1,250 1,350 670 2,130 740 1,200 730 280 1,060 820 700 590 210 220 320 300
22.7 21.9 21.6 20.7 19.9 18.9 18.8 17.9 17.5 16.9 16.1 15.3 15.1 13,2 13.1 10.1 9.9 8.8 8.3 8.2 7.5 6.9 4.8 3.9 3.9 3.8 3.5 3.4 2.0 1.9 1.3 1.2 1.1 0.7 0.6 0.3 0.2
* GNP figures are based on World Bank Atlas, 1974; Cancer mortality rates derived from WHO Statistical Annexes 1973.
that colonic cancer is mediated by environmental factors. The consistent upward trend in colonic cancer mortality rates displayed in various ethnic or racially distinguished populations moving from areas of low colonic cancer endemicity to areas of high epidemicity argues against heredity aS a major predisposing influence, and suggests that Some aspect of the environment has a primary influence on the etiology of colonic cancer. Such evidence is further corroborated by data which indicate regional variations in colonic cancer mortality rates within the United States. Significant fluctuations in these rates among regionally defined populations indicate
209
K A S S I R A ET A L Countries with less than 3.5/100,000 m o r t a l i t y rate f o r colonic cancer
Countries w i t h greater than 16.0/100,000 m o r t a l i t y rate f o r colonic cancer
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210
Digestive Diseases, Vol. 21, No. 3 (March 1976)
COLON CANCER that environmental factors (reflecting geographic variances) may contribute to the level of risk noted for a given population. In light of the data presented thus far, this latter possibility deserves serious consideration. The second assumption is that the increased predisposition to colonic cancer may be associated with economically developed or industrialized countries. Any attempt to define the various parameters involved in the etiology of colonic cancer must, therefore, take into account the potentially carcinogenic substances which are present in quantities sufficient to effect widespread predisposition to colonic cancer. Because of the nature and function of the large intestine, exogenous substances commonly inhaled, ingested or absorbed through the skin could exert a profound effect on the colon. Thus, it is possible that air and water pollutants (eg, trace elements, metal ions, etc) common to the industrialized world have a carcinogenic potential in association with the large intestine. Although there is little concrete evidence to support an etiological correlation between colonic cancer and environmental pollutants, further research is needed before these substances can be discarded as possible causational determinants. It has been suggested that various chemicals which are routinely added to processed foods might also be incriminated in carcinogenesis within the large bowel. However, epidemiological data argues against such a theory since Denmark, one of the few Western nations to impose strict control over the use of food additives, nevertheless exhibits a very high mortality rate for cancer of the colon (30). Such data lends encouragement to those who would look elsewhere in the environment for etiologic determinants. A third assumption is that some aspect(s) of Western society (eg, habits, customs, stress, etc) contributes directly or indirectly to the high risk of colonic cancer. A statistical association between cancer of the colon and Western society has encouraged etiologic hypotheses based upon the degree of development or industrialization. However, colonic cancer mortality data gathered for certain countries reveal statistical anomalies which must be critically examined. Japan, as previously noted, is one of the few exceptions to the colonic cancer risk/industrialized or "developed" economy correlative. Because there is both a low colonic cancer mortality rate and a high standard of living in Japan, the theory might be Digestive Diseases, Vol. 21, No. 3 (March 1976)
advanced that a "Western" standard or style of living as opposed to a mere condition of material abundance or economic development may contain one of a number of causational factors leading to the development of cancer of the colon. Such an assumption gains credibility when data reflecting a slow yet steady rise in colonic cancer mortality rates among indigenous Japanese is considered. (In 1950 the colonic cancer mortality rate per 100,000 was 2.4; by 1968 the rate had increased to 3.9 per 100,000). A movement toward the adoption of Western customs (eg, dietary habits) is evident among the economically advanced sectors of Japanese society. Therefore, alterations in the Japanese social fabric may play a significant role in the increase of colonic cancer incidence. A fourth assumption is an a priori theory of dietary complicity in large-bowel carcinogenesis, readily postulated on the basis of the following evidence: 1. As noted, Western and non-Western societies differ significantly with regard to patterns of food consumption. (Refer to charts.) Also, dietary variances are more marked between Western and nonWestern as opposed to industrialized versus nonindustrialized societies. 2. Western diets have changed dramatically over the last century (4, 5). 3. Within individual Western countries there are dietary variations which might account for regional differences in colonic cancer mortality rates. 4. Immigrants moving from non-Western to Western countries usually adopt the dietary habits of the latter. The rapid increase in incidence of colonic cancer among these people may therefore reflect fundamental changes in food consumption. DISEASES OF WESTERN CIVILIZATION A number of chronic diseases (eg, diverticular disease, gallstones, pulmonary embolism, etc) have been statistically associated with Western societies. Incidence rates are high within the developed countries with correspondingly low rates in those considered underdeveloped. These "diseases of Western civilization" are often discussed in terms of related etiology, the characteristic "Western" diet receiving emphasis as a prime etiologic determinant (4, 5). It has been suggested that cancer of the colon might also be placed in this category since largebowel carcinogenesis can be epidemiologically
211
KASSIRA ET AL linked with specific patterns of food consumption. This pattern has been labeled "malnutrition of the affluent" (35), and refers to the high consumption of processed food, sugar, and cholesterol which are characteristic of Western populations. DIETARY HABIT/COLONIC CANCER RISK HYPOTHESIS
Epidemiological evidence in support of the dietary habits/colonic cancer risk hypothesis is rapidly accumulating. For example, a recent experiment involving Japanese immigrants residing in Hawaii reveals that a high beef intake corresponds well with a higher rate of colonic cancer (34, 35). It has been demonstrated that indigenous Japanese of high socioeconomic position are more prone to colonic cancer than is the wider population. Data indicate that this high-risk group has, to a large degree, "Westernized" its diet, eg, decreased rice consumption and increased fruit and milk intake (4). In South Africa, colonic cancer incidence rates for Caucasians, although lower for members of the same race in the United States, are significantly higher than for the indigenous (or native) population. This fact may be related to the higher socioeconomic level and resultant dietary predilections of the higher-risk population (14). The increase in colonic cancer incidence in black Americans suggests an association between cancer predisposition and a fundamental change in dietary patterns. Historically, black Americans consumed greater amounts of maize and related fibrous substances than they do today (7). Seventh Day Adventists are reported as having relatively lower rates of colonic, pancreatic and breast cancer. This low incidence could be attributed to the low-fat, vegetarian diet dictated by their beliefs (22). Wynder (35) citing data published by I. Martinez in 1962 draws attention to the observation that rates of colonic cancer among Puerto Ricans in the U.S. are significantly higher than rates computed for residents of Puerto Rico. However, dietary changes among the immigrant population may explain this difference. BIOCHEMICAL CONFIRMATION OF DIETARY COMPLICITY IN CANCER
A statistical correlation between dietary habits and colonic cancer incidence will remain artifactual
212
unless bowel cancer can be directly related to food consumption. Such a relationship is strongly implied in the following observations: (1) dietary components are capable of significantly altering the environmental constituents of the large intestine and (2) the gastrointestinal tract is composed of cancerprone epithelial ducts which may be adversely stimulated by the introduction of ingested substances. However, before specific food items can be implicated in the etiology of colonic cancer, it is necessary to determine which dietary compounds contain or excite natural or adventitious carcinogens. A preponderance of researchers currently investigating the association of dietary factors with intestinal carcinogenesis emphasize one or more of the following food items: animal fat, animal protein, cholesterol and dietary fiber. All of these substances have been related in some degree with alterations in intestinal microflora and/or bile salt metabolism. The bacterial content of the gut may be an important factor in colonic cancer development. For example, the amount of bacteria present within the small intestine relative to the large intestine is exceedingly low. Therefore the observed infrequency of cancer of the small intestine may suggest a relationship between intestinal bacteria and carcinogenesis (4). It has been suggested that undigested fat in the intestine might alter the microflora in such a way as to increase its ability to degrade various intestinal constituents resulting, therefore, in the production of carcinogens (17). An examination of fecal samples from individuals residing in countries with very high and very low rates of colonic cancer revealed a higher concentration of steroids in samples obtained from individuals consuming a Western-style diet (13). American and British fecal samples contained higher counts of Bacteroides and other anerobic bacteria than did samples o b t a i n e d from nonWestern subjects. Laboratory investigations indicate that anerobic bacteria metabolize steroids more actively than the aerobesl The biochemical ramifications include (1) a greater dehydroxylation of fecal steroids and (2) an increase in the production of deoxycholic acid. Since conjugates of deoxycholic acid have been shown to exert carcinogenic activity when injected into rats (21), a similar response may occur within the human intestinal tract. Animal protein and vegetable fiber have also been connected with alterations in intestinal microflora and must, therefore, be considered as possible precarcinogenic agents. Lack of dietary fiber has, for a number of reaDigestive Diseases, Vol. 21, No. 3 (March 1976)
COLON
CANCER
sons, also been implicated in the etiology of colonic cancer. Dietary fiber is not a totally inert substance as it is capable of significantly altering the metabolic processes and physiological functions of the intestinal tract. Furthermore, there is sufficient evidence to establish a connection between fiber intake and the digestibility of other dietary components. Laboratory experimentation indicates that the presence of fiber within the large intestine influences fecal volume, bowel motility, and transit time as well as bacterial metabolism (7). It is possible that a malfunction in one of these intestinal processes may encourage colonic carcinogenesis. One of the chief functions of the large intestine is fluid absorption; it has been postulated that some soluble nonabsorbable substance(s) of a precarcinogenic or carcinogenic nature may become highly concentrated as they move from the cecum to the rectum. Such a concentration would be affected by intestinal bulk and transit time (12). It has been hypothesized by several investigators (4, 5, 12, 14) that if colonic cancer can, in fact, be related to food consumption then the formation of carcinogens is probably dependent on a wide variety of dietary factors. Furthermore, if the intestinal contact time of fecal material is increased (due to dietary deficiencies or intestinal disorders) greater interaction between the carcinogen and the intestinal mucosa would ensue. Intestinal transit time could, therefore, be a key element in colonic cancer predisposition. Laboratory investigations and clinical studies indicate that the fiber-depleted diets characteristic of Western populations promote relatively slower fecal transit than do diets which contain large amounts or roughage (in the form of coarse grains, nuts, etc) (5). Transit times vary considerably among populations with different dietary habits. Studies indicate that African villagers consuming a high-residue diet have an average intestinal transit time of 35 hr while English volunteers on a low-residue diet demonstrate an average intestinal transit time of 70 hr. Communities on mixed diets, such as Indians, more westernized Africans, and English vegetarians, have stool weights and intestinal transit times intermediate between the two extremes (5, 6, 28-
30). Colonic stasis (often associated with poor fiber intake) can be hypothetically incriminated in the development of colonic cancer when data relating to anatomical distribution of malignant tumors within Digestive Diseases, Vol. 21, No. 3 (March 1976)
this site is considered (4). Tumors (both benign and malignant) are found most often in those areas where fecal retention is most prolonged and bacterial action most prevalent (4, 5). The generally smaller fecal masses generated by fiber-depleted diets could exacerbate a potentially carcinogenic situation (14). As previously mentioned high concentrations of chemical irritants in close association with the epithelial lining of the bowel would suggest increased colonic cancer predisposition. Social inhibitions with regard to bowel evacuation could conceivably contribute to the discrepancies in transit time noted for various populations. In economically developed societies, it is considered "normal" to retain stools for prolonged periods of time if specific facilities are not available. On the contrary, populations in less developed areas of the world demonstrate an ability to evacuate the bowel at will (29, 30). The high incidence of intestinal disorders such as dysentery (amebic and bacillary), diarrhea, and schistosomes and other intestinal parasites among inhabitants of non-Western countries contributes to increased bowel motility and must not be ignored as a possible mitigating factor in colonic cancer development (26). It appears, then, that dietary factors, either directly, indirectly, or both, play an important role in the etiology of colon cancer. Differentiation between primary initiating and secondary aggravating factors has not yet been elucidated.
ACKNOWLEDGMENT
The authors are indebted to Dr. William Dobbins, Gastroenterology Division, Department of Medicine, of The George Washington University Medical Center for his encouragement and for editing this manuscript. REFERENCES 1. American Cancer Society: Cancer Facts and Figures. New York, The Society, 1962 2. Bremner CG, Ackerman LV: Polyps and carcinoma of the large bowel in the South African Bantu. Cancer 26:991-999, 1970 3. Buckley RM: Patterns of cancer at Ishaka Hospital in Uganda. E Afr Med J 44:465--468, 1967 4. Burkitt DP: Epidemiology of cancer of the colon and rectum. Cancer 28:3-13, 1971 5. Burkitt DP, Walker AR, Painter NS: Effect of dietary fiber on stools and transit-times and its role in the causation of disease. Lancet 2:1408-1412, 1972
21 3
KASSIRA ET AL
6. Cleave TL, Campbell GD, Painter NS: Diabetes, Coronary Thrombosis and the Saccharine Disease. Bristol, John Wright and Sons, Ltd., 1969 7. Cummings JH: Progress r e p o t - - D i e t a r y fibre. Gut 14:6981, 1973 8. Denues ART, Munz W: Malignancies at the Hospital of Dr. Albert Schweitzer, Lambarene, Gabon, 1950-65. Int J Cancer 2:406--411, 1967 9. Eshleman JL: A study of the relative incidence of malignant tumours seen at Shirati Hospital in Tanzania. E Afr Med J 43:273-283, 1966 10. Food and Agricultural Organization: Food Balance Sheets, 1964-66 Average, F.A.O. of the U.N., Rome, 1971 11. Gregor O, Toman R, Prusova F: Gastrointestinal cancer and nutrition. Gut 10:1031-1034, 1969 12. Haenszel WM, Correa P: Cancer of the colon and rectum adenomatous polyps: A review of epidemiologic findings. Cancer 28:14-24, 1971 13. Hill MJ, Draser BS, Aries V, et al: Bacteria and etiology of cancer of large bowel. Lancet 1:95-99, 1970 14. Hutt MS, Templeton AC: The geographical pathology of bowel cancer and some related diseases. Proc R Soc Med 64:962-964, 1971 15. Lacassagne A, Buu-Hoi NP, Zajdela F: Carcinogenic activity of apocholic acid. Nature 1970:1007-1008, 1961 16. MacDonald, AB: Epidemiology of gastric cancer. Cancer of the gastrointestinal tract (a collection of papers presented at the Tenth Annual Clinical Conference on Cancer, 1965). Chicago, Year Book Medical Publishers, 244-245, 1967 17. Nigro ND, Bhadrachari N, Chomchai C: A rat model for studying colonic cancer: Effect of cholestryramine on induced tumours. Dis Colon Rectum 16:438-443, 1973 18. Oettle AG: Cancer in Africa, especially in regions south of the Sahara. J Natl Cancer Inst 33:383-389, 1964 19. Painter NS, Burkitt DP: Diverticular disease--a deficiency disease of civilization. Br Med J (in press). 20. Prates MD, Torres FO: A cancer survey in Lourenco Mar-
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21. 22.
23.
24. 25. 26. 27. 28. 29. 30. 31.
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Digestive Diseases, VoI. 2l, No. 3 (March I976)