- Email: [email protected]
A new direction in preventive oncology: Chemoprevention
A New Direction in Preventive Oncology: Chemoprevention Sharon J. Olsen and Richard R. Love
P
REVENTION is one of the most appealing but also the most challenging ways of controlling human cancer. Until recently efforts in preventive oncology have been threefold: (I) to identify risk factors associated with cancer, (2) to understand the behavior and education needed to decrease risk, and (3) to identify and manage premalignant conditions. The identification of risk factors should allow their manipulation to decrease the incidence of cancer. However, while progress in the first and third areas has been made, translation into effective clinical prevention has been infrequent and difficult. Paralleling activities in these three areas has been research in the biology of cancer, which has suggested possibilities for chemoprevention. The purposes of this paper are to provide an introduction to chemoprevention, to discuss the theoretical and known mechanisms of action for selected agents and review their current daily dose recommendations and potential overconsumption toxicities, to identify human studies underway to determine the influence of these specific agents on the development of cancer, and finally, to dileneate issues of concern in this new approach for nursing practice. Chemoprevention is the taking of a drug (vitamin, hormone or other agent) for the purpose of preventing cancers or precancerous lesions or reversing premalignant conditions to normal. To date, most chemoprevention studies have involved micronutrients. While the possibility that something as simple as taking a pill might prevent cancer is appealing, the successful application of such a proven biologic intervention may be more challenging than is immediately apparent. The data for planning chemoprevention have come from studies in epidemiology, carcinogenesis, and biology. Epidemiologic studies have shown that environmental factors are important in most human cancers, dietary factors and tobacco being the most important in the United States. Doll and Peto! concluded that perhaps 35% of all US cancer deaths may be attributable to diet. General dietary factors include macronutrients (eg, fat and fiber) and micro nutrients (eg, vitamins and minerals). The majority of the research regarding micronutrients associates low consumption with Seminars in Oncology Nursing, Vol 2, No J (August), 1986: pp 211-221
cancer. It is not known if raising consumption to above normal levels will prevent cancer. Since human cancers take many years to develop, only prospective studies with large populations can tell us whether supplementation of normal diets with various micronutrients will prevent cancer. Experimental models of carcinogenesis suggest that tumors evolve through a multistage process including initiation and promotion.? Tumor initiation, which can be brought about by exposure to chemicals, viruses, or ultraviolet light, appears to cause an irreversible change in cellular DNA. Tumor promotion, on the other hand, must follow initiation, and exposure must be repeated at relatively frequent intervals to produce cancer. Because tumor promotion results from repetitive events occurring over a long time and is reversible, this stage has been a target for chemoprevention.? Data support an inhibitory influence on carcinogenesis of such micronutrients as vitamins C, E, A (both naturally occurring and synthetic reiinoids), and most recently, vitamin D. A similar role has been suggested for the two minerals, selenium and calcium. Deficiencies of vitamin A and Col and folic acid" have been associated with suppression of immune function. Watson" cites multiple animal studies documenting enhancement of the immune response with dietary supplements of vitamin E, an increase in T-Iymphocyte mitogenesis and natural killer cell activities with a high vitamin A intake, enhancement of cellular immunity with increased tumor resistance by retinoids, and enhanced resistance to immunogenic tumors in the presence of beta-carotene. CURRENT RESEARCH IN CHEMOPREVENTION
Agents used for chemoprevention include both natural and synthetic products. These agents can
From the Cancer Prevention Clinic, University of Wisconsin Clinical Cancer Center, Madison. Address reprint requests to Sharon 1. Olsen, RN, ~tS, Cancer Prevention Program. Wisconsin Clinical Cancer Center, Room 7660. 1300 University Ave, Madison, WI 53706. © 1986 by Grune & Stratton. Inc. 0749-2081/86/0203-0010505.00/0
211
212
be chemically defined and administered in precisely specified dosages." The intent is interference in the formation or activation of carcinogens in vivo, strengthening host defenses and/or blocking or reversing tumor progression in the early stages of carcinogenesis." Current efforts in chemoprevention are directed to three areas: clinical trials in high risk individuals without disease, determination of the impact of micronutrients on premalignant conditions, and the definition of ultra-highrisk groups suitable for further intervention studies. The aims of trials in chemoprevention are to evaluate systematically the efficacy and toxicity of chemoprevention agents. Such human cancer trials are not only expensive but they require the enrollment of hundreds or thousands of individuals to have enough statistical power to convincingly demonstrate effects. The effect of micronutrients on premalignant conditions appears promising: precancerous oral lesions can be reversed's? and levels of the enzyme ornithine decarboxylase (ODC) can be reduced. This enzyme may playa central role in the promotional stage of tumor development. 3 Individuals at risk for the development of second primary cancers or for recurrence of primary cancers are considered important target populations for chemoprevention. Two studies'P-'! have demonstrated the usefulness of micronutrients in decreasing the incidence of recurrent superficial bladder cancer in humans. Long-term survivors of a single childhood neoplasm have a cumulative risk of developing a second cancer approaching 12% by 25 years.F Individuals treated with alkylating agents are at risk for developing acute nonlymphocytic leukemia as are some patients treated with combined modality therapy (radiation plus chemotherapyj.P The latency periods involved in the development of second malignancies in these high risk groups are much shorter than those of other populations, a second aspect which makes these groups of individuals appropriate for chemoprevention studies. In response to mounting laboratory and epidemiologic evidence indicating that micronutrients can halt or reverse cancer progression in animals or reduce the incidence or risk of cancer in humans, the National Cancer Institute (NCI) developed the chemoprevention program. This program is currently sponsoring multiple human in-
OLSEN AND LOVE
tervention trials.!" Table 1 presents the clinical trials currently supported by NCI. REVIEW OF CURRENT DATA ON SELECTED CHEMOPREVENTIVE AGENTS
Studies in tissue culture, animals, and human populations have identified two groups of potential chemoprevention agents: naturally occurring substances found in many foods and synthetic compounds considered safe for clinical trials. Such agents include vitamin A and its precursor [3-carotene, synthetic derivatives of vitamin A, vitamin C, vitamin D, vitamin E, folic acid, calcium, and the trace metal selenium. An exhaustive review of the literature concerning the studies to date on chemoprevention agents may be found elsewhere. 15,16 VITAMIN A
Retinoid is a generic term that includes both natural and synthetic forms of vitamin A. Dietary vitamin A can be derived from its precursor known as carotenoid ([3-carotene) in plant foods, such as carrots, leafy green vegetables, and sweet potatoes. The f3-carotene derived from leafy green and yellow vegetables is converted to vitamin A in the digestive tract. It is uncertain whether the association of [3-carotene with reduced cancer risk is due only to its conversion to vitamin A or if [3carotene has some protective effect of its own. Animal foods have vitamin A in the form of retinol, retinal, and retinyl esters. Sources of retinol include butter, whole milk, egg yolk, liver, and vitamin A pills.
Toxicity The recommended dietary allowance (RDA) for vitamin A in the adult male is 1,000 retinol equivalents, or 5,000 IV. Women appear to have similar liver stores and adequate blood levels with a lower intake of vitamin A than males, probably because of their smaller body size. The allowance for adult females is set at 80% of that for males, or 800 retinol equivalents (4,000 IU).17 Toxicity in adults is seen with daily intakes of more than 15,000 retinol equivalents (50,000 IV) for prolonged periods.!? Side effects have greatly limited the use of vitamin A: these include fatigue, irritability, anorexia, nausea, cracked lips and dry skin with desquamation, and eventually vomiting, headaches, hair loss, bone pain, and hepatomeg-
aly."
213
A NEW DIRECTION: CHEMOPREVENTION Table 1. Current Cancer Prevention Clinical Trials (1984)114) Cancer Site
Intervention
Population Studied
All
US physicians, ages 40-84
l3-carotene Aspirin
All
US nurses
Retinyl palmitate Sodium selenite Vitamin B. Vitamin E
Breast
Family history of breast cancer, history of breast biopsy, first pregnancy after age 30
Low fat diet
Breast
Women with Stage I breast cancer
4-hydroxyphenyl-retinamide
Lung
Smokers Asbestos exposed individuals Sputum cytology: dysplasia
Folic acidNitamin B12 Retinol 13-cis-retinoic acid l3-carotene Vitamin E
Skin
Previous skin cancer Actinic keratosis Albinos
l3-carotene Vitamins C and E Retinol 13-cis-retinoic acid
Esophagus
Cytology: dysplasia General population (China)
MUltiple micronutrients
Colon
Familial polyposis Adenomatous polyps
l3-carotene Vitamins C and E 13-cis-retinoic acid Low fat diet Wheat bran
Cervix
Pap smear: dysplasia
Folic acid Retinyl acetate gel
Data from DeWys et al.'4
J3-carotene is easily measured in the serum, making compliance easy to monitor. Meyskens'? cautions, however, that serum retinol levels generally do not change until the liver has been saturated and do not necessarily reflect whole body or hepatic burden. Because of the known cellular effects on differentiation, women of childbearing potential who are enrolled in vitamin A trials must have a negative pregnancy test performed within 2 weeks prior to the initiation of treatment. 20 They must use an effective means of contraception during treatment and for a prolonged interval after cessation of treatment.
Synthetic Retinoids Natural retinoids are known to have toxic effects in animals, particularly at high doses. Re-
searchers are now trying to develop synthetic retinoids that are as effective as natural retinoids in inhibiting tumor growth, are less toxic, and are more site-specific. During the past 15 years, approximately 1,500 retinoids have been synthesized. The synthetic 4-hydroxyphenyl retinamide (4HPR) has been shown to prevent the development of breast and bladder cancer in animal models. Early testing has shown a very low toxicity compared to other retinoids. Several clinical studies of 13-cis-retinoic acid and a new retinoid, etretinate, have been conducted in dermatology and oncology patients. Toxicity appears to be diminished and etretinate has a tenfold enhancement of therapeutic action over vitamin A in test systems. Activity has been reported for 13-cis-retinoic acid in the treatment of actinic keratoses;" basal cell carcinomas,22 and refractory mycosis fungoides.P Etre-
214
tinate significantly reduces the degree of bronchial metaplasia in heavy smokers" and appears to prevent the recurrence of skin tumors in patients with xeroderma pigrnentosum.P
Mechanism of Action Much has been written about the physiology and biochemistry of vitamin A,I8 the role of retinoids in cell differentiation and carcinogenesis.P and the possible mechanisms by which carotenoids act to prevent cancer.F Derivatives of retinol are required for normal growth, vision, reproduction, and maintenance of epithelial differentiation. Retinoids have powerful effects on cell differentiation and proliferation. They can control DNA synthesis and mitotic activity and they have been shown to act during the promotion stage of cancer induction. 1 These effects have been demonstrated with both normal and neoplastic cells. Since carcinogenesis is fundamentally a disorder of cell differentiation, it is possible that the retinoid status of a cell influences its potential for cancer development.28 Pet027 has suggested that carotenes may prevent cancer by deactivating certain cellular changes and thereby preventing cellular damage, breaking the chain of events leading to the development of cancer. Evidence for this was demonstrated in a recent study by Stich et aI.9 A threefold decrease in chromosome breakage rates was achieved by supplementing the diet of Filipinos who chew betel nuts, a known carcinogen, with capsules of retinol and carotene. How retinoids interfere with the later stages of cancer development is not known, but several ways have been suggested in numerous studies. 29-32
Clinical Trials Over the years multiple studies have examined human cancer risk in relation to dietary intake of vitamin A or f3-carotene. One methodological problem in conducting these studies is the extreme difficulty in determining with any precision what people eat, especially retrospectively. Another potential problem is that an epidemiologic association between a given dietary component and cancer protection may be confounded by unrecognized ingestion of protective components or avoidance of harmful components. One argument against this is that epidemiologic data on dietary
OLSEN AND LOVE
retinoid intake and cancer risk are consistent with findings in the laboratory. Another is that the epidemiologic data are internally consistent; that is, the results of multiple studies support each other. 33 Epidemiologic evidence exists for the role of 13carotene and vitamin A in the reduction of cancer risk in lung,34-39 prostate,36,40,41 colon,36,42 cervix and stomach." larynx," esophagus;" and bladder. 45 Greenwald'? cautions that these studies do not enable researchers to conclude whether dietary vitamin A or f3-carotene intake is important nor do they clarify the exact internal physiologic mechanism for this protection. Therefore, further study is necessary.
Recommendations The National Academy of Sciences has recommended that people eat foods containing vitamin A on a daily basis. While increasing one's dietary intake of vitamin A from the RDA of 5,000 IV to 15,000 IU/d can be done relatively safely, 4 in higher doses, serious toxic side effects can be expected. The natural precursor of vitamin A, f3-carotene, has a lower risk of side effects and is the safest way to supplement vitamin A intake. In addition to the foods listed previously additional good sources of f3-carotene include tomatoes, spinach, greens, winter squash, pumpkin, dried fruits (such as apricots, prunes, or raisins), strawberries, melon, and brussel sprouts. VITAMIN C
Reduced intake of foods that contain vitamin C has been associated with some forms of cancer. 43,46 Vitamin C is present in many fruits, fruit juices, and vegetables. It is also put into certain foods, such as hot dogs, that have nitrate added as a preservative.
Mechanism of Action Vitamin C is involved in many biochemical processes in the body. Probably the most important function in the context of chemoprevention is its role as a nitrite scavenger, preventing the nitrosation of amines, which are carcinogenic in animal species.? Nitrites react with amines or amides in the digestive tract to form nitrosamines and nitrosamides. Vitamin C and E compete with the amine or amide for the nitrosating agent." Pickled, salt-cured, and smoked foods often
A NEW DIRECTION: CHEMOPREVENTION
contain precursors of nitrosamines. Populations that have a high incidence of stomach cancer also have a high intake of these foods and this suggests that conditions that promote the formation of ni- . trosamines increase the risk of cancer of the stornach.f" It has been hypothesized that the addition of ascorbic acid to the diet would, because it is an antioxidant, inhibit the alteration of nitrates to nitrites and the formation of nitrosamines.:" While this has not been established in human populations,48 it is clearly the case in experimental animal studies.f?
Toxic Effects Adverse effects appear in some people using extremely high vitamin C intakes (2,000 to 10,000 mg/d). Some of the adverse effects reported include fatigue, acidosis, oxaluria, diarrhea, and renal stones." It is known that vitamin C interferes with anticoagulants by shortening the prothrombin time.P? Sestili-? suggests researchers may need to exclude diabetics, women of reproductive age, persons with a proclivity to kidney stone formation, and those on anticoagulant therapy when considering subjects for chemoprevention trials utilizing pharmacologic doses of vitamin C.
Experimental and Clinical Studies In animal studies there is some evidence that vitamin C inhibits the formation of gastric carcinogens>' and induction of bladder tumors.V Howeve,r, this is not a uniform finding. 53.54 There are several human studies that support the contention that ascorbic acid is protective against cancer. There is evidence that vitamin C ingestion is associated with lower risks for human cancers of the sfomach,55-58 larynx.P bladder," cervix,59.60 and esophagus.44.61-63 The data remain controversial because several case control studies have found no relationship between ascorbic acid and cancer ri"sk. 40,42.45.64 With few exceptions, these studies have not attempted to assess vitamin C intake either by calculated intakes or by biochemical markers. Rather, they have simply determined usual consumption of food groups, a method that does not address the problem of nutrient interaction.
Recommendations A dietary allowance of 60 mg of vitamin C per day is recommended for adults of both sexes.'?
215
The National Dairy Council's warns that when megadoses of vitamin C are discontinued, deficiency symptoms such as bleeding gums may briefly appear until the body adapts. In conclusion, animal studies are suggestive'? but human studies do not strongly support an association of vitamin C with human cancer. 16.66 However, because there does appear to be some evidence, the current recommendation is to increase consumption of foods containing vitamin C. 49 Clearly, there is need for much more research in this area. VITAMIN E
The functional form of vitamin E is a-tocopherol. Its concentration in foods is usually proportional to the amount of linoleic acid present. A minimum daily requirement is estimated to be about 10 mg, an amount that is likely to be present in almost every type of diet consumed by human populations. Vitamin E is present in a wide variety of natural foods, including vegetable oils, margarines, shortening, eggs, whole grains, and many cereals. I7 Vitamin E appears to be nontoxic in moderate doses; the ingestion of 800 IV daily for three years was shown to cause no ill effects in humans.s? Animal studies have demonstrated that a deficiency in vitamin E results in disorders of the reproductive, musculoskeletal, central nervous, and vascular systems."? Because of its antioxidant activity, a-tocopherol is hypothesized to inhibit tumor formation via a mechanism similar to that of ascorbic acid. It appears to prevent the formation of nitrosamines, There is some experimental evidence68- 7o of a cancer-inhibitory effect of vitamin E in animal studies, but epidemiologic data are Iacking.P-?' . However, Watson" maintains that even though the necessary human trials to show efficacy have not been done, the animal data suggest that vitamin E may prove to be a useful adjunct to current cancer prevention. VITAMIN D AND CALCIUM
Recently, two findings have resulted in an increased interest in the investigation of the relationship between vitamin D and calcium, and colon cancer. Lipkin and Newmark'? studied ten individuals predisposed to colorectal cancer who were given supplemental dietary calcium for two to
OLSEN AND LOVE
216
three months. They observed a reversal of an abnormal proliferative state of the colonic mucosa known to be associated with an increased incidence of colonic cancer. Although it cannot be concluded from these results that the risk for colon cancer was reduced, that possibility was suggested. Animal studies by previous investigators corroborate these findings.t-' A second major finding'" was that mortality rates from colon cancer were highest in populations exposed to the least amounts of natural sunlight; difference in endogenous vitamin D production and calcium absorption were thought to be responsible. Garland et aJ73 investigated whether dietary vitamin D and calcium were associated with a 19-year risk of colorectal cancer in almost 2,000 middle-aged white men. Forty-nine colorectal cancers were found. As hypothesized, there was an inverse association between risk for developing colorectal cancer and intake of both vitamin D and calcium. Their results supported the suggestion?? that vitamin D and calcium may reduce the risk of colorectal cancer. The authors noted that dietary vitamin D and calcium are closely related and that calcium is dependent on vitamin D for intestinal absorption. Epidemiologic data are sparse, but results from Scandinavia" based on milk consumption suggest a protective effect for calcium and vitamin D. An inverse association between milk consumption and risk of colon cancer was also observed in a casecomparison study of Seventh-Day Adventists in the USA,76 where milk was routinely supplemented with vitamin D.
SELENIUM
Selenium is an essential constituent of the diet. A range of 50 to 200 ~g/d is suggested as adequate.!? Total dietary intake will vary with the source, class of food, processing, and cooking. Seafood, meat (especially kidney and liver), and whole grains are generally good sources. Fruits and vegetables are generally poor sources. 17.77 Selenium is thought to attach to free electrons and decrease the activity of enzymes that activate procarcinogens.
Toxic Effects Although selenium is essential, it is also toxic."? Toxicity will be dependent upon the form in which selenium is provided and the presence of other dietary constituents. Toxicity may be modified by high dietary levels of arsenic, silver, mercury, copper, and cadmium. In rats it has been shown that high protein diets protect against the toxic effects of selenium. Selenium is detoxified in the liver and excreted mainly via the kidneys. Symptoms of toxicity include pulmonary symptoms such as cough, coryza, and bronchitis probably secondary to the production of dimethylselenide, a volatile substance excreted by the lungs. This is responsible for the garlic breath that characterizes toxicity in both animals and man. Other symptoms include indigestion, lassitude, and irritability. Skin rash indicates direct dermal toxicity. 77 Selenium can be transmitted through the placenta to the fetus, and toxic reproductive and teratogenic effects have been reported. 77
Recommendations At this time there is no reason to suggest that individuals should ingest more than the current RDA levels of vitamin D (5 ug) and calcium (800 rng). 17 In fact, overconsumption of vitamin Dean lead to nausea, weight loss, and irritability.s" It is known that vitamin D may be synthesized when the skin is exposed to sunlight. 65 Food sources common to both elements include fortified dairy products and margarine. Fish oils and egg yolk are additional sources of vitamin D. In conclusion, the present evidence does not show conclusively that vitamin D or calcium protect against the occurrence of colorectal cancer. Nevertheless, current evidence indicates that this line of investigation is worthy of pursuit.
Animal and Human Studies Laboratory animals fed selenium have demonstrated a reduction in liver tumors,"! inhibition of carcinogenesis.P a decrease in number of colon tumors,79,80 inhibition of the formation of papillomas.f" and inhibition of mammary carcinoma. 82-87 Studies of human populations have shown provocative results. In 1979 Robinson et al 88 studied natives in New Zealand, a country where the soil content of selenium is low and individuals have a known low level of selenium in their serum and tissues. They looked at patients with stomach, colon, bladder, breast, liver, and pancreatic cancer and found no relationship between sele-
217
A NEW DIRECTION: CHEMOPREVENTION
nium and these cancers. However, two correlation studies indicated that higher dietary intakes of selenium in humans may be protective. 78 •89 Four case control studies 90 - 93 have demonstrated that blood selenium levels were lower in cancer patients than in controls. A three-year study to test the hypothesis that persons with low levels of dietary selenium are at increased risk of developing cancer of the breast, lung, and large bowel was begun in 1983. 16 Results from this study should provide further insight into the potential impact of selenium on carcinogenesis. FOLIC ACID
Folic acid (folate) plays a key role in the maturation and differentiation of normal cells. It functions as a coenzyme in nucleic acid metabolism. Folic acid is found in liver, legumes, and green leafy vegetables. The RDA is 0.4 mg for adults and children over four years of age. Folate deficiency has been implicated in the development of cervical dysplasia in women taking oral contraceptives. Butterworth et al 94 studied 47 women with mild or moderate cervical dysplasia who were given oral folic acid or placebo (vitamin C) daily for three months. These women continued their use of a combination-type oral contraceptive. Significant improvement was observed in the folic acid-treated group compared to the placebo group, which showed no change. These results suggested that folate may prevent the progression of precancereous lesions, and in some cases may promote a reversal to normalcy. TAMOXIFEN
Although, to date, chemoprevention trials have focused on micronutrients, one promising opportunity for chemoprevention lies in the use of hormonal therapy to prevent hormonally dependent cancer in high risk individuals. The emerging understanding of breast cancer biology, particularly the role of hormones and hormonal receptors, provides a firm basis for consideration of antiestrogen therapy as a preventive measure in high risk women. Tamoxifen holds promise as one such agent. The theoretical rationale for prevention trials in humans and the anticancer biologic activity of this drug have been reviewed.f" Briefly, tamoxifen and its metabolites can inhibit the binding of es-
tradiol to estrogen receptors in human breast tumors, which appears to produce a block in the breast cancer cell cycle at the G-l stage. Theoretically, tamoxifen may be as effective in inhibiting the development of tumors as in the control of advanced disease." Animal data have demonstrated the influence of tamoxifen on breast cancer prevention. Studies describe the inhibition of both initiation96 •97 and promotion'T" in induced mammary tumors of the rat. No human prevention trials with tamoxifen have yet begun. Further studies are needed to assess the long-term effects of tamoxifen prior to using it in large numbers of healthy women. Toxicity associated with tamoxifen used in the treatment of human breast cancer over the past 12 years is mlnimal" NURSING AND CHEMOPREVENTION
Involvement in chemoprevention efforts represents an expanded role for oncology nurses and carries with it particular personal and professional responsibilities. Two aspects of nursing practice are important in cancer prevention: education and research. Education Information regarding cancer prevention is expanding, both in the professional and lay literature. Almost daily new reports claim one agent or another prevents or causes cancer. Professionals, as well as the public, are often overwhelmed and confused. It is all too easy to say that if some of a micronutrient supplement is good, more would be better. There is evidence that our society is megadosing on vitamins. Kerr- notes that if responsible information is not provided by those most competent to do so, the public will look to health fadists for information. Nurses have the skills necessary to provide nutritional counseling through educational efforts, which can be coordinated either in the physician's office or in the hospital setting. First, however, nurses must avail themselves of the current health care literature and keep abreast of what is being published in the lay literature. Nurses need not be epidemiologists, but they can be critical reviewers. In addition, they need to share this information with colleagues by discussing and clarifying concerns or misconceptions. KerrS notes that quackery such as "Dr Johnson's Mild Combination Treatment for Cancer"
218
led to the 1912 Sherley Amendment to the Food and Drug Act, which made it a criminal offense to label pharmaceutical products with fraudulent claims of therapeutic value. Nevertheless, the First Amendment to the Constitution permits such claims to be made in pamphlets or brochures that may be available in the immediate vicinity of a product. Responsible nutritional counseling for cancer prevention should recognize nutritional quackery as a menace to the public and in particular to those whose health problems may have a nutritional component. Nurses need to recognize and convey to the public that the physiologic or pharmacologic effects of megadoses of nutrients consumed alone or in combination have not,been defined; that indeed, in some instances, megadoses of vitamins can have life threatening consequences, At the same time, nurses must appreciate that unchecked mass media sensationalism or entrepreneurial marketing can sway personal practices and convictions with the potential for selfdiagnosis and self-treatment. Such practices can have potentially disastrous health consequences. Until definitive results of current ongoing clinical trials become available, the current NCI dietary recommendations involve minimal nutritional risk, recognize the large amount of evidence accumulated during the past few decades, and are compatible with a preventive approach to other nutrition-associated health problems of our society.!" The dietary recommendations specify a balanced diet providing the recommended dietary fruits, vegetables, and whole grains, in place of vitamin supplements; that the total number of daily calories be moderate; the amount of fat in the diet be reduced to less than 30% of the daily calorie intake; the amount of fiber and complex carbohydrates in the diet be increased; foods be baked, roasted, or boiled rather than fried; and alcohol be limited to two drinks daily. Educating patients and the public presents a unique challenge. Most people associate illness, at any stage, with symptoms. Cancer prevention by its very nature necessitates a lifetime of vigilance in the absence of symptoms. The latency and multicausal nature of cancer may demand multiple lifestyle changes. Attention to the principles of health education such as those advocated by Bartlett99 provides a useful guideline for effective patient and public education.
OLSEN AND LOVE
Research Attention to the outcome of biologic chernoprevention trials will initially focus on the impact of specific agents on carcinogenesis. Certainly, this is important and appropriate, but data from other prevention studies indicate additional outcomes are likely and may confound the results of these trials, such as when individuals in the control groups change their behavior. Because nurses diagnose and treat certain human responses, they are in an ideal position to assess the potential impact that chemoprevention trials may have on all behaviors, not only those of subjects but also those of controls. Some important considerations are .as follows: How will individuals respond to chernoprevention trials? How will they react to the potential of a "magic bullet" and what will this mean with respect to the exclusion or adoption of other health related behaviors? If retinoids prevent skin cancers, will individuals become less concerned about the skin damaging effects of the sun and seek tans at all costs? What will smokers in chemoprevention trials do about their smoking habits? Will men and women who ingest agents to prevent colon or breast cancer ignore dietary recommendations to limit fat in their diet? Will recommendations for regular screening exams go unheeded? Attention must be given to the behavioral and psychosocial influences that may result through an individual's participation in chemoprevention clinical trials. Increasingly, nurses participate in protocol development and as members of human subjects review committees. Knowledge regarding the issues mentioned above must be shared with fellow researchers. Additional responsibilities include advocating subjects' rights and protection through knowledgeable and thoughtful protocol review. Weed l OO has expressed concern that chemoprevention studies are not, for the most part, performed on ailing individuals and that this has important ethical implications. He encourages well planned experiments wherein all unnecessary risks are minimized. In chemoprevention research, the role of the nurse is further expanded. Nurses must accept the personal and professional responsibilities that such an expanded role demands. Attention to the impact of clinical trials on behavior and active re-
219
A NEW DIRECTION: CHEMOPREVENTION
view of institutional protocols and consent forms with attention to study design and subjects safety broaden the scope of the patient advocate role of the nurse. CONCLUSION
This paper has provided an overview of chemoprevention. Three aspects of this new focus in cancer prevention were addressed: the past and current directions in chemoprevention, the epidemiologic, carcinogenic, and biologic basis for chemoprevention efforts, and the potential impact this new focus may have on nursing. The prospects for
the future in chemoprevention are excitmg , but much research in the educational and psychosocial aspects of prevention is needed if biologically promising interventions are to result in the clinical prevention of cancer. Of particular concern is the means by which health care consumers, both participants and nonparticipants in clinical chemoprevention trials, will change their health behaviors over time. As clinical trials begin and the medical and lay literature abound with new information, medicine and nursing must work together, each assessing different, but complementary, aspects of the impact of these new studies on the health and behavior of the individual.
REFERENCES I. Doll R, Peto R: The causes of cancer: Quantitative cstimates of avoidable risks of cancer in the United States today. INCI 66: 1192- 1308, 1981 2. Love RR, Olsen SJ: An agenda for cancer prevention in nursing practice. Cancer Nurs 8:329-338, 1985 3. Loprinzi CL. Verma AK, Boutwell RK. et al: Inhibition of phorbol ester-induced human epidermal ornithine decarboxylase activity by oral compounds: A possible role in human chernoprevention studies. 1 C1in Oncol 3:751- 757, 1985 4. Watson RR: Vitamin E. A and C: Cancer prevention agents? Ariz Med 151:671-673. 1984 5. Kerr GR: Nutritional counseling for cancer prevention. in GR Newell (ed): Cancer Prevention in Clinical Medicine. New York. Raven, 1983, pp 165-189 6. Greenwald P: Epidemiology: A step forward in the scientific approach to preventing cancer through chernoprevention. Public Health Rep 99:259-264, 1984 7. Shanmugaratnarn K: Prevention and early detection of cancer. Cancer Detect Prev 8:431-445. 1985 8. Koch HF: Biochemical treatment of precancerous oral lesions: The effectiveness of various analogues of retinoic acid. 1 Maxillofac Surg 6:59-63, 1978 9. Stitch HF, Rosin MP, Vallejera MO: Reduction with vitamin A and beta-carotene administration of proportion of micro nucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet I: 1204-1206, 1984 10. Alfthan O. Tarkkanen 1, Grohn P, et al: Tigason (etrctinate) in prevention of recurrence of superficial bladder tumors: A double-blind clinical trial. Eur Urol 9:6-9. 1983 II. Studer UE, Biedermann C, Chollett D, et al: Prevention of recurrent superficial bladder tumors by oral ctrctinate: Preliminary results of a randomized. double-blind multicenter trial in Switzerland. 1 Urol 131:47-49, 1984 12. Tucker MA, Meadows AT, Boice ID, et al: Cancer risk following treatment of ehildhood cancer, in Boice ID, Fraumeni IF (eds): Radiation Carcinogenesis: Epidemiology and Biological Significance. New York. Raven. 211-224, 1984 13. Greene ~IH: Epidemiologic studies of chemotherapyrelated acute leukemia. in Castellani A (ed): Epidemiology and Quantitation of Environmental Risks in Humans from Radia-
tion and Other Agents-Potential and Limitations. New York. Plenum, 1985, pp 499-514 14. DeWys WE. Greenwald P: Prevention program overview, in Sestili MA (ed): Chernoprevention Clinical Trials: Problems and Solutions. Bethesda Md, National Cancer Institute, NIH Publication 85-2715,1984. pp 1-3 15. Committee on Diet, Nutrition. and Cancer, Assembly of Life Sciences, National Research Council: Diet, Nutrition and Cancer. Washington. DC. National Academy Press. 1982 16. Office of Cancer Communications: Backgrounder: Cancer prevention research: Chemoprevention and diet. Bethesda, Md. National Cancer Institute, 1984 17. Committee on Dietary Allowances, Food and Nutrition Board: Recommended Dietary Allowances. Washington, DC, National Academy of Sciences, 1980 18. Kummet T, Meyskens FL: Vitamin A: A potential inhibitor of human cancer. Semin Oncol 10:281-289, 1983 19. Meyskens FL: Laboratory monitoring for vitamin A and the retinoids in chemoprevention trials. in Sestili MA (ed): Chernoprevention Clinical Trials: Problems and Solutions. Bethesda, Md. National Cancer Institute. NIH Publication 85-2715. 1984. pp 93-95 20. Sestili MA: Safety considerations in the conduct of chernoprevention trials. in Sestili MA (ed): Chemoprevention Clinical Trials. Bethesda, Md. National Cancer Institute, NIH Publication 85-2715, 1984, pp 83-86 21. Moriarty M, Dunn 1, Darragh A, et al: Etretinate in the treatment of actinic keratoses. Lancet 1:364-365, 1982 22. Peck GL, Olsen TG, Butkus D. et al: Treatment of basal cell carcinomas with 13-cis-retinoic acid. Proc Am Assoc Cancer Res 20:56, 1979 (abstr) 23. Kessier IF, Meyskens FL. Levene N, et al: Treatment of cutaneous T-cell lymphoma (mycosis fungoidcs) with l3-cisrctinoic acid. Lancet I: 1345-1347, 1983 24. Gouveia 1, Mathe G, Hercent T, et al: Degree of bronchial metaplasia in heavy smokers and its regression after treatment with a retinoid. Lancet 1:710-712, 1982 25. Schnitzler L. Verret lL: Retinoid and skin cancer prevention. in Orfanos EE, Braun-Falco 0, Farber EM, et al
220
(eds): Retinoids: Advances in Basic Research and Therapy. Berlin, Springer Verlag, 1981, pp 385-388 26. Sporn MB, Roberts AB: Role ofretinoids in differentiation and carcinogenesis. JNCI73:1381-1387, 1984 27. Peto R: The marked differences between carotenoids and retinoids: Methodological implications for biochemical epidemiology. Cancer Surv 2:327-340, 1983 28. Goodman DS: Vitamin A and retinoids in health and disease. N Engl J Med 310:1023-1031,1984 29. Boutwell RK: Retinoids and inhibition of ornithine decarboxylase activity. Am Acad Dermatol 6:796-798, 1982 30. Elias PM, Williams ML: Retinoids, cancer and the skin. Arch DermatoI17:160-182, 1981 31. Sporn MB: Retinoids and cancer prevention, in Siaga TJ (ed): Carcinogenesis-A Comprehensive Survey. Modifiers of Chemical Carcinogenesis. New York, Raven, 1980, pp 99-109 32. Sporn MB, Newton DL: Recent advances in the use of retinoids for cancer prevention, in Burchenal JH, Dettgen HG (eds): Cancer Achievements, Challenges and Prospects for the 1980's. Orlando, F1a, Grone & Stratton, 1981, pp 541-548 33. Greenwald P: Manipulation of nutrients to prevent cancer. Hosp Pract 19:119-134, 1984 34. Bjelke E: Dietary vitamin A and human lung cancer. Int J Cancer 15:561-565, 1975 35. Gregor A, Lee PN, Roc FJC, et al: Composition of dietary histories in lung cancer cases and controls with special reference to vitamin A. Nutr Cancer 2:93-97, 1980 36. Hirayama T: Diet and cancer. Nutr Cancer 1:67-82, 1979 37. Lacl.ennan R, DaCosta J, Day N, et al: Risk factors for lung cancer in Sjngapore Chinese, a population with high female incidence rates. Int J Cancer 20:854-860, 1977 38. Mettlin C, Graham S, Swanson M: Vitamin A and lung cancer. JNCI 62:1435-1438,1979 39. Shekelle RB, Liu S, Raynor WJ, et al: Dietary vitamin A and risk of cancer in the Western Electric Study. Lancet 2:1185-1189, 1981 40. Graham S, Haughey B, Marshall J, et al: Diet in the epidemiology of carcinoma of the prostate gland. JNCI 70:687-690, 1983 41. Schuman LM, Mandel JS, Radke A, et al: Some selected features of the epidemiology of prostatic cancer: Minneapolis-St Paul, Minnesota case-control study. 1976-1979, in Magnus K (ed): Trends in Cancer Incidence, Causes and Practical Implications. New York, Hemisphere, 1982, pp 345-354 42. Graham S, Dayal H, Swanson M, et al: Diet in the epidemiology of cancer of the colon and rectum. JNCI 61:709714, 1978 43. Graham S, Mettlin C, Marshall J, et al: Dietary factors in the epidemiology of cancer of the larynx. Am J Epidemiol 113:675-680, 1981 44. Mettlin C, Graham S, Priore R, et al: Diet and cancer of the esophagus. Nutr Cancer 2:143-147,1981 45. Mettlin C, Graham S: Dietary risk factors in human bladder cancer. Am J Epidemiol 110:255-263, 1979 46. Cook-Mozaffari P: The epidemiology of cancer of the esophagus. Nutr Cancer 1:51-60, 1979 47. Wynder EL, McCoy GD, Reddi BS, et al: Nutritional and metabolic epidemiology of cancers of the oral cavity, esophagus, colon, breast, prostate and stomach, in Newell GR,
OLSEN AND LOVE
Ellison NM (eds): Nutrition and Cancer. New York, Raven, 1983,pp 11-48 48. Graham S: Toward dietary prevention of cancer. Epidemiol Rev 5:38-50, 1983 49. Newberne PM, Suphakarn V: Nutrition and cancer: A review, with emphasis on the role of vitamins C and E and selenium. Nutr Cancer 5:107-119, 1983 50. Young VE, Newberne PM: Vitamins and cancer prevention: Issues and dilemmas. Cancer 47:1226-1240, 1981 51. Mirvish SS: Inhibition of the formation of carcinogenic N-nitroso compounds by ascorbic acid and other compounds, in Burchenal JH, Oettgen HF (eds): Cancer: Achievements, Challenges and Prospects for the 1980's, vol I. Orlando, F1a, Grone & Stratton, 1981, pp 557-587 52. Pipkin GE, Schlegel 10, Nishimura R, et al: Inhibitory effect of L-ascorbate on tumor formation in urinary bladders implanted with 3-hydroxyanthranilic acid. Proc Soc Exp BioI Med 131:522-524, 1969 53. Banic S: Vitamin C acts as a cocarcinogen to methylcholanthrene in guinea pigs. Cancer Lett 11:239-242, 1981 54. Soloway MS, Cohen SM, Dekernion JB, et al: Failure of ascorbic acid to inhibit FANFf-induced bladder cancer. J Urol 113:483-486, 1975 55. Haenszel W, Correa P: Developments in the epidemiology of stomach cancer over the past decade. Cancer Res 35:3452-3459, 1975 56. Higginson J: Etiological factors in gastro-intestinal cancer in man. JNCI 37:527-545, 1966 57. Hirayama T: The epidemiology of cancer of the stomach in Japan with special reference to the role of diet, in Harris RJC (ed): Proceedings of the 9th International Cancer Congress. UICC Monograph Series, vol 10. Berlin, Springer-Verlag, 1967, pp 37-48 58. Kolonel LN, Nomura A, Hirohata T, et al: Association of diet and place of birth with stomach cancer incidence in Hawaiian Japanese and Caucasians. Am J Clin Nutr 34:24782485, 1981 59. Marshall J, Graham S, Byers T, et al: Diet and smoking in the epidemiology of cancer of the cervix. JNCI 70:847-851, 1983 60. Wassertheil-Srnoller S, Romney SL, Wylie-Rosen J, et al: Dietary vitamin C and uterine cervical dysplasia. Am J Epidemiol 114:714-724, 1981 61. Cook-Mozaffari PJ, Azordegan F, Day NE, et al: Oesophageal cancer studies in the Caspian littoral of Iran: Results of a case-control study. Br J Cancer 39:293-309, 1979 62. Tuyns AJ: Protective effect of citrus fruit on esophageal cancer. Nutr Cancer 5:195-200, 1983 63. Yang CS: Research on esophageal cancer in China: A review. Cancer Res 40:2633-2644, 1980 64. Jain M, Cook GM, Davis FG, et al: A case control study of diet and colorectal cancer. Int J Cancer 26:757-768, 1980 65. National Dairy Council: Vitamin Facts. Rosemont, 111, 1982 66. Epstein SS, Joshi S, Audrea J, et al: The null effect of antioxidants on the carcinogenicity of 3,4,9-IO-dibenzpyrene in mice. Life Sci 6:225-233, 1967 67. Farrell P, Bieri J: Megavitamin E supplementation in man. Am J Clin Nutr 28:1381-1385,1975
A NEW DIRECTION: CHEMOPREVENTION
68. Shamberger R. RUdolphG: Protection against cocarcinogens by antioxidants. Experientia 22:116. 1966 69. Bonmassar E. DalIavalIe R. Giuliani G: Influence of vitamin E and propylgallate on carcinogenesis with benzopyrene in mice. Arch Ital Pathol Clin Tumor 11:245-250, 1968 70. Cook MG, McNamara P: Effect of dietary vitamin Eon dimethylhydrazine-induced colonic tumors in mice. Cancer Res 40:1329-1331,1980 71. Clayton CC, Baumann CA: Diet and axotumors: Effect of dietary period when the diet is not fed. Cancer Res 9:575582, 1949 72. Lipkin M, Newmark H: Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 313:1381-1384, 1985 73. Garland C, Barrett-Connor E, Rossof AH, et al: Dietary vitamin D and calcium and risk of colorectal cancer: A 19-year prospective study in men. Lancet 1:307-309, 1985 74. Garland CF, Garland FC: Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 9:227231, 1980 75. Teppo I, Saxen E: Epidemiology of colon cancer in Scandinavia. Isr J Med Sci 15:322-328, 1979 76. Philips RL: Role of the life-style and dietary habits in risk of cancer among Seventh Day Adventists. Cancer Res 35:3515-3522, 1975 77. Buell DN: Potential hazards of selenium as a chemopreventive agent. Semin Oncol 10:311-321, 1983 78. Shamberger RJ: Relation of selenium to cancer. 1. Inhibitory effect of selenium on carcinogenesis. JNCI 44:931936, 1970 79. Griffin AC: The chemopreventive role of selenium in carcinogenesis, in Arnot MS, Van Eys J. Wang YM (eds): Molecular Interactions of Nutrition and Cancer. New York, Raven, 1982, pp 401-408 80. Soullier BK, Wilson PS. Nigro ND: Effect of selenium on Azoxymethane-induced intestinal cancer in rats fed high fat diet. Cancer Lett 12:343-348, 1981 81. Wilt S, Pereira M, Couri D: Selenium effect on initiation and promotion of tumors by benzo(a)pyrene and 12-0tetradecanoylphorboI. Proc Am Assoc Cancer Res 20:21,1979 (abstr) 82. Ip C: Modification of mammary carcinogenesis and tissue peroxidation by selenium deficiency and dietary fat. Nutr Cancer 2:136-142, 1981 83. Ip C: Prophylaxis of mammary neoplasia by selenium supplementation in the initiation and promotion phases of chemical carcinogenesis. Cancer Res 41:4386-4390, 1981 84. Ip C, Ip MM: Chemoprevention of mammary tumorigenesis by a combined regimen of selenium and vitamin A. Carcinogenesis 2:915-918, 1981
221
85. Ip C, Sinha DK: Anticarcinogenic effect of selenium in rats treated with dimethylbenz(a)anthracene and fed different levels and types of fat. Carcinogenesis 2:435-438, 1981 86. Ip C, Sinha DK: Enhancement of mammary tumorigenesis by dietary selenium deficiency in rats with a high polyunsaturated fat intake. Cancer Res 41:31-34, 1981 87. Thompson HJ, Becci PJ: Selenium inhibition of Nmethyl-n-nitrosourea-induced mammary carcinogenesis in the rat. JNCI 65:1299-1301,1980 88. Robinson MF, Godfrey PJ, Thomson DC, et al: Blood selenium and glutathione peroxidase activity in normal subjects and in surgical patients with and without cancer. Am J Clin Nutr 32:1477-1485, 1979 89. Schrauzer GN, White DA, Schneider CJ: Cancer mortality correlation studies. III. Statistical associates with dietary selenium intakes. Bioinorg Chern 7:23-34, 1974 90. Broghamer WL, McCc,nell WL, Blotcky KP: Relationship between serum selenium levels and patients with carcinoma. Cancer 37:1384-1388, 1976 91. Calautti P, Moschini G, Stievano BM, et al: Serum selenium levels in malignant Iymphoproliferative diseases. Scand J Haematol 24:63-66, 1980 92. Shamberger RJ, Rukovena E, Longfield AK, et al: Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. JNCI 50:867-870. 1977 93. Willett WC, Polk BF, Morris SJ, et al: Prediagnostic serum selenium and risk of cancer. Lancet 2:130-133, 1983 94. Butterworth CE, Hatch KD, Gore H, et al: Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 35:73-82, 1982 95. Love RR, Carbone PP, Jordan VC, et al: Strategies in preventive oncology: A clinical trial of tamoxifen as a chemopreventive agent for women with a family history of breast cancer, in Lynch HT, Kullander S (eds): Cancer Genetics in Women. Boca Raton, Fla, CRC, (in press) 96. Jordan VC: Effect of tamoxifen (ICI 46, 474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12:419-424, 1976 97. Welsch \VW, Goodrich-Smith M, Brown DK, et al: 2Bromo-ergocryptine (CB·154) and tamoxifen (ICI-46, 474) induced suppression of the genesis of mammary carcinomas in female rats treated with 7,12-dimethylbenzanthrene (DMBA): A comparison. Oncology 39:88-92, 1982 98. Jordan VC, Allen KE: Evaluation of the antitumor activity of the nonsteroidal antiestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16:239-251, 1980 99. Bartlet EE: Principles in health education. Prev Med 14:667-669, 1985 100. Weed DL: Ethics and chemoprevention research. Semin Oncol 10:355-359, 1983
P
REVENTION is one of the most appealing but also the most challenging ways of controlling human cancer. Until recently efforts in preventive oncology have been threefold: (I) to identify risk factors associated with cancer, (2) to understand the behavior and education needed to decrease risk, and (3) to identify and manage premalignant conditions. The identification of risk factors should allow their manipulation to decrease the incidence of cancer. However, while progress in the first and third areas has been made, translation into effective clinical prevention has been infrequent and difficult. Paralleling activities in these three areas has been research in the biology of cancer, which has suggested possibilities for chemoprevention. The purposes of this paper are to provide an introduction to chemoprevention, to discuss the theoretical and known mechanisms of action for selected agents and review their current daily dose recommendations and potential overconsumption toxicities, to identify human studies underway to determine the influence of these specific agents on the development of cancer, and finally, to dileneate issues of concern in this new approach for nursing practice. Chemoprevention is the taking of a drug (vitamin, hormone or other agent) for the purpose of preventing cancers or precancerous lesions or reversing premalignant conditions to normal. To date, most chemoprevention studies have involved micronutrients. While the possibility that something as simple as taking a pill might prevent cancer is appealing, the successful application of such a proven biologic intervention may be more challenging than is immediately apparent. The data for planning chemoprevention have come from studies in epidemiology, carcinogenesis, and biology. Epidemiologic studies have shown that environmental factors are important in most human cancers, dietary factors and tobacco being the most important in the United States. Doll and Peto! concluded that perhaps 35% of all US cancer deaths may be attributable to diet. General dietary factors include macronutrients (eg, fat and fiber) and micro nutrients (eg, vitamins and minerals). The majority of the research regarding micronutrients associates low consumption with Seminars in Oncology Nursing, Vol 2, No J (August), 1986: pp 211-221
cancer. It is not known if raising consumption to above normal levels will prevent cancer. Since human cancers take many years to develop, only prospective studies with large populations can tell us whether supplementation of normal diets with various micronutrients will prevent cancer. Experimental models of carcinogenesis suggest that tumors evolve through a multistage process including initiation and promotion.? Tumor initiation, which can be brought about by exposure to chemicals, viruses, or ultraviolet light, appears to cause an irreversible change in cellular DNA. Tumor promotion, on the other hand, must follow initiation, and exposure must be repeated at relatively frequent intervals to produce cancer. Because tumor promotion results from repetitive events occurring over a long time and is reversible, this stage has been a target for chemoprevention.? Data support an inhibitory influence on carcinogenesis of such micronutrients as vitamins C, E, A (both naturally occurring and synthetic reiinoids), and most recently, vitamin D. A similar role has been suggested for the two minerals, selenium and calcium. Deficiencies of vitamin A and Col and folic acid" have been associated with suppression of immune function. Watson" cites multiple animal studies documenting enhancement of the immune response with dietary supplements of vitamin E, an increase in T-Iymphocyte mitogenesis and natural killer cell activities with a high vitamin A intake, enhancement of cellular immunity with increased tumor resistance by retinoids, and enhanced resistance to immunogenic tumors in the presence of beta-carotene. CURRENT RESEARCH IN CHEMOPREVENTION
Agents used for chemoprevention include both natural and synthetic products. These agents can
From the Cancer Prevention Clinic, University of Wisconsin Clinical Cancer Center, Madison. Address reprint requests to Sharon 1. Olsen, RN, ~tS, Cancer Prevention Program. Wisconsin Clinical Cancer Center, Room 7660. 1300 University Ave, Madison, WI 53706. © 1986 by Grune & Stratton. Inc. 0749-2081/86/0203-0010505.00/0
211
212
be chemically defined and administered in precisely specified dosages." The intent is interference in the formation or activation of carcinogens in vivo, strengthening host defenses and/or blocking or reversing tumor progression in the early stages of carcinogenesis." Current efforts in chemoprevention are directed to three areas: clinical trials in high risk individuals without disease, determination of the impact of micronutrients on premalignant conditions, and the definition of ultra-highrisk groups suitable for further intervention studies. The aims of trials in chemoprevention are to evaluate systematically the efficacy and toxicity of chemoprevention agents. Such human cancer trials are not only expensive but they require the enrollment of hundreds or thousands of individuals to have enough statistical power to convincingly demonstrate effects. The effect of micronutrients on premalignant conditions appears promising: precancerous oral lesions can be reversed's? and levels of the enzyme ornithine decarboxylase (ODC) can be reduced. This enzyme may playa central role in the promotional stage of tumor development. 3 Individuals at risk for the development of second primary cancers or for recurrence of primary cancers are considered important target populations for chemoprevention. Two studies'P-'! have demonstrated the usefulness of micronutrients in decreasing the incidence of recurrent superficial bladder cancer in humans. Long-term survivors of a single childhood neoplasm have a cumulative risk of developing a second cancer approaching 12% by 25 years.F Individuals treated with alkylating agents are at risk for developing acute nonlymphocytic leukemia as are some patients treated with combined modality therapy (radiation plus chemotherapyj.P The latency periods involved in the development of second malignancies in these high risk groups are much shorter than those of other populations, a second aspect which makes these groups of individuals appropriate for chemoprevention studies. In response to mounting laboratory and epidemiologic evidence indicating that micronutrients can halt or reverse cancer progression in animals or reduce the incidence or risk of cancer in humans, the National Cancer Institute (NCI) developed the chemoprevention program. This program is currently sponsoring multiple human in-
OLSEN AND LOVE
tervention trials.!" Table 1 presents the clinical trials currently supported by NCI. REVIEW OF CURRENT DATA ON SELECTED CHEMOPREVENTIVE AGENTS
Studies in tissue culture, animals, and human populations have identified two groups of potential chemoprevention agents: naturally occurring substances found in many foods and synthetic compounds considered safe for clinical trials. Such agents include vitamin A and its precursor [3-carotene, synthetic derivatives of vitamin A, vitamin C, vitamin D, vitamin E, folic acid, calcium, and the trace metal selenium. An exhaustive review of the literature concerning the studies to date on chemoprevention agents may be found elsewhere. 15,16 VITAMIN A
Retinoid is a generic term that includes both natural and synthetic forms of vitamin A. Dietary vitamin A can be derived from its precursor known as carotenoid ([3-carotene) in plant foods, such as carrots, leafy green vegetables, and sweet potatoes. The f3-carotene derived from leafy green and yellow vegetables is converted to vitamin A in the digestive tract. It is uncertain whether the association of [3-carotene with reduced cancer risk is due only to its conversion to vitamin A or if [3carotene has some protective effect of its own. Animal foods have vitamin A in the form of retinol, retinal, and retinyl esters. Sources of retinol include butter, whole milk, egg yolk, liver, and vitamin A pills.
Toxicity The recommended dietary allowance (RDA) for vitamin A in the adult male is 1,000 retinol equivalents, or 5,000 IV. Women appear to have similar liver stores and adequate blood levels with a lower intake of vitamin A than males, probably because of their smaller body size. The allowance for adult females is set at 80% of that for males, or 800 retinol equivalents (4,000 IU).17 Toxicity in adults is seen with daily intakes of more than 15,000 retinol equivalents (50,000 IV) for prolonged periods.!? Side effects have greatly limited the use of vitamin A: these include fatigue, irritability, anorexia, nausea, cracked lips and dry skin with desquamation, and eventually vomiting, headaches, hair loss, bone pain, and hepatomeg-
aly."
213
A NEW DIRECTION: CHEMOPREVENTION Table 1. Current Cancer Prevention Clinical Trials (1984)114) Cancer Site
Intervention
Population Studied
All
US physicians, ages 40-84
l3-carotene Aspirin
All
US nurses
Retinyl palmitate Sodium selenite Vitamin B. Vitamin E
Breast
Family history of breast cancer, history of breast biopsy, first pregnancy after age 30
Low fat diet
Breast
Women with Stage I breast cancer
4-hydroxyphenyl-retinamide
Lung
Smokers Asbestos exposed individuals Sputum cytology: dysplasia
Folic acidNitamin B12 Retinol 13-cis-retinoic acid l3-carotene Vitamin E
Skin
Previous skin cancer Actinic keratosis Albinos
l3-carotene Vitamins C and E Retinol 13-cis-retinoic acid
Esophagus
Cytology: dysplasia General population (China)
MUltiple micronutrients
Colon
Familial polyposis Adenomatous polyps
l3-carotene Vitamins C and E 13-cis-retinoic acid Low fat diet Wheat bran
Cervix
Pap smear: dysplasia
Folic acid Retinyl acetate gel
Data from DeWys et al.'4
J3-carotene is easily measured in the serum, making compliance easy to monitor. Meyskens'? cautions, however, that serum retinol levels generally do not change until the liver has been saturated and do not necessarily reflect whole body or hepatic burden. Because of the known cellular effects on differentiation, women of childbearing potential who are enrolled in vitamin A trials must have a negative pregnancy test performed within 2 weeks prior to the initiation of treatment. 20 They must use an effective means of contraception during treatment and for a prolonged interval after cessation of treatment.
Synthetic Retinoids Natural retinoids are known to have toxic effects in animals, particularly at high doses. Re-
searchers are now trying to develop synthetic retinoids that are as effective as natural retinoids in inhibiting tumor growth, are less toxic, and are more site-specific. During the past 15 years, approximately 1,500 retinoids have been synthesized. The synthetic 4-hydroxyphenyl retinamide (4HPR) has been shown to prevent the development of breast and bladder cancer in animal models. Early testing has shown a very low toxicity compared to other retinoids. Several clinical studies of 13-cis-retinoic acid and a new retinoid, etretinate, have been conducted in dermatology and oncology patients. Toxicity appears to be diminished and etretinate has a tenfold enhancement of therapeutic action over vitamin A in test systems. Activity has been reported for 13-cis-retinoic acid in the treatment of actinic keratoses;" basal cell carcinomas,22 and refractory mycosis fungoides.P Etre-
214
tinate significantly reduces the degree of bronchial metaplasia in heavy smokers" and appears to prevent the recurrence of skin tumors in patients with xeroderma pigrnentosum.P
Mechanism of Action Much has been written about the physiology and biochemistry of vitamin A,I8 the role of retinoids in cell differentiation and carcinogenesis.P and the possible mechanisms by which carotenoids act to prevent cancer.F Derivatives of retinol are required for normal growth, vision, reproduction, and maintenance of epithelial differentiation. Retinoids have powerful effects on cell differentiation and proliferation. They can control DNA synthesis and mitotic activity and they have been shown to act during the promotion stage of cancer induction. 1 These effects have been demonstrated with both normal and neoplastic cells. Since carcinogenesis is fundamentally a disorder of cell differentiation, it is possible that the retinoid status of a cell influences its potential for cancer development.28 Pet027 has suggested that carotenes may prevent cancer by deactivating certain cellular changes and thereby preventing cellular damage, breaking the chain of events leading to the development of cancer. Evidence for this was demonstrated in a recent study by Stich et aI.9 A threefold decrease in chromosome breakage rates was achieved by supplementing the diet of Filipinos who chew betel nuts, a known carcinogen, with capsules of retinol and carotene. How retinoids interfere with the later stages of cancer development is not known, but several ways have been suggested in numerous studies. 29-32
Clinical Trials Over the years multiple studies have examined human cancer risk in relation to dietary intake of vitamin A or f3-carotene. One methodological problem in conducting these studies is the extreme difficulty in determining with any precision what people eat, especially retrospectively. Another potential problem is that an epidemiologic association between a given dietary component and cancer protection may be confounded by unrecognized ingestion of protective components or avoidance of harmful components. One argument against this is that epidemiologic data on dietary
OLSEN AND LOVE
retinoid intake and cancer risk are consistent with findings in the laboratory. Another is that the epidemiologic data are internally consistent; that is, the results of multiple studies support each other. 33 Epidemiologic evidence exists for the role of 13carotene and vitamin A in the reduction of cancer risk in lung,34-39 prostate,36,40,41 colon,36,42 cervix and stomach." larynx," esophagus;" and bladder. 45 Greenwald'? cautions that these studies do not enable researchers to conclude whether dietary vitamin A or f3-carotene intake is important nor do they clarify the exact internal physiologic mechanism for this protection. Therefore, further study is necessary.
Recommendations The National Academy of Sciences has recommended that people eat foods containing vitamin A on a daily basis. While increasing one's dietary intake of vitamin A from the RDA of 5,000 IV to 15,000 IU/d can be done relatively safely, 4 in higher doses, serious toxic side effects can be expected. The natural precursor of vitamin A, f3-carotene, has a lower risk of side effects and is the safest way to supplement vitamin A intake. In addition to the foods listed previously additional good sources of f3-carotene include tomatoes, spinach, greens, winter squash, pumpkin, dried fruits (such as apricots, prunes, or raisins), strawberries, melon, and brussel sprouts. VITAMIN C
Reduced intake of foods that contain vitamin C has been associated with some forms of cancer. 43,46 Vitamin C is present in many fruits, fruit juices, and vegetables. It is also put into certain foods, such as hot dogs, that have nitrate added as a preservative.
Mechanism of Action Vitamin C is involved in many biochemical processes in the body. Probably the most important function in the context of chemoprevention is its role as a nitrite scavenger, preventing the nitrosation of amines, which are carcinogenic in animal species.? Nitrites react with amines or amides in the digestive tract to form nitrosamines and nitrosamides. Vitamin C and E compete with the amine or amide for the nitrosating agent." Pickled, salt-cured, and smoked foods often
A NEW DIRECTION: CHEMOPREVENTION
contain precursors of nitrosamines. Populations that have a high incidence of stomach cancer also have a high intake of these foods and this suggests that conditions that promote the formation of ni- . trosamines increase the risk of cancer of the stornach.f" It has been hypothesized that the addition of ascorbic acid to the diet would, because it is an antioxidant, inhibit the alteration of nitrates to nitrites and the formation of nitrosamines.:" While this has not been established in human populations,48 it is clearly the case in experimental animal studies.f?
Toxic Effects Adverse effects appear in some people using extremely high vitamin C intakes (2,000 to 10,000 mg/d). Some of the adverse effects reported include fatigue, acidosis, oxaluria, diarrhea, and renal stones." It is known that vitamin C interferes with anticoagulants by shortening the prothrombin time.P? Sestili-? suggests researchers may need to exclude diabetics, women of reproductive age, persons with a proclivity to kidney stone formation, and those on anticoagulant therapy when considering subjects for chemoprevention trials utilizing pharmacologic doses of vitamin C.
Experimental and Clinical Studies In animal studies there is some evidence that vitamin C inhibits the formation of gastric carcinogens>' and induction of bladder tumors.V Howeve,r, this is not a uniform finding. 53.54 There are several human studies that support the contention that ascorbic acid is protective against cancer. There is evidence that vitamin C ingestion is associated with lower risks for human cancers of the sfomach,55-58 larynx.P bladder," cervix,59.60 and esophagus.44.61-63 The data remain controversial because several case control studies have found no relationship between ascorbic acid and cancer ri"sk. 40,42.45.64 With few exceptions, these studies have not attempted to assess vitamin C intake either by calculated intakes or by biochemical markers. Rather, they have simply determined usual consumption of food groups, a method that does not address the problem of nutrient interaction.
Recommendations A dietary allowance of 60 mg of vitamin C per day is recommended for adults of both sexes.'?
215
The National Dairy Council's warns that when megadoses of vitamin C are discontinued, deficiency symptoms such as bleeding gums may briefly appear until the body adapts. In conclusion, animal studies are suggestive'? but human studies do not strongly support an association of vitamin C with human cancer. 16.66 However, because there does appear to be some evidence, the current recommendation is to increase consumption of foods containing vitamin C. 49 Clearly, there is need for much more research in this area. VITAMIN E
The functional form of vitamin E is a-tocopherol. Its concentration in foods is usually proportional to the amount of linoleic acid present. A minimum daily requirement is estimated to be about 10 mg, an amount that is likely to be present in almost every type of diet consumed by human populations. Vitamin E is present in a wide variety of natural foods, including vegetable oils, margarines, shortening, eggs, whole grains, and many cereals. I7 Vitamin E appears to be nontoxic in moderate doses; the ingestion of 800 IV daily for three years was shown to cause no ill effects in humans.s? Animal studies have demonstrated that a deficiency in vitamin E results in disorders of the reproductive, musculoskeletal, central nervous, and vascular systems."? Because of its antioxidant activity, a-tocopherol is hypothesized to inhibit tumor formation via a mechanism similar to that of ascorbic acid. It appears to prevent the formation of nitrosamines, There is some experimental evidence68- 7o of a cancer-inhibitory effect of vitamin E in animal studies, but epidemiologic data are Iacking.P-?' . However, Watson" maintains that even though the necessary human trials to show efficacy have not been done, the animal data suggest that vitamin E may prove to be a useful adjunct to current cancer prevention. VITAMIN D AND CALCIUM
Recently, two findings have resulted in an increased interest in the investigation of the relationship between vitamin D and calcium, and colon cancer. Lipkin and Newmark'? studied ten individuals predisposed to colorectal cancer who were given supplemental dietary calcium for two to
OLSEN AND LOVE
216
three months. They observed a reversal of an abnormal proliferative state of the colonic mucosa known to be associated with an increased incidence of colonic cancer. Although it cannot be concluded from these results that the risk for colon cancer was reduced, that possibility was suggested. Animal studies by previous investigators corroborate these findings.t-' A second major finding'" was that mortality rates from colon cancer were highest in populations exposed to the least amounts of natural sunlight; difference in endogenous vitamin D production and calcium absorption were thought to be responsible. Garland et aJ73 investigated whether dietary vitamin D and calcium were associated with a 19-year risk of colorectal cancer in almost 2,000 middle-aged white men. Forty-nine colorectal cancers were found. As hypothesized, there was an inverse association between risk for developing colorectal cancer and intake of both vitamin D and calcium. Their results supported the suggestion?? that vitamin D and calcium may reduce the risk of colorectal cancer. The authors noted that dietary vitamin D and calcium are closely related and that calcium is dependent on vitamin D for intestinal absorption. Epidemiologic data are sparse, but results from Scandinavia" based on milk consumption suggest a protective effect for calcium and vitamin D. An inverse association between milk consumption and risk of colon cancer was also observed in a casecomparison study of Seventh-Day Adventists in the USA,76 where milk was routinely supplemented with vitamin D.
SELENIUM
Selenium is an essential constituent of the diet. A range of 50 to 200 ~g/d is suggested as adequate.!? Total dietary intake will vary with the source, class of food, processing, and cooking. Seafood, meat (especially kidney and liver), and whole grains are generally good sources. Fruits and vegetables are generally poor sources. 17.77 Selenium is thought to attach to free electrons and decrease the activity of enzymes that activate procarcinogens.
Toxic Effects Although selenium is essential, it is also toxic."? Toxicity will be dependent upon the form in which selenium is provided and the presence of other dietary constituents. Toxicity may be modified by high dietary levels of arsenic, silver, mercury, copper, and cadmium. In rats it has been shown that high protein diets protect against the toxic effects of selenium. Selenium is detoxified in the liver and excreted mainly via the kidneys. Symptoms of toxicity include pulmonary symptoms such as cough, coryza, and bronchitis probably secondary to the production of dimethylselenide, a volatile substance excreted by the lungs. This is responsible for the garlic breath that characterizes toxicity in both animals and man. Other symptoms include indigestion, lassitude, and irritability. Skin rash indicates direct dermal toxicity. 77 Selenium can be transmitted through the placenta to the fetus, and toxic reproductive and teratogenic effects have been reported. 77
Recommendations At this time there is no reason to suggest that individuals should ingest more than the current RDA levels of vitamin D (5 ug) and calcium (800 rng). 17 In fact, overconsumption of vitamin Dean lead to nausea, weight loss, and irritability.s" It is known that vitamin D may be synthesized when the skin is exposed to sunlight. 65 Food sources common to both elements include fortified dairy products and margarine. Fish oils and egg yolk are additional sources of vitamin D. In conclusion, the present evidence does not show conclusively that vitamin D or calcium protect against the occurrence of colorectal cancer. Nevertheless, current evidence indicates that this line of investigation is worthy of pursuit.
Animal and Human Studies Laboratory animals fed selenium have demonstrated a reduction in liver tumors,"! inhibition of carcinogenesis.P a decrease in number of colon tumors,79,80 inhibition of the formation of papillomas.f" and inhibition of mammary carcinoma. 82-87 Studies of human populations have shown provocative results. In 1979 Robinson et al 88 studied natives in New Zealand, a country where the soil content of selenium is low and individuals have a known low level of selenium in their serum and tissues. They looked at patients with stomach, colon, bladder, breast, liver, and pancreatic cancer and found no relationship between sele-
217
A NEW DIRECTION: CHEMOPREVENTION
nium and these cancers. However, two correlation studies indicated that higher dietary intakes of selenium in humans may be protective. 78 •89 Four case control studies 90 - 93 have demonstrated that blood selenium levels were lower in cancer patients than in controls. A three-year study to test the hypothesis that persons with low levels of dietary selenium are at increased risk of developing cancer of the breast, lung, and large bowel was begun in 1983. 16 Results from this study should provide further insight into the potential impact of selenium on carcinogenesis. FOLIC ACID
Folic acid (folate) plays a key role in the maturation and differentiation of normal cells. It functions as a coenzyme in nucleic acid metabolism. Folic acid is found in liver, legumes, and green leafy vegetables. The RDA is 0.4 mg for adults and children over four years of age. Folate deficiency has been implicated in the development of cervical dysplasia in women taking oral contraceptives. Butterworth et al 94 studied 47 women with mild or moderate cervical dysplasia who were given oral folic acid or placebo (vitamin C) daily for three months. These women continued their use of a combination-type oral contraceptive. Significant improvement was observed in the folic acid-treated group compared to the placebo group, which showed no change. These results suggested that folate may prevent the progression of precancereous lesions, and in some cases may promote a reversal to normalcy. TAMOXIFEN
Although, to date, chemoprevention trials have focused on micronutrients, one promising opportunity for chemoprevention lies in the use of hormonal therapy to prevent hormonally dependent cancer in high risk individuals. The emerging understanding of breast cancer biology, particularly the role of hormones and hormonal receptors, provides a firm basis for consideration of antiestrogen therapy as a preventive measure in high risk women. Tamoxifen holds promise as one such agent. The theoretical rationale for prevention trials in humans and the anticancer biologic activity of this drug have been reviewed.f" Briefly, tamoxifen and its metabolites can inhibit the binding of es-
tradiol to estrogen receptors in human breast tumors, which appears to produce a block in the breast cancer cell cycle at the G-l stage. Theoretically, tamoxifen may be as effective in inhibiting the development of tumors as in the control of advanced disease." Animal data have demonstrated the influence of tamoxifen on breast cancer prevention. Studies describe the inhibition of both initiation96 •97 and promotion'T" in induced mammary tumors of the rat. No human prevention trials with tamoxifen have yet begun. Further studies are needed to assess the long-term effects of tamoxifen prior to using it in large numbers of healthy women. Toxicity associated with tamoxifen used in the treatment of human breast cancer over the past 12 years is mlnimal" NURSING AND CHEMOPREVENTION
Involvement in chemoprevention efforts represents an expanded role for oncology nurses and carries with it particular personal and professional responsibilities. Two aspects of nursing practice are important in cancer prevention: education and research. Education Information regarding cancer prevention is expanding, both in the professional and lay literature. Almost daily new reports claim one agent or another prevents or causes cancer. Professionals, as well as the public, are often overwhelmed and confused. It is all too easy to say that if some of a micronutrient supplement is good, more would be better. There is evidence that our society is megadosing on vitamins. Kerr- notes that if responsible information is not provided by those most competent to do so, the public will look to health fadists for information. Nurses have the skills necessary to provide nutritional counseling through educational efforts, which can be coordinated either in the physician's office or in the hospital setting. First, however, nurses must avail themselves of the current health care literature and keep abreast of what is being published in the lay literature. Nurses need not be epidemiologists, but they can be critical reviewers. In addition, they need to share this information with colleagues by discussing and clarifying concerns or misconceptions. KerrS notes that quackery such as "Dr Johnson's Mild Combination Treatment for Cancer"
218
led to the 1912 Sherley Amendment to the Food and Drug Act, which made it a criminal offense to label pharmaceutical products with fraudulent claims of therapeutic value. Nevertheless, the First Amendment to the Constitution permits such claims to be made in pamphlets or brochures that may be available in the immediate vicinity of a product. Responsible nutritional counseling for cancer prevention should recognize nutritional quackery as a menace to the public and in particular to those whose health problems may have a nutritional component. Nurses need to recognize and convey to the public that the physiologic or pharmacologic effects of megadoses of nutrients consumed alone or in combination have not,been defined; that indeed, in some instances, megadoses of vitamins can have life threatening consequences, At the same time, nurses must appreciate that unchecked mass media sensationalism or entrepreneurial marketing can sway personal practices and convictions with the potential for selfdiagnosis and self-treatment. Such practices can have potentially disastrous health consequences. Until definitive results of current ongoing clinical trials become available, the current NCI dietary recommendations involve minimal nutritional risk, recognize the large amount of evidence accumulated during the past few decades, and are compatible with a preventive approach to other nutrition-associated health problems of our society.!" The dietary recommendations specify a balanced diet providing the recommended dietary fruits, vegetables, and whole grains, in place of vitamin supplements; that the total number of daily calories be moderate; the amount of fat in the diet be reduced to less than 30% of the daily calorie intake; the amount of fiber and complex carbohydrates in the diet be increased; foods be baked, roasted, or boiled rather than fried; and alcohol be limited to two drinks daily. Educating patients and the public presents a unique challenge. Most people associate illness, at any stage, with symptoms. Cancer prevention by its very nature necessitates a lifetime of vigilance in the absence of symptoms. The latency and multicausal nature of cancer may demand multiple lifestyle changes. Attention to the principles of health education such as those advocated by Bartlett99 provides a useful guideline for effective patient and public education.
OLSEN AND LOVE
Research Attention to the outcome of biologic chernoprevention trials will initially focus on the impact of specific agents on carcinogenesis. Certainly, this is important and appropriate, but data from other prevention studies indicate additional outcomes are likely and may confound the results of these trials, such as when individuals in the control groups change their behavior. Because nurses diagnose and treat certain human responses, they are in an ideal position to assess the potential impact that chemoprevention trials may have on all behaviors, not only those of subjects but also those of controls. Some important considerations are .as follows: How will individuals respond to chernoprevention trials? How will they react to the potential of a "magic bullet" and what will this mean with respect to the exclusion or adoption of other health related behaviors? If retinoids prevent skin cancers, will individuals become less concerned about the skin damaging effects of the sun and seek tans at all costs? What will smokers in chemoprevention trials do about their smoking habits? Will men and women who ingest agents to prevent colon or breast cancer ignore dietary recommendations to limit fat in their diet? Will recommendations for regular screening exams go unheeded? Attention must be given to the behavioral and psychosocial influences that may result through an individual's participation in chemoprevention clinical trials. Increasingly, nurses participate in protocol development and as members of human subjects review committees. Knowledge regarding the issues mentioned above must be shared with fellow researchers. Additional responsibilities include advocating subjects' rights and protection through knowledgeable and thoughtful protocol review. Weed l OO has expressed concern that chemoprevention studies are not, for the most part, performed on ailing individuals and that this has important ethical implications. He encourages well planned experiments wherein all unnecessary risks are minimized. In chemoprevention research, the role of the nurse is further expanded. Nurses must accept the personal and professional responsibilities that such an expanded role demands. Attention to the impact of clinical trials on behavior and active re-
219
A NEW DIRECTION: CHEMOPREVENTION
view of institutional protocols and consent forms with attention to study design and subjects safety broaden the scope of the patient advocate role of the nurse. CONCLUSION
This paper has provided an overview of chemoprevention. Three aspects of this new focus in cancer prevention were addressed: the past and current directions in chemoprevention, the epidemiologic, carcinogenic, and biologic basis for chemoprevention efforts, and the potential impact this new focus may have on nursing. The prospects for
the future in chemoprevention are excitmg , but much research in the educational and psychosocial aspects of prevention is needed if biologically promising interventions are to result in the clinical prevention of cancer. Of particular concern is the means by which health care consumers, both participants and nonparticipants in clinical chemoprevention trials, will change their health behaviors over time. As clinical trials begin and the medical and lay literature abound with new information, medicine and nursing must work together, each assessing different, but complementary, aspects of the impact of these new studies on the health and behavior of the individual.
REFERENCES I. Doll R, Peto R: The causes of cancer: Quantitative cstimates of avoidable risks of cancer in the United States today. INCI 66: 1192- 1308, 1981 2. Love RR, Olsen SJ: An agenda for cancer prevention in nursing practice. Cancer Nurs 8:329-338, 1985 3. Loprinzi CL. Verma AK, Boutwell RK. et al: Inhibition of phorbol ester-induced human epidermal ornithine decarboxylase activity by oral compounds: A possible role in human chernoprevention studies. 1 C1in Oncol 3:751- 757, 1985 4. Watson RR: Vitamin E. A and C: Cancer prevention agents? Ariz Med 151:671-673. 1984 5. Kerr GR: Nutritional counseling for cancer prevention. in GR Newell (ed): Cancer Prevention in Clinical Medicine. New York. Raven, 1983, pp 165-189 6. Greenwald P: Epidemiology: A step forward in the scientific approach to preventing cancer through chernoprevention. Public Health Rep 99:259-264, 1984 7. Shanmugaratnarn K: Prevention and early detection of cancer. Cancer Detect Prev 8:431-445. 1985 8. Koch HF: Biochemical treatment of precancerous oral lesions: The effectiveness of various analogues of retinoic acid. 1 Maxillofac Surg 6:59-63, 1978 9. Stitch HF, Rosin MP, Vallejera MO: Reduction with vitamin A and beta-carotene administration of proportion of micro nucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet I: 1204-1206, 1984 10. Alfthan O. Tarkkanen 1, Grohn P, et al: Tigason (etrctinate) in prevention of recurrence of superficial bladder tumors: A double-blind clinical trial. Eur Urol 9:6-9. 1983 II. Studer UE, Biedermann C, Chollett D, et al: Prevention of recurrent superficial bladder tumors by oral ctrctinate: Preliminary results of a randomized. double-blind multicenter trial in Switzerland. 1 Urol 131:47-49, 1984 12. Tucker MA, Meadows AT, Boice ID, et al: Cancer risk following treatment of ehildhood cancer, in Boice ID, Fraumeni IF (eds): Radiation Carcinogenesis: Epidemiology and Biological Significance. New York. Raven. 211-224, 1984 13. Greene ~IH: Epidemiologic studies of chemotherapyrelated acute leukemia. in Castellani A (ed): Epidemiology and Quantitation of Environmental Risks in Humans from Radia-
tion and Other Agents-Potential and Limitations. New York. Plenum, 1985, pp 499-514 14. DeWys WE. Greenwald P: Prevention program overview, in Sestili MA (ed): Chernoprevention Clinical Trials: Problems and Solutions. Bethesda Md, National Cancer Institute, NIH Publication 85-2715,1984. pp 1-3 15. Committee on Diet, Nutrition. and Cancer, Assembly of Life Sciences, National Research Council: Diet, Nutrition and Cancer. Washington. DC. National Academy Press. 1982 16. Office of Cancer Communications: Backgrounder: Cancer prevention research: Chemoprevention and diet. Bethesda, Md. National Cancer Institute, 1984 17. Committee on Dietary Allowances, Food and Nutrition Board: Recommended Dietary Allowances. Washington, DC, National Academy of Sciences, 1980 18. Kummet T, Meyskens FL: Vitamin A: A potential inhibitor of human cancer. Semin Oncol 10:281-289, 1983 19. Meyskens FL: Laboratory monitoring for vitamin A and the retinoids in chemoprevention trials. in Sestili MA (ed): Chernoprevention Clinical Trials: Problems and Solutions. Bethesda, Md. National Cancer Institute. NIH Publication 85-2715. 1984. pp 93-95 20. Sestili MA: Safety considerations in the conduct of chernoprevention trials. in Sestili MA (ed): Chemoprevention Clinical Trials. Bethesda, Md. National Cancer Institute, NIH Publication 85-2715, 1984, pp 83-86 21. Moriarty M, Dunn 1, Darragh A, et al: Etretinate in the treatment of actinic keratoses. Lancet 1:364-365, 1982 22. Peck GL, Olsen TG, Butkus D. et al: Treatment of basal cell carcinomas with 13-cis-retinoic acid. Proc Am Assoc Cancer Res 20:56, 1979 (abstr) 23. Kessier IF, Meyskens FL. Levene N, et al: Treatment of cutaneous T-cell lymphoma (mycosis fungoidcs) with l3-cisrctinoic acid. Lancet I: 1345-1347, 1983 24. Gouveia 1, Mathe G, Hercent T, et al: Degree of bronchial metaplasia in heavy smokers and its regression after treatment with a retinoid. Lancet 1:710-712, 1982 25. Schnitzler L. Verret lL: Retinoid and skin cancer prevention. in Orfanos EE, Braun-Falco 0, Farber EM, et al
220
(eds): Retinoids: Advances in Basic Research and Therapy. Berlin, Springer Verlag, 1981, pp 385-388 26. Sporn MB, Roberts AB: Role ofretinoids in differentiation and carcinogenesis. JNCI73:1381-1387, 1984 27. Peto R: The marked differences between carotenoids and retinoids: Methodological implications for biochemical epidemiology. Cancer Surv 2:327-340, 1983 28. Goodman DS: Vitamin A and retinoids in health and disease. N Engl J Med 310:1023-1031,1984 29. Boutwell RK: Retinoids and inhibition of ornithine decarboxylase activity. Am Acad Dermatol 6:796-798, 1982 30. Elias PM, Williams ML: Retinoids, cancer and the skin. Arch DermatoI17:160-182, 1981 31. Sporn MB: Retinoids and cancer prevention, in Siaga TJ (ed): Carcinogenesis-A Comprehensive Survey. Modifiers of Chemical Carcinogenesis. New York, Raven, 1980, pp 99-109 32. Sporn MB, Newton DL: Recent advances in the use of retinoids for cancer prevention, in Burchenal JH, Dettgen HG (eds): Cancer Achievements, Challenges and Prospects for the 1980's. Orlando, F1a, Grone & Stratton, 1981, pp 541-548 33. Greenwald P: Manipulation of nutrients to prevent cancer. Hosp Pract 19:119-134, 1984 34. Bjelke E: Dietary vitamin A and human lung cancer. Int J Cancer 15:561-565, 1975 35. Gregor A, Lee PN, Roc FJC, et al: Composition of dietary histories in lung cancer cases and controls with special reference to vitamin A. Nutr Cancer 2:93-97, 1980 36. Hirayama T: Diet and cancer. Nutr Cancer 1:67-82, 1979 37. Lacl.ennan R, DaCosta J, Day N, et al: Risk factors for lung cancer in Sjngapore Chinese, a population with high female incidence rates. Int J Cancer 20:854-860, 1977 38. Mettlin C, Graham S, Swanson M: Vitamin A and lung cancer. JNCI 62:1435-1438,1979 39. Shekelle RB, Liu S, Raynor WJ, et al: Dietary vitamin A and risk of cancer in the Western Electric Study. Lancet 2:1185-1189, 1981 40. Graham S, Haughey B, Marshall J, et al: Diet in the epidemiology of carcinoma of the prostate gland. JNCI 70:687-690, 1983 41. Schuman LM, Mandel JS, Radke A, et al: Some selected features of the epidemiology of prostatic cancer: Minneapolis-St Paul, Minnesota case-control study. 1976-1979, in Magnus K (ed): Trends in Cancer Incidence, Causes and Practical Implications. New York, Hemisphere, 1982, pp 345-354 42. Graham S, Dayal H, Swanson M, et al: Diet in the epidemiology of cancer of the colon and rectum. JNCI 61:709714, 1978 43. Graham S, Mettlin C, Marshall J, et al: Dietary factors in the epidemiology of cancer of the larynx. Am J Epidemiol 113:675-680, 1981 44. Mettlin C, Graham S, Priore R, et al: Diet and cancer of the esophagus. Nutr Cancer 2:143-147,1981 45. Mettlin C, Graham S: Dietary risk factors in human bladder cancer. Am J Epidemiol 110:255-263, 1979 46. Cook-Mozaffari P: The epidemiology of cancer of the esophagus. Nutr Cancer 1:51-60, 1979 47. Wynder EL, McCoy GD, Reddi BS, et al: Nutritional and metabolic epidemiology of cancers of the oral cavity, esophagus, colon, breast, prostate and stomach, in Newell GR,
OLSEN AND LOVE
Ellison NM (eds): Nutrition and Cancer. New York, Raven, 1983,pp 11-48 48. Graham S: Toward dietary prevention of cancer. Epidemiol Rev 5:38-50, 1983 49. Newberne PM, Suphakarn V: Nutrition and cancer: A review, with emphasis on the role of vitamins C and E and selenium. Nutr Cancer 5:107-119, 1983 50. Young VE, Newberne PM: Vitamins and cancer prevention: Issues and dilemmas. Cancer 47:1226-1240, 1981 51. Mirvish SS: Inhibition of the formation of carcinogenic N-nitroso compounds by ascorbic acid and other compounds, in Burchenal JH, Oettgen HF (eds): Cancer: Achievements, Challenges and Prospects for the 1980's, vol I. Orlando, F1a, Grone & Stratton, 1981, pp 557-587 52. Pipkin GE, Schlegel 10, Nishimura R, et al: Inhibitory effect of L-ascorbate on tumor formation in urinary bladders implanted with 3-hydroxyanthranilic acid. Proc Soc Exp BioI Med 131:522-524, 1969 53. Banic S: Vitamin C acts as a cocarcinogen to methylcholanthrene in guinea pigs. Cancer Lett 11:239-242, 1981 54. Soloway MS, Cohen SM, Dekernion JB, et al: Failure of ascorbic acid to inhibit FANFf-induced bladder cancer. J Urol 113:483-486, 1975 55. Haenszel W, Correa P: Developments in the epidemiology of stomach cancer over the past decade. Cancer Res 35:3452-3459, 1975 56. Higginson J: Etiological factors in gastro-intestinal cancer in man. JNCI 37:527-545, 1966 57. Hirayama T: The epidemiology of cancer of the stomach in Japan with special reference to the role of diet, in Harris RJC (ed): Proceedings of the 9th International Cancer Congress. UICC Monograph Series, vol 10. Berlin, Springer-Verlag, 1967, pp 37-48 58. Kolonel LN, Nomura A, Hirohata T, et al: Association of diet and place of birth with stomach cancer incidence in Hawaiian Japanese and Caucasians. Am J Clin Nutr 34:24782485, 1981 59. Marshall J, Graham S, Byers T, et al: Diet and smoking in the epidemiology of cancer of the cervix. JNCI 70:847-851, 1983 60. Wassertheil-Srnoller S, Romney SL, Wylie-Rosen J, et al: Dietary vitamin C and uterine cervical dysplasia. Am J Epidemiol 114:714-724, 1981 61. Cook-Mozaffari PJ, Azordegan F, Day NE, et al: Oesophageal cancer studies in the Caspian littoral of Iran: Results of a case-control study. Br J Cancer 39:293-309, 1979 62. Tuyns AJ: Protective effect of citrus fruit on esophageal cancer. Nutr Cancer 5:195-200, 1983 63. Yang CS: Research on esophageal cancer in China: A review. Cancer Res 40:2633-2644, 1980 64. Jain M, Cook GM, Davis FG, et al: A case control study of diet and colorectal cancer. Int J Cancer 26:757-768, 1980 65. National Dairy Council: Vitamin Facts. Rosemont, 111, 1982 66. Epstein SS, Joshi S, Audrea J, et al: The null effect of antioxidants on the carcinogenicity of 3,4,9-IO-dibenzpyrene in mice. Life Sci 6:225-233, 1967 67. Farrell P, Bieri J: Megavitamin E supplementation in man. Am J Clin Nutr 28:1381-1385,1975
A NEW DIRECTION: CHEMOPREVENTION
68. Shamberger R. RUdolphG: Protection against cocarcinogens by antioxidants. Experientia 22:116. 1966 69. Bonmassar E. DalIavalIe R. Giuliani G: Influence of vitamin E and propylgallate on carcinogenesis with benzopyrene in mice. Arch Ital Pathol Clin Tumor 11:245-250, 1968 70. Cook MG, McNamara P: Effect of dietary vitamin Eon dimethylhydrazine-induced colonic tumors in mice. Cancer Res 40:1329-1331,1980 71. Clayton CC, Baumann CA: Diet and axotumors: Effect of dietary period when the diet is not fed. Cancer Res 9:575582, 1949 72. Lipkin M, Newmark H: Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 313:1381-1384, 1985 73. Garland C, Barrett-Connor E, Rossof AH, et al: Dietary vitamin D and calcium and risk of colorectal cancer: A 19-year prospective study in men. Lancet 1:307-309, 1985 74. Garland CF, Garland FC: Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 9:227231, 1980 75. Teppo I, Saxen E: Epidemiology of colon cancer in Scandinavia. Isr J Med Sci 15:322-328, 1979 76. Philips RL: Role of the life-style and dietary habits in risk of cancer among Seventh Day Adventists. Cancer Res 35:3515-3522, 1975 77. Buell DN: Potential hazards of selenium as a chemopreventive agent. Semin Oncol 10:311-321, 1983 78. Shamberger RJ: Relation of selenium to cancer. 1. Inhibitory effect of selenium on carcinogenesis. JNCI 44:931936, 1970 79. Griffin AC: The chemopreventive role of selenium in carcinogenesis, in Arnot MS, Van Eys J. Wang YM (eds): Molecular Interactions of Nutrition and Cancer. New York, Raven, 1982, pp 401-408 80. Soullier BK, Wilson PS. Nigro ND: Effect of selenium on Azoxymethane-induced intestinal cancer in rats fed high fat diet. Cancer Lett 12:343-348, 1981 81. Wilt S, Pereira M, Couri D: Selenium effect on initiation and promotion of tumors by benzo(a)pyrene and 12-0tetradecanoylphorboI. Proc Am Assoc Cancer Res 20:21,1979 (abstr) 82. Ip C: Modification of mammary carcinogenesis and tissue peroxidation by selenium deficiency and dietary fat. Nutr Cancer 2:136-142, 1981 83. Ip C: Prophylaxis of mammary neoplasia by selenium supplementation in the initiation and promotion phases of chemical carcinogenesis. Cancer Res 41:4386-4390, 1981 84. Ip C, Ip MM: Chemoprevention of mammary tumorigenesis by a combined regimen of selenium and vitamin A. Carcinogenesis 2:915-918, 1981
221
85. Ip C, Sinha DK: Anticarcinogenic effect of selenium in rats treated with dimethylbenz(a)anthracene and fed different levels and types of fat. Carcinogenesis 2:435-438, 1981 86. Ip C, Sinha DK: Enhancement of mammary tumorigenesis by dietary selenium deficiency in rats with a high polyunsaturated fat intake. Cancer Res 41:31-34, 1981 87. Thompson HJ, Becci PJ: Selenium inhibition of Nmethyl-n-nitrosourea-induced mammary carcinogenesis in the rat. JNCI 65:1299-1301,1980 88. Robinson MF, Godfrey PJ, Thomson DC, et al: Blood selenium and glutathione peroxidase activity in normal subjects and in surgical patients with and without cancer. Am J Clin Nutr 32:1477-1485, 1979 89. Schrauzer GN, White DA, Schneider CJ: Cancer mortality correlation studies. III. Statistical associates with dietary selenium intakes. Bioinorg Chern 7:23-34, 1974 90. Broghamer WL, McCc,nell WL, Blotcky KP: Relationship between serum selenium levels and patients with carcinoma. Cancer 37:1384-1388, 1976 91. Calautti P, Moschini G, Stievano BM, et al: Serum selenium levels in malignant Iymphoproliferative diseases. Scand J Haematol 24:63-66, 1980 92. Shamberger RJ, Rukovena E, Longfield AK, et al: Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. JNCI 50:867-870. 1977 93. Willett WC, Polk BF, Morris SJ, et al: Prediagnostic serum selenium and risk of cancer. Lancet 2:130-133, 1983 94. Butterworth CE, Hatch KD, Gore H, et al: Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 35:73-82, 1982 95. Love RR, Carbone PP, Jordan VC, et al: Strategies in preventive oncology: A clinical trial of tamoxifen as a chemopreventive agent for women with a family history of breast cancer, in Lynch HT, Kullander S (eds): Cancer Genetics in Women. Boca Raton, Fla, CRC, (in press) 96. Jordan VC: Effect of tamoxifen (ICI 46, 474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12:419-424, 1976 97. Welsch \VW, Goodrich-Smith M, Brown DK, et al: 2Bromo-ergocryptine (CB·154) and tamoxifen (ICI-46, 474) induced suppression of the genesis of mammary carcinomas in female rats treated with 7,12-dimethylbenzanthrene (DMBA): A comparison. Oncology 39:88-92, 1982 98. Jordan VC, Allen KE: Evaluation of the antitumor activity of the nonsteroidal antiestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16:239-251, 1980 99. Bartlet EE: Principles in health education. Prev Med 14:667-669, 1985 100. Weed DL: Ethics and chemoprevention research. Semin Oncol 10:355-359, 1983