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NUTRITION AND CANCER An International Journal Vol. 1 Fall 1978 - ' No. 1 EDITORIAL FillingaNeed...,GioB.G-o_ri ........................................ ............... 4 --- .,_ SPECIAL COMMUNICATIONS Diet and Nutrition in Cancer Causation, Gio B. Gori ......................................... . 5 Nutrition and the Cancer Patient, Maurice E. Shils ......................................... 9 Mycotoxins in Food and the Variations in Tumor Incidence in Laboratory Rodents, R. Schoental ...13 REPORTS Fiber-Standardized Sources, Lon Crosby ........................... .................... 15 Inhibition of In Vitro Metabolic Activation of Carcinogens by Wheat Sprout Extracts, Chiu-Nan Lai, Betty J. Dabney, and Charles R. Shaw ..................................... _ 27 . , - --- -= ~~ ~-- - REVIEW - Early Nutrition, Growth, Disease, and Human Longevity, William A. Stini ....................... _ 31 ANNOUNCEMENTS ............. ............. -------- INSTRUCTIONS FOR AUTHORS ........................................................... .43 IIITHE FRANKLIN INSTITUTE PRESSSM TIMN 222758

THE FRANKLIN INSTITUTE PRESSSM VIRAL HEPATITIS Etiology, Epidemiology, Pathogenesis and Prevention G. Vyas, S. Cohen and R. Schmid, Editors A handsome case-bound volume, this book is intended to bring the reader up-to-date with all the very latest developments in the field of viral hepatitis. It carefully details all the proceedings of the worldwide symposium sponsored in March 1978 by the University of California. Every aspect of the gathering is covered including 32 comprehensive reviews, 12 workshop summaries, 25 general discussions and four panel discussions. LC#78-008822, Oct. 1978, 740 pp. Price: $49.50 NEOPLASM IMMUNITY: SOLID TUMOR THERAPY R. Crispen, Editor With this official publication of the proceedings of the 1977 Chicago Symposium, practitioners and re- searchers can now consult 29 papers detailing the latest methods of treating lung, gastrointestinal, breast, head and neck cancer as well as sarcomas. Included are a number of important papers on new therapeutic studies using tumor cell vaccines, viral oncolysates and MER. There are also pieces on staging categories, prognostic factors and natural history of the disease. LC#77-24479, Dec. 1977, 266 pp. Price: $22.50 CANCER THERAPY ABSTRACTS Dr. C. M. Southam, Dr. G. F. Schwartz, Dr. J. J. Saukkonen, Dr. G. P. Studzinski, and Dr. G. F. Zinninger, Editors A monthly journal devoted to the experimental and applied clinical aspects of immunotherapy and chemotherapy (including steroid hormones, or other natural products) plus documents dedicated to the treatment of malignant or premalignant cancer in humans by means of surgical excision and/or radiation. Eleven issues per year with subject and author indexes; yearly cumulative index issue. Monthly. Price per volume: US $75.00; foreign $90.00 CARCINOGENESIS ABSTRACTS Dr. George P. Studzinski, Editor Dr. Jussi J. Saukkonen, Associate Editor Dr. Elizabeth Weisburger and Joan W. Chase, IYCI Staff Consultants A monthly journal dealing with the epidemiology, biometry, pathogenesis and immunology of cancer. In ad- dition, it covers investigations relating to all aspects of chemical, physical and viral carcinogenesis. Each issue contains 600 abstracts and citations of studies reported in world-wide technical journals, reports, monographs and books. Twelve issues per year plus cumulative index. Monthly. Price per volume: US $75.00; foreign $90.00 Please remit to: The Franklin Institute Press Box 2266 Philadelphia, PA 19103 TIMN 222759 -

NUTRITION AND CANCER Dr. Gio B. Gori, Editor EDITORIAL BOARD Dr. Stanley John Dudrick Professor and Chairman Department of Surgery University of Texas Medical School at Houston John Freeman Building, Room 123 6400 West Cullen Street Houston, Texas 77025 Dr. D. Mark Hegsted Professor of Nutrition Department of Nutrition Harvard School of Public Health 665 Huntington Avenue Boston, Massachusetts 02115 Dr. Charles E. Butterworth, Jr. Professor of Medicine and Director of Nutrition Program University of Alabama Birmingham School of Medicine University Station Birmingham, Alabama 35294 Dr. George Beaton Professor and Chairman Department of Nutrition and Food Science Faculty of Medicine University of Toronto Toronto, Canada Dr. Takeshi Hirayama Chief Epidemiology Division National Cancer Center Research Institute Tokyo,Japan Dr. Lionel A. Poirier Head Nutrition and Metabolism Section Division of Cancer Cause and Prevention National Cancer Institute Bethesda, Maryland 20014 Dr. Claude Solassol General Practitioner Villa Thalia Rue Louis Bertrand Montpellier-Herault, France Dr. Ernst L. Wynder President American Health Foundation ~ 1370 Avenue of the Americas New York, New York 10019 An International Journal Dr. Lon Crosby, Assistant Editor Dr. William White, Jr., Publisher ASSOCIATE EDITORS Dr. Adrianne E. Rogers Senior Research Scientist Department of Nutrition and Food Science Massachusetts Institute of Technology Cambridge. Massachusetts 02139 Dr. Roswell K. Boutwell Professor of Oncology McArdle Laboratory for Cancer Research Medical Center University of Wisconsin Madisum, Wiscontiin 53706 Dr. Doris Howes Calloway Professor of Nutrition University of California Berkeley, California 94 720 Dr. Theodore P. Labuza Profcswr of Food Science and 1 cx'hnolop. Department of Food Sc•iena• Universitv of Minnesota St. Paul, \finncsota .55108 Dr. Jean-Pierre Habicht Professor of Epidemioloj,n• Division of Nutritional Scienccs Cornell Universitv Ithaca, Ne«• York 1484() Dr. Norge W. Jerome Associate Professor Department of Human Eaolo*• and Communitv Health University of Kansas College of Health Scienc•es and Hospital Rainbo,w Boulevard at 39th Street Kansas Citt, Kansas 66103 Dr. Kenneth K. Carroll Professor, Department of Biochemistry University of «`estern Ontario London, Ontario, Canada Dr. Isidro Martinez Director Cancer Control Program Department of Health Santurce, Puerto Rico 00908 Dr. Baruch Modan Head Department of Clinical Epidemiolo*• Chaim Sheba Medical Center Tel Hashomer and Tel Aviv University Medical School Tel Hashomer, Israel Dr. Richard G. Buckles Principal Scientist and Director Alza Company 950 Page Mill Road Palo Alto, California 94304 Dr. Johanna Dwyer Director Franc•cs Stern Nutrition Center New England Medical Center Hospital 185 Harrison Avenue Boston, Massachusetts 02111 Dr. O. L. Kline Executive Officer National Nutritional Consortium 9ti.50 Rockville Pike Bethesda, Man•land 20014 Dr. Maurice Shils Director of Nutrition Memorial Hospital 1275 York Avenue : New York, New York 10021 Dr. Jan van Eys Professor of Pediatrics University of Texas System Cancer Center M.D. Anderson Hospital and Tumor Institute 6723 Bertner Avenue Houston, Texas 77030 Dr. Okura Akira Department of Surgery Osaka University 14eciical School Fukushima - KU Usaka,Japan Dr. Harry Shizgal Royaj Victoria Hospital 687 Pine Avenue Montreal, Quebec H3A181 Dr. Edwardo Souchon Aparpado #89690 LEL HATILLO 108 Caracas, Venezuela Nutrition and Cancer, An International iournal Copyright 1978 © by The Franklin Institute Press, 20th and The Parkway, Box 2266, Phila., Pa., 19103. Published quarterly. Rates: U.S., Canada and Mexico $48.00, foreign$56.00 per year. All subscriptions are for a volume year. All rights reserved. No part of this journal may be reproduced in any form, for any purpose or by any means, abstracted, or entered into any data base, electronic or otherwise, without specific permission in writing from the publisher. TIMN 222760

EDITORIAL Filling a Need . . . Nutrition and Cancer is born not to hail a new scien- tific society or some esoteric specialty, but rather to fill a need created by the mounting interest in nutrition and its relationship to health and disease. While infectious diseases are still a reality in modern societies, chronic disease, especially cardiovascular problems, cancer, diabetes, and stroke, are now the ma- jor sources of public anxiety, disability, and overall mor- tality. Epidemiologic studies in the last thirty years have shown that most chronic diseases result from the in- teraction of individual genotypes and the combined in- fluence of diet, environment, and behavior. As the suc- cessful research and prevention efforts of the last 100 years enable us to overcome most infectious diseases, we have come to appreciate health implications of the in- fluence of human interactions with the "nonliving" en- vironment. In this context, diet offers by far the greater probability of cellular-molecular encounters than either the respiratory tract or skin contact, over an individual's lifetime. Although the preponderant etiologic role of diet in health and disease has been recognized by epidemiologic studies, it has not been as well studied as other factors. This is partly because other factors are easier to define (eg, a carcinogenic molecule) and partly because there is a reluctance to believe that diet could actually represent a hazard. Throughout history, man has experienced, as a rule, famine and scarcity and has traditionally assigned special importance to food; only in the last fifty years have significant segments of mankind, and especially Americans, enjoyed continuing abundance, resulting in excessive consumption. Perhaps this "hunger" is merely an ancestral conditioned reflex that future generations may unlearn if food remains plentiful; and, of course, food abundance may become a major evolutionary force, reducing the cultural significance of food to its purely nutritional and dietary functions, while human energy and resources historically forced toward food produc- tion, could be freed for other worthy pursuits. But until present perspectives change, people will likely continue to overeat when possible. Unfortunately, it appears that evolution has not prepared us to consume this bounty, and in fact, most chronic disease risks that are associated with diet reflect excessive food intakes. For this reason and for many more, nutrition research has become a major area of interest in modern public health. Nutrition now plays a definite role in cancer therapy. Anorexia and cachexia are the common ex- perience of most cancer patients, and nutritional ap- proaches have proved effective in alleviating the often devastating effects of modern therapies. Moreover, the nutritional therapy of cancer remains in itself an alluring hope. Nutrition and Cancer was designed as an international forum for researchers in this field and is meant to stimulate interest and enthusiasm in those scientists who are not as yet committed to it. The journal will in- clude issues in etiology; , therapy, and prevention. Etiologic interests are in clinical and experimental research in nutrition, carcinogenesis, epidemiology, an- thropology, toxicology, pharmacology, biochemistry, metabolism, and food production. Therapeutic aspects center on clinical and experimental research in clinical nutrition, clinical oncology, psychosocial intervention, dietetics, bioengineering and rehabilitation. Prevention interests include education, preventive medicine, behavior modification, and food technology. In addition, the journal will consider the impact of other disciplines on other cancer and nutrition research, methods for definition and assessment of nutritional status, nutri- tional requirements of the healthy and the ill, food com- position and microbiology, interactions of diet, nutrition and cancer with other disease, and the related method- ological advances. In this field, the journal will also offer editorials and news comments on issues relevant to research and policy. Gio B. GoRi Editor Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. 4 Nutrition and Cancer TIMN 222761

SPECIAL COMMUNICATIONS Diet and Nutrition in Cancer Causation Epidemiology Disease patterns and resulting motality have changed considerably in the US and other developed countries since the beginning of the 20th century. Infectious diseases are no longer a major threat; rather, chronic problems, such as cancer and cardiovascular disease, are the major factors in disease and mortality.25 It has been estimated that 80-90% of the cancer in- cidence rate in the US is attributable to environmental factors.° If the causative agents could be reduced or eliminated altogether, then a vast potential for disease prevention exists. It has also been estimated that the por- tion of total cancer incidence related to diet and nutrition is 60% for women and greater than 40% for men.48 Thus, diet and nutrition appear related to the largest number of human cancers, with a specificity second only to tobac- co smoking, the next largest contributing etiologic fac- tor. These data are not meant to imply that cancer is caused directly by diet, but they do reflect the observed relationships between increased cancer incidence for particular sites and certain nutritional practices. The development of cancer depends on a number of factors, those intrinsic to an individual and those originating in his environment.74 These factors operating together can produce cellular transformations leading to cancer. Ingested substances may contain initiating as well as directly carcinogenic components,3°," and the diet may modulate susceptibility and response to causative factors. Some of the best evidence of nutrition's role in the causation of cancer comes from studies of migrant populations.48 Generally, cancer incidence patterns of migrants change from that of their native country to that common to the population of their new country. These shifts take a few generations because dietary habits learned in the country of origin are slowly changed in the process of acculturation to the new country. In Japan, the incidence rates of colon and breast cancer are low, while that of stomach cancer is high.5 The reverse is true in the US. Within two or three genera- tions, Japanese migrants to the US show a shift of cancer incidence patterns from those common in Japan Vol. I, No. 1 to those prevalent in the US.12 This observation correlates with a shift of dietary habits, and particularly with in- creased caloric and fat intake. Data collected by Staszewski and Haenszel on Polish migrants in 1965 follow the same pattern of change seen in Japanese migrant data.38 The observations on cancer incidence patterns are not confined to migrants to the US. The same pattern ap- pears for migrants to Israel and Hong Kong, and for rural migrants to Cali, Colombia.3 One could argue that the environment or lifestyle of different countries could explain the observed dif- ferences. However, general pollution and food con- tamination are similar in Japan and the US; therefore, these are not likely to be responsible for observed in- cidence differences in colon and breast cancer between the two countries, nor for the shifting patterns of in- cidence rates observed in migrant populations. Also, within a given population group, smokers are ex- posed to enormous quantities of carcinogenic substances similar to and in far larger quantities than those normally found in air, water, or food pollution."2 If these substances were important etiologic factors for those cancers associated with diet, such as colon and breast, then high incidence rates could be expected among tobacco smokers. In fact, smokers do not have an excess of these cancers and it is reasonable to surmise that carcinogens present in smoke and in air are not likely causative factors for these particular diseases.10 Such evidence suggests that environmental pollutants are not significant factors in the observed relationship of nutrition and the incidence and mortality of some cancers. Al.so, breast and colon cancer are not known to be more prevalent in occupational groups where ex- posure to environmental carcinogens is much higher than in the general population. Other major studies reinforce the evidence that diet, rather than other environmental or genetic factors, is in- volved in the causation of certain types of cancer. The best evidence comes from studies of homogeneous pop- ulation groups who live and work in the same environ- ment as their cohorts and are exposed to the same en- vironmental pollutants.78,26 Comparison of the cancer incidence and mortality Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. 5 TIMN 222762

rates in Seventh-Day Adventists living and workirig in Los Angeles shows significant differences in cancer in- cidence for almost all tumor types.19 Some of these dif- ferences, such as for lung cancer, are clearly linked to their abstinence from smoking, even though they are ex- posed to the same environmental pollutants. Their epidemiologic evidence is consistent with the hypothesis that the Adventist lifestyle can account for a major portion of the reduced risk of non-smoking-related cancers. Phillips2' contends that the most distinctive feature in this lifestyle is their unique vegetarian diet, substantially lower In protein and higher in dietary fiber and unrefined carbohydrates than that of their counter- parts. Comparison of the cancer incidences of Mormon and non-Mormon populations living in Utah show similar significant differences in cancer incidence.s Ethnic differences also provide insights into the prob- able role of diet in causing cancer. For instance, Jews in the US show a higher rate of cancer of the stomach, col- on, pancreas, and kidney than the general population.2t Many epidemiologic studies of different ethnic groups show considerable differences for stomach and breast cancer among populations with similar genetic and en- vironmental backgrounds, but with sharply different dietary habits.15 Breast, colon, esophageal, and pancreatic cancers, which have a high correlation with diet, also have great variation in incidence around the world.5 Many epidemiologic studies have found worldwide correlation between bowel and breast cancer and fat intake. The high incidence of colon cancer in the US and low in- cidence in Japan are consistent with the differences in fat intake between the two countries. The greater in- cidence of colonic cancer in Japanese migrants to the US reflects an increase in fat intake as they change from their native habits to western dietary habits." During the last 10 years, the rates of breast and colon cancers in Japan itself have increased, probably for the same reason. Leveille has correlated the occurrence of cancer of the large intestine with foods of animal origin," especially meat, though it is not clear whether the protein, fat con- tent, or an associated factor is the significant factor. Seventh-Day Adventists have a restricted fat and meat in- take when compared to other populations living in the same district and, as indicated, they suffer considerably less often from breast and colon cancer.21 Some re- searchers have postulated that a low fiber intake in western countries may be responsible for a high in- cidence in colon cancer. Indeed the Japanese diet is high in fiber content, as is the diet of African populations. Both groups may experience a lower rate of colon cancer for this reason. Despite epidemiological evidence, the specific role of diet and nutrition in cancer etiology is still unclear. One current theory about the mechanism of dietary fats in causing certain forms of cancer is that an excessive fat intake modifies the metabolism of cholesterol, bile acids, 6 and neutral Steroids in the intestine, as well°gs the metabolism and secretion of steroid hormones in circula- tion.'s The bile acids secreted in the intestine could be degraded by the bacteria growing in the intestine to form carcinogenic substances that may initiate colon cancer." This process of degradation and transformation of bile acids could be modulated by the presence of fiber in the diet, which is known to affect the composition of bacterial and chemical conditions in the intestine,2' or by other conditions, such as the absence of antioxidants."^ It is also possible that the altered metabolism of steroid hormones could impose unnatural burdens on cellular receptors of specific target tissues, such as the uterus or breast, again to initiate cancer at those sites. The relationship between diet and certain forms of cancer still does not mean an exclusive link to causation. Many contributing factors may be involved, but perhaps the modification of even one of these factors (eg, diet) would be sufficient to stop or retard the chain of causative events. For instance, if we consider alcohol an abnormal dietary component, then clearly its excessive consumption is a very significant causative factor, par- ticularly for cancers of the upper alimentary tract a,'3 Other studies that reinforce the link of nutrition and certain cancer forms have noted changes in cancer rates over time. The sharp decrease in stomach cancer in- cidence for the US in the last 20 years suggests the prob- able introduction of as yet unknown protective factors in the diet. Gortner's recent study on nutrition in the US in- dicates changes in the consumption of specific dietary components during this same period that may explain the decrease in stomach cancer incidence. Animal Studies The epidemiological evidence relating diet and nutri- tion to cancer etiology is strongly supported by numer- ous animal studies. Of all dietary modifications, caloric restriction has had the most regular influence on tumor formation40 With few exceptions, caloric restriction generally inhibits tumor formation and increases life expectancy. Furthermore, even within a group of animals being fed identical diets, the incidence of tumors tends to be consistently greater in heavier rats than in lean rats.32 Other research in- dicates that the optimum caloric intake for an animal depends upon age and stage of development.' Longevity studies" that include the evaluation of tumor development indicate that optimum protein intake is also dependent upon developmental stage. Generally, a lower protein intake inhibits growth of spontaneous or chemically induced tumors.22,33 Amino acids have also been noted to influence cancer development in animals, indicating that neoplastic tissues may have different amino acid requirements than the normal tissues of the host.'5 Both the amount of fat in the diet as well as the satura- Duplication of Nutrition and Cancer, in whole or 7n parf, by any means for any purpose Is illeyal. Nutrition and Cancer TIMN 222763

tion of the fat tend to influence tumor incidence.',z,B,30 In- creased amounts of fat in animal diets have resulted in an increased incidence of certain tumors, notably breast tumors, and the tumors have also occurred earlier in the life of the animal. Tannenbaum" has shown that an in- crease from 25% to 28% fat in the diet of mice resulted in a doubled incidence of spontaneous mammary cancers. Vitamins have varying effects on tumor formation and growth. Certain vitamin deficiencies tend to enhance tumor development while other deficiencies suppress it. Vitamin excesses can also influence tumor development in either direction. A deficiency of vitamin A appears to enhance suscep- tibility of animals to chemical carcinogens. Supplemen- tal vitamin A has been shown to reduce chemical car- cinogenesis in epithelial cells and depress gastric tumor growth.3' Studies of the relationship between vitamin A and the growth of colonic tumors have produced conflict- ing findings; in general, however, present evidence sug- gests that vitamin A and its retinoid analogs may have anticarcinogenic or antitumorigenic in effects. Riboflavin deficiency retards the growth of spon- taneous and transplanted tumors, probably by starving the tumor cells of flavin coenzymes.24 In the case of tumors induced by chemicals such as azo dyes, however, riboflavin is needed as a protective agent in order to degrade these carcinogens." Nicotinamide has been shown to reduce the incidence of pulmonary adenomas in mice.' Vitamin E is believed to have antitumor proper- ties because of its role as an antioxidant in preventing formation of epoxides and peroxides.34 Ascorbic acid has been shown to inhibit in vitro nitrosation, thus having a potentially protective effect against the carcinogenicity of nitrosamines and nitrosamides.28 Minerals appear to have a more complex role than vitamins40 in the carcinogenic process. Most minerals ap- pear to have an optimum range for dietary consumption. Intakes above or below this range may increase tumor in- cidence or susceptibility to an exogenous carcinogen. The minerals most often associated with increased cancer incidence include arsenic, beryllium, chromium, lead, cadmium, nickel, and radium. The roles of sodium, potassium, calcium, and magnesium have not yet been clarified, but selenium, zinc, copper, and iodine have been shown to be protective under certain conditions.'5,'9 Nonnutritive dietary components also seem to play a role in cancer etiology. Dietary fiber may alter intestinal microflora concentrations or microbial metabolic path- ways. Fiber has also been shown to bind to dietary car- cinogens and precarcinogens, possibly lessening their effect, and to affect intestinal transit time. Other nutritive dietary components, such as flavones, may enhance or repress carcinogenesis through effects on a cell's drug- metabolizing system. Antioxidants have been shown to Vol. I, No. 1 decrease both the incidence of tumorigenesis and the number of tumors per mouse, following DMBA induc- tion.49 Similarly, the antioxidant BHA50 has been shown to reduce the binding of benzo(a)pyrene to the DNA in the microsomes in calf thymus.3' Although the animal data relative to the specific role individual nutrients play in carcinogenesis are not yet conclusive, it is obvious that diet and nutrition are ex- tremely important in the etiology of both naturally occur- ring and experimentally induced cancers. Conclusion While the epidemiological and laboratory data sum- marized here do not allow us to make final statements on the relationship of specific dietary components to the in- cidence of certain forms of cancer, they do show that significant correlations exist. The evidence indicates that diet functions as an etiologic factor distinct from dietary contaminants and from genetic and environmental fac- tors. Correlations between cancer incidence and dietary habits have been shown in studies of migrant popula- tions, high- and low-cancer incidence populations, and special populations. Epidemiologic and metabolic studies should be con- tinued and expanded to gain a more precise picture of nutrition interactions with health and disease. Methods for rapid and objective measurements of the nutritional status of individuals are sorely needed, as a basic premise for sound nutritional research and intervention in man. Clearly the commitment and development of these research problems cannot be expected from isolated scientists, as they require resources beyond the capabil- ity or interest of the academic laboratory. Such research would most likely be organized by government agencies, assisted by advisers from the academic community. Research in nutrition and health must develop basical- ly in physiologic, biochemical, cellular, and molecular directions, but must also strive to translate these find- ings into applicable human trends. Patient work is need- ed to identify individual dietary requirements according to different genetic, somatic, behavioral, and en- vironmental situations. In view of the multiple interactions of diet and nutrition with human health and development and with diseases that are major.sources of mortality in modern society, hardly any biomedical research field seems to hold a bet- ter promise of improved health for mankind. National Cancer Institute Bethesda, MD 20014 Gio BATTA GoRi Duplication of Nutrition and Cancer, in whole or !n part, by any means for any purpose is illeyal. 7 TIMN 222764

References and Notes ' Carrol, KK: "Experimental Evidence of Dietary Factors and Hormone-Dependent Cancers." Cancer Res 35, 3374-3383, 1975. ZCarroll, KK, and Khor, HT: "Effects of Level and Type of Dietary Fat on Incidence of Mammary Tumors Induced in Female Sprague- Dawley Rats by 7,12-dimethylbenz(a)anthracene." Lipids 6, 416. 1971. 3Correa, P, Cuello, C, and Dugue, E: "Carcinoma and Intestinal Metaplasia of the Stomach in Colombian Migrants." J Natl Cancerlnst 44, 297-306, 1970. "Doll, R: "Strategy for Detection of Cancer Hazards to Man." Nature 265, 589-596, 1977. 5Doll, R, Muir, C, and Waterhouse, J (eds): Cancer Incidence in Five Continents, Vol II. New York: Springer-Verlag, 1970. 6Enstrom, JE: "Cancer Mortality among Mormons." Cancer 36, 825-841, 1974. 'French, A: "Nicotinamide Inhibition of Urethane-Induced Pulmonary Adenomas in Mice." J Int Res Commun 1(3), 33, 1973. aGammal, EA. Carroll, KK, and Plunkett, ER: "Effects of Dietary Fat on Mammary Carcinogenesis by 7,12-dimethylbenz(a)anthracene in Rats." Cancer Res 27, 1737, 1967. 9Graham, S, Lilienfeld, AM, and Tidings, JE: "Dietary and Purga- tion Factors in the Epidemiology of Gastric Cancer." Cancer 20, 2224- 2234, 1967. tOHaenszel, W: "Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases." National Cancer Institute. Monograph 19. 1966. "Haenszel, W, and Kurihara. M: "Studies of Japanese Migrants. I. Mortality from Cancer and Other Diseases among Japanese in the United States." J Natl Cancer Inst 40, 43-68, 1968. 7zHaenszei, W. Kurihara. M, Segi, M, and Lee. RKC: "Stomach Cancer Among Japanese in Hawaii." J Natl Cancer Inst 49, 969-988, 1972. "Hankin, JH. Nomura, A, and Rhoades, AG: "Dietary Patterns Among Men of Japanese Ancestry in Hawaii." Cancer Res 35, 3259- 3264, 1975. - t4Higginson, J: "Present Trends in Cancer Epidemiology." Proc c Can Cancer Conf 8, 40-75, 1969.. 15Higginson. J,and Muir, CS: "Epidemiology in Cancer." In Holland, JF and Frei, F (eds): Cancer Medicine, Philadelphia: Lea and Febiger, 1973. 16Hili, JJ: "Metabolic Epidemiology of Dietary Factors in Large Bowel Cancer." Cancer Res 35, 3398-3402, 1975. '7Kraybill, HF: "Carcinogenesis Associated with Foods, Food Ad- ditives, Food Degradation Products, and Related Dietary Factors: " Clin Pharmacol Ther 4, 73, 1963. 18Lemon, FR, and Walden, RT: "Death from Respiratory System Disease Among Seventh-Day Adventist Men." JAMA 198,117-126, 1966. 19Lemon, FR, Walden, RT, and Woods, RW: "Cancer of the Lung and Mouth in Seventh-Day Adventists." Cancer 17(4), 486-497, 1964. 20Leveilie, GA: "Issue in Human Nutrition and their Probable Impact on Foods of Animal Origin." J Animal Science 41(2), 723-731, 1975. 2tMacMahon, B: "The Ethnic Distribution of Cancer Mortaility in New York City, 1955." Acta; Union Internationalis Contra Cancer 16, 1716-1724, 1960. Z2Madhaven, TV and Gopalan, C: "The Effect of Dietary Protein on Carcinogenesis of Afiatoxin." Arch Path 85, 133-137, 1968. 23 Moore, WEC and Holdeman, LV: "Discussion of Current Bacteriological Investigations of the Relationship between Intestinal Flora, Diet, and Colon Cancer." Cancer Res 35, 3326-3331, 1975. 8 24The Nutrition Foundation: "Riboflavin Metabolism in Cancer." Nutr Rev 32. 308. 1974. Z5Perry, TM: "The New and Old Diseases. A Study of Mortality Trends in the United States. 1900-1969:' Am J Clin Pathol 63,453, 1975. 26Phillips. RL. "Cancer and Adventists." Science 183, 471, 1974. 27Philiips. RL. --Role of Lifestyle and Dietary Habits in Risk of Cancer Among Seventh-Day Adventists." Cancer Res 35, 3513-3522, 1975. Z8Raineri, R. and Weisburger, JH: "Reduction of Gastric Car- cinogens with Ascorbic Acid." Ann NY Acad Sci 258, 181, 1975. 29Reddy. BS. Mastromarino. A, and Wynder, EL: "Further Leads on Metabolic Epidemiology of Large Bowel Cancer." Cancer Res 35, 3403-3406. 1975. 'OReddy. BS. Narisawa. T, Maronpot, R, Weisburger, JH, and Wynder, EL: "Animal Models for the Study of Dietary Factors and Cancer of the Large Bowel."Cancer Res 35, 3421-3426, 1975. 31Ross, MH: "Dietary Behavior and Longevity." Nutr Rev 35, 257-265, 1977. 'ZRoss, MH and Bras, G: "Lasting Influence of Early Caloric Restric- tion on Prevalence of Neoplasms in the Rat." J Natl Cancer Inst 47, 1095, 1971. 33Ross, MH and Bras. G: "Tumor Incidence Patterns and Nutrition in the Rat." J Nutr 87, 245-250, 1965. 34Shamberger. RJ. Baughman, FF, Kalchert, SL, Willis, CE, and Hoffman. GC: "Carcinogen-induced Chromosomal Breakage De- creased by Antioxidants." Proc Natl Acad Sci 70, 1461-1463, 1973. 35Shapiro. JR: "Seleniurri and Carcinogenesis: A Review." Ann NY Acad Sci 192. 215. 1972. 3sShubik• P: "Potential Carcinogenicity of Food Additives and Con- taminants." Cancer Res 35. 3475-3480, 1975. 37Sporn. MG. Dunlop. NM. Newton, L, and Smith, JM: "Prevention of Chemical Carcinogenesis by Vitamin A and its Synthetic Analogs (Retinoids)." Fed Proc 35. 1332-1338, 1976. 38Staszewski. J and Haenszel, W: "Cancer Mortality among the Polish Born in the United States." J Natl Cancer Inst 35, 291-297, 1965. 39Stoner, GD, Shimkin, MB, Troxell, MC, Thompson, TL, and Terry, LS: "Test for Carcinogenicity of Metallic Compounds by the Pulmonary Tumor Response in Strain A Mice." Cancer Res 36, 1744-1747, 1976. 40Tannenbaum, A: "Nutrition and Cancer." In Homburger, F(ed): Physiopathology of Cancer (2nd edition) New York: Hoeber-Harper, 1959, pp 517-562. °tTannenbaum, A: "The Genesis and Growth of Tumors. 111. Effects of a High-Fat Diet." Cancer Res 2, 468-475, 1942. 42US Department of Health, Education, and Welfare: "Toward Less Hazardous Cigarettes." Publ. No. (NIH) 76-905. 43Vitale, JJ and Coffey, J: "Alcoholism and Vitamin Metabolism." In Kissin, B and Begleiter (eds): Biochemistry. New York: Plenum Press, 1971, pp 327-352. 44Wattenberg, LW: "Effects of Dietary Constituents on the Metabolism of Chemical Carcinogens." Cancer Res 35, 3326-3331, 1975. 45Wattenberg, LW, Loub, WD, Lam, LK, and Speier, JL: "Dietary Constituents Alerting the Responses to Chemical Carcinogens." Fed Proc 35, 1327-1331, 1976. 'sWeisburger, JH and Raineri, R: "Dietary Factors and the Etiology of Gastric Cancer." Cancer Res 35, 3469-3474, 1975. 47Wissler, RW and Geer, JC (eds): The Pathogenesis of Atheroschlerosis. Baltimore: Williams and Wilkins, Co. 1972, pp 41-119. 48Wynder, EL and Gori, GB: "Contribution of the Environment to Cancer Incidence: An Epidemiologic Exercise." J Natl Cancer Inst 58, 825-832, 1977. 49DMBA =9, 10-dimethyl-1, 2-benzanthracene. 50BHA = butylated hydroxyanisole. Duplication of Nutrition and Cancer, In whole or in part, by any means for any purpose is illegal. Nutrition and Cancer TIMN 222765

N utrition and the Cancer Patient Renewed interest in clinical nutrition has accom- panied major advances in the treatment of cancer and a generally more optimistic outlook for many cancer pa- tients. This has resulted in the increasing appreciation of the close interrelations between the nutritional status of the cancer patient and the effects of cancer and its various treatments. With the exception of acute leukemias, cancer has rarely been an acutely fatal disease. With the advent of more effective treatments, it has become more and more a chronic or protracted ill- ness and, consequently, a matter of concern for long periods to the patient and the physician. Remission or potential "cure" of cancer is associated with long-term chemotherapy treatment. There is a lapse of years before the patient and the physician are willing to admit that the disease is "cured." The physician and patient are there- fore faced, each in his own way, with the effects of the disease process, the psychologic impact of its presence and long-term problems of treatment modalities and their side effects. If physicians undertake the treatment modalities indicated at the present time, they should make a sincere effort to improve or maintain a quality of life which makes for a reasonably comfortable and func- tioning individual. This concern about patient status should begin with the planning for the initial treatment and continue through to the desired long-term survival. Since it is possible to prolong life by surgery, radiation and chemotherapy or their combinations, attention must be given to the quality of life of those who survive.23 The interrelations between cancer and nutrition in- volve 1) the systemic effects of cancer, 2) the local ef- fects of cancer, 3) the effects of each of the various treatments of cancer and 4) the psychological stresses of the actual or imagined presence of cancer. While each category has its specific influences, it is important to realize that they interact and that one or more may operate simultaneously. An important manifestation of the presence of cancer is anorexia. This is not unique to cancer, but its in- cidence, prolonged duration and deleterious effect make it of special concern. It occurs most commonly and noticeably in patients with involvement of one or more areas of the alimentary tract including the liver and pan- creas?2 The onset of anorexia is often insidious and may Vol. I, No. 1 be unaccompanied by symptoms other than progressive weight loss for a significant period. It is a dictum of medicine that a patient with an unexplained weight loss should undergo a thorough search for an occult neoplasm. The anorexia may range from mild to severe. Its etiology is uncertain although many conferences and publications have considered It 8,9,",ze It has been variably attributed to the development of a toxin (although none_has ever been isolated or identified) or to abnormalities of hypothalamic control (although current evidence is against this)." It may be related to any one or more of a variety of metabolic changes associated with modified energy requirements;'~2~9 however, a specific association, if any, has not been documented.29 Whatever the etiology, anorexia is a real and trouble- some problem to the patient and to the physician. It is often associated with altered taste, and patients fre- quently ascribe their loss of appetite to a changed taste of one or more foods. Efforts have been made recently to determine the prevalence and types of taste alterations in cancer patients.8 These efforts are still very preliminary and more precise studies are needed to establish what patterns (if any) occur in relation to the type and stage of various malignancies. Alterations in taste are probably not primary to anorexia, but are part of the underlying changes initiated by tumors and psychosomatic factors. Depressed cellular immunity has been known to occur in cancer patients and in the past, has frequently been attributed to the effects of cancer per se. However, as the result of studies done initially in children,25 then in adults,i3 and then in cancer patients,5 it has become ob- vious that altered immune responses can result from malnutrition per se. Malnutrition also induces altered phagocytosis, macrophage activity and depressed com- plement levels. In cancer patients the respective effects of malnutrition and of the malignancy per se are not yet known. It has been well demonstrated in surgical pa- tients that morbidity and mortality increase in the presence of depressed cellular immunity. Active interven- tion to overcome malnutrition and to treat infection im- proves the immune response and significantly decreases morbidity and mortality.7e Data from malnourished cancer patients5 and tumor-bearing animals' show that improved nutrition substantially reverses depressed im- Duplicathn of Nutrition and Cancer, in whole or in part, by any means for any purpose is illeyal. 9 TIMN 222766

munity and that the immune response has prognostic significance on the effectiveness of antitumor therapy. Data are accumulating on the effects of malnutrition and endocrine function, particularly in children." Un- doubtedly, changes in endocrine status induced by malnutrition have relevance for the cancer patient, but this area has not been sufficiently researched. Many of the most serious effects of cancer on nutri- tional status stem from localized organ problems, such as partial or total intestinal obstruction, whereby the in- take of food is partially or totally prevented.22 In addition to impaired nutrient intake, maldigestion and malabsorp- tion may occur. Diarrhea and vomiting may be severe enough to lead to problems of fluid and electrolyte and acid-base balance. The physician must be aware of not only sodium, potassium, chloride and bicarbonate requirements in such situations but of magnesium, phosphate, calcium and trace-element requirements. This is especially important when long-term replacement is indicated or when complications arise from renal tubular defects (e.g., secondary to administration of sodium carbenicillin and/or amphotericin) which may lead to serious metabolic abnormalities if uncorrected. Production of ectopic hormones with marked effects on the intestinal tract and elsewhere is a striking illustra- tion of the interrelation of localized tumor growth with systemic effects. These ectopic hormones are produced by a group of cells derived embryologically from the neural crest and characterized by the ability to form biologically active polypeptides.27 Specific tumors pro- ducing these polypeptide hormones include the medullary carcinoma of the thyroid, oat cell carcinoma of the lung, malignant epithelial thyoma, pancreatic non- beta cell tumors, and carcinoid tumors of the foregut. Insulin-secreting tumors of the pancreas also may cause severe nutritional and metabolic problems. Often the cells produce a variety of hormones in the same patient. The secretion of hormones without the normal controls may have dramatic effects on the alimentary tract and elsewhere. The Zollinger-Ellison syndrome is associated with the ectopic production of gastrin with resultant gastric hyperacidity, ulcer formation, and maldigestion. The Verner-Morrison syndrome30 is characterized by copious diarrhea, low gastric acid production and hypokalemia. It is associated with ectopic production of vasoinhibitory peptide (VIP) and other hormones.te In- creased production of ACTH, corticosteroids, anti- diuretic hormone, serotonin, calcitonin, and others pro- duce systemic effects that disturb the nutritional status of the patient. Gastrointestinal lymphomas, particularly those of the small intestine, are often associated with malabsorption. There is a positive correlation between long-standing adult celiac disease and the development of both in- testinal lymphomas and carcinomas?2 The major therapeutic modalities of cancer-surgery, radiation therapy and chemotherapy, separately and in various combinations-may induce significant changes leading to the development of nutritional problems. Surgical procedures to cure or palliate cancer may in- volve any part of the alimentary tract from the mouth to the anus including pancreas, liver, and gall bladder. It is essential that the physician and dietition involved be aware of the potentially adverse nutritional effects that the particular surgical ablation and any anatomical rear- rangement may induce,'•,21 in order to effectively prevent development of nutritional deficiencies in these patients. Our knowledge of nutrition and of gastrointestinal physiology has reached a point where rational principles can be applied in the treatment of the patient who has undergone major alimentary tract surgery. Where surgery involves multiple portions of the alimentary tract, tradi- tional nutritional therapy may be modified and com- plicated. The clinical effects of ionizing radiation to various por- tions of the alimentary tract have been described.10 Radiotherapy to the head and neck, often in conjunction with surgery, or to the abdomen may result in nutritional problems secondary to difficulties in ingestion, chewing and swallowing or absorption. The great majority of cases with high abdominal radiation have a short-lived acute episode. However, with a tendency to increasing radiation dosage or to individual hypersensitivity there may be rapid or slow changes over months or years resulting in persistent intestinal dysfunction with stenosis, fistula formation and/or malabsorption. Obstruction or fistulas often require surgical resection of affected portions of the bowel. They often recur with fur- ther need of resection. As the result of the combination of radiation damage and resection, the patient may become an intestinal cripple requiring drastic nutritional intervention which may include long-term total parenteral nutrition. Early and adequate nutritional therapy can drastically improve the quality of life of such patients. While much has been written about the dietary management of the patient undergoing radiation therapy, such dietary prescriptions are based on limited anec- dotal experience without adequate objective com- parative studies of different modalities. Pending such ob- jective data on optimum formulations of diets and liquid formulas, the physician and dietitian must adopt the policy of testing one or more diet formulations until satisfactory results are obtained. While chemotherapy is a latecomer in cancer therapy, its development has been rapid in recent years in terms of new drug development and application. Relatively high dose, multiple combination, cyclical chemotherapy is already well established in many institutions. In addition to the bone marrow depression induced by many of these drugs, there is also a high incidence of anorexia, nausea and vomiting, mucositis, and, less commonly, diarrhea. Certain agents may induce obstipation and ulceration.15 Dosages vary depending upon patient tolerance and response, and there are marked individual responses in the degree of undesirable gastrointestinal effects and willingness to ingest food. Of particular Duplication of Nutrttton and Cancer, in whole or !n part, by any means for any purpose !s illegal. Nutrition and Cancer TIMN 222767