Cancer prevention

Abstract

Cancer prevention includes primary prevention (eg, avoiding cancer-causing substances in the environment or dietary elements associated with increased risk; dietary supplementation with putative protective agents) and secondary prevention (eg, detection and removal of benign neoplasms, early detection of breast cancer by mammography). Here we focus on primary prevention. Measures aimed at primary cancer prevention have led to various health-education programmes and modified diets and dietary supplementations with naturally occurring nutrients and with pharmaceutical agents. Epidemiology provides compelling evidence that many cancers may be avoidable. Different populations experience different levels of different forms of cancer and these levels change with time. Groups of migrants acquire the cancer pattern of their new home, sometimes within decades (as demonstrated by migrants to Australia) or sometimes requiring generations, as in the case of breast cancer in Japanese migrants to the USA. Furthermore, groups of individuals in a community with some characteristic which differentiates them from other members of the same community (such as Seventh Day Adventists, Mormons, blacks in parts of the USA) have different cancer patterns. It is widely held that 80–90% of human cancer may be attributable to environmental factors, defining environment in its broadest sense to include a wide range of life-style and sometimes poorly defined factors, including dietary, social, and cultural practices. Unfortunately, avoidable causes of many common cancers have not yet been identified. Tobacco smoking remains the largest single avoidable cause of premature death internationally and the most important known carcinogen to human beings.1Peto R Lopez AD Boreham J Thun M Heath C Mortality from tobacco in developed countries: indirect estimation from national vital statistics.Lancet. 1992; 39: 1268-1278Summary Scopus (1083) Google Scholar Between 25 and 30% of all cancers in developed countries are tobacco-related. Throughout Europe, in 1990, tobacco smoking caused three-quarters of a million deaths in middle age (between 35 and 69). In the member states of the European Union in 1990 there were over one-quarter of a million deaths in middle age directly caused by tobacco smoking: 219 700 in men and 31 900 in women. There were many more deaths caused by tobacco at older ages. In countries of central and eastern Europe, including the former USSR, there were 441 200 deaths in middle age in men and 42 100 deaths in women.2Peto R Lopez AD Boreham J Thun M Heath C Doll R Mortality from smoking world-wide.Br Med Bull. 1996; 52: 12-21Crossref PubMed Scopus (486) Google Scholar On the basis of 30 epidemiological studies, the US Environmental Protection Agency has concluded that environmental tobacco smoke (passive smoking) is a human lung carcinogen. It has been estimated that each year in the USA, 434 000 deaths are attributable to tobacco use, in particular cigarette smoking, 112 000 of these smoking-related deaths being from lung cancer.3Centres for Disease Control Smoking-attributable mortality and years of potential life lost—United States, 1988.MMWR. 1991; 40: 62-71PubMed Google Scholar, 4USDHHS (United States Department of Health and Human Services) Reducing the health consequences of smoking: 25 years of progress, a report of the Surgeon General. US Government Printing Office, Washington, DC1989Google Scholar There are an estimated 1500 deaths in non-smoking women due to passive smoking and 500 deaths in nonsmoking men annually. The situation in women worldwide is alarming, with increasing numbers of women smokers and with lung cancer now rising strongly in women as well as men in many countries.5La Vecchia C Lucchini F Negri E Boyle P Maisonneuve P Levi F Trends of cancer mortality in Europe, 1955–89: II respiratory tract, bone, connective and soft tissue sarcomas, and skin.Eur J Cancer. 1992; 28: 514-599Summary Full Text PDF PubMed Scopus (51) Google Scholar, 6La Vecchia C Lucchini F Negri E Boyle P Levi F Trends in cancer mortality in the Americas, 1955–1989.Eur J Cancer. 1993; 29A: 431-470Summary Full Text PDF PubMed Scopus (35) Google Scholar In Japan, since 1950, lung cancer mortality has increased ten-fold in men and eight-fold in women. There is a major build-up of tobacco-related disease in China where the effects of increasing prevalence of cigarette smoking in the 1950s and 1960s are being translated into increases in the incidence and mortality of smoking-related cancers. In central and eastern Europe, there are currently more than 400 000 premature deaths each year caused by tobacco smoking.1Peto R Lopez AD Boreham J Thun M Heath C Mortality from tobacco in developed countries: indirect estimation from national vital statistics.Lancet. 1992; 39: 1268-1278Summary Scopus (1083) Google Scholar There are several core strategies for a comprehensive tobacco-control programme that have the support of the International Union Against Cancer, the WHO, and the Europe Against Cancer programme of the European Community. In any programme of cancer control, top priority should be given to control of tobacco: this is likely to have the greatest impact on reducing cancer incidence and cancer mortality compared with any other strategy currently known. A series of recommendations for tobacco control has been made by the European Cancer Experts Committee7Boyle P Cancer, cigarette smoking and premature death in Europe: a review including the recommendations of European Cancer Experts Consensus Meeting, Helsinki Lung Cancer. October, 1996Google Scholar that deserves the active support of the international scientific community. Alcohol drinking is causally associated with cancers at various sites, mainly in the oral cavity, pharynx, larynx, and oesophagus.8IARC (International Agency for Research on Cancer) Monographs on the evaluation of carcinogenic risk to humans: alcohol drinking. Vol 44. IARC, Lyon1988Google Scholar The main effect seems to be synergistic with cigarette smoking. Heavy consumers of alcohol should be advised to moderate their consumption and to stop smoking. The impact of this health advice could be important since cancers of the upper respiratory tract are estimated to account for over 850 000 new cases each year worldwide.9Parkin DM Ferlay J Pisani P Estimates of the worldwide incidence of eighteen major cancers in 1985.Int J Cancer. 1993; 54: 594-606Crossref PubMed Scopus (1582) Google Scholar Despite being the centre of a great deal of attention in many developed countries, where the incidence is increasing quickly, it has been estimated that malignant melanoma accounted for 92 000 incident cases in 1985 or 1·2% of the total cancer burden.9Parkin DM Ferlay J Pisani P Estimates of the worldwide incidence of eighteen major cancers in 1985.Int J Cancer. 1993; 54: 594-606Crossref PubMed Scopus (1582) Google Scholar The important message is to avoid overexposure to sunlight and, in particular, to avoid sunburns at all times and to be especially careful to protect children.10Boyle P Veronesi U Tubiana M et al.European School of Oncology advisory report to the European Commission for the “Europe Against Cancer Programme”: European Code Against Cancer.Eur J Cancer. 1995; 9: 1395-1405Summary Full Text PDF Scopus (76) Google Scholar There is strong evidence that human papillomavirus is associated with an increased risk of cervix cancer in women,11IARC (International Agency for Research on Cancer) Monographs on the evaluation of carcinogens to man: human papilloma viruses. Vol XX. IARC, Lyon1996Google Scholar Epstein-Barr virus with nasopharyngeal cancer,12Epstein MA Epstein-Barr virus—discovery, properties and relationship to nasopharyngeal carcinoma.in: De Thç G Ito Y Nasopharyngeal carcinoma: etiology and control. IARC, Lyon1978Google Scholar hepatitis B virus with primary liver cancer,13Beasley RP Lin C Hwang LY Chien CS Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22 707 men in Taiwan.Lancet. 1981; ii: 1129-1133Summary Scopus (402) Google Scholar and HIV with Kaposi's sarcoma and some forms of lymphoma.14Biggar RJ Rosenberg PS Cote T Kaposi's sarcoma and non-Hodgkin's lymphoma following the diagnosis of AIDS: multistate AIDS/cancer match study.Int J Cancer. 1996; 68: 754-758Crossref PubMed Scopus (91) Google Scholar, 15Pedersen C Barton SE Chiesi A et al.HIV-related non-Hodgkin's lymphoma among European AIDS patients.Eur J Haematol. 1995; 55 (AIDS in Europe Study Group): 245-250Crossref PubMed Scopus (27) Google Scholar It would appear that there are at least 850 000 incident cases of cancer each year where infective processes have an important determining role: this represents about 11% of the global cancer burden. Obviously, successful vaccination programmes against these virus infections would have a considerable impact. The effects would be greatest in the developing world, where over three-quarters of the world's cases of liver cancer are diagnosed. Because of the timing of the infection in developing and developed countries, two-thirds of all cases could be prevented by the introduction of vaccination against hepatitis B virus into the primary vaccination schedule for infants.16Tomatis L Day NE Heseltine E et al.Cancer: causes, occurrence and control. IARC, Lyon1990Google Scholar Many classes of chemopreventive agents, including naturally occurring and pharmaceutical compounds are being studied for chemopreventive efficacy.17Lipkin M Strategies for colon cancer prevention.Ann NY Acad Sci. 1995; 768: 129-140Crossref PubMed Scopus (3) Google Scholar The diverse manifestations of abnormally developing cells, from early-stage to late-stage preneoplasia, are also being studied for their ability to measure the activity of these cancer-preventive regimens on proliferating and differentiating cells. We have classified current chemopreventive approaches by mechanism of activity, including intermediate endpoints for assessing such activities (panel).PanelChemopreventive strategies17Lipkin M Strategies for colon cancer prevention.Ann NY Acad Sci. 1995; 768: 129-140Crossref PubMed Scopus (3) Google Scholar Tabled 1Chemopreventive strategies17Lipkin M Strategies for colon cancer prevention.Ann NY Acad Sci. 1995; 768: 129-140Crossref PubMed Scopus (3) Google ScholarChemopreventive approachesPostulated mechanismBiomarkersAvoid cancer-related agents in environmentReduce DNA damage and/or promotionReduced urinary and blood markers that identify specific agents (eg, DNA adducts, oxidation, and alkylation products)Tobacco products, High dietary fat, calories, Chemicals leg, aflatoxin, heterocyclic amines), Viruses leg, hepatitis)AntioxidantsReduce risk of excessive oxidative DNA damage and call toxicityReduced DNA oxidative metabolites in blood and urine, proliferationTocopherots, ascorbate, carotenes, seleniumβ-caroteneReduce oxidation reactionsReduced hyperuroliferation, modulate cell differentiationInhibit arachidonic acid or oxidationInhibit arachidonic acid metabolism, oxidative reactionsReduced lipoxygenase, cyclo-oxygenase activity, inflammation, proliferationNSAIDs plant phenolic compounds, flavonoids, conjugated linoleic acid, ω-3 (n3) fatty acids, cyclo-oxygenase-2 inhibitorsAlter enzyme actionAlter enzyme detoxificationModified carcinogenic metabolites in biological fluids, urineIsothiocyanates, dithlolthiones, flavones, indoles, sulphur compoundsIndole 3 carbinolIncrease 2 OH-oestradiol oxidationIncreased urinary 2-OH/16-OH oestradiol ratiod-giucaratesInhibit glucuronidaseIncreased urinary glucuronide excretion (eg, oestrogens)Calcium, vitamin DReduce bile acid, fatty-acid irritation in colon, proliferationModified gene expression, reduced hyperproliferation, cytotoxicity, increased serum 25-OH-vitamin D3DifluoromethylomithineInhibit ODCReduced ODC levels associated with cell proliferationDehydroeplandrosteroneReduce G-6PDH activityReduced carcinogen activation, cell proliferationRetinoidsInduce cell differentiationReverse squamous metaplasia, modulate cell differentiation markers, leukoplasiaTerpenesReduce oncogene iseprenylation and ubiquinone synthesisModulations of HMG-CoA metabolic pathways and productsAntioestrogens (eg, tamoxifen)Reduce oestrogen-stimulated proliferationModulate proliferation, oestrogen metabolism and gene expressionNSAID=non-steroidal anti-inflammatory agents, ODC=ornithine decarboxylase, G-6PDH=glucose-6-phosphate dehydrogenase, HMG-CoA=3 - hydroxyl-3-methylglutaryl coenzyme A. Open table in a new tab Tabled 1Chemopreventive strategies17Lipkin M Strategies for colon cancer prevention.Ann NY Acad Sci. 1995; 768: 129-140Crossref PubMed Scopus (3) Google ScholarChemopreventive approachesPostulated mechanismBiomarkersAvoid cancer-related agents in environmentReduce DNA damage and/or promotionReduced urinary and blood markers that identify specific agents (eg, DNA adducts, oxidation, and alkylation products)Tobacco products, High dietary fat, calories, Chemicals leg, aflatoxin, heterocyclic amines), Viruses leg, hepatitis)AntioxidantsReduce risk of excessive oxidative DNA damage and call toxicityReduced DNA oxidative metabolites in blood and urine, proliferationTocopherots, ascorbate, carotenes, seleniumβ-caroteneReduce oxidation reactionsReduced hyperuroliferation, modulate cell differentiationInhibit arachidonic acid or oxidationInhibit arachidonic acid metabolism, oxidative reactionsReduced lipoxygenase, cyclo-oxygenase activity, inflammation, proliferationNSAIDs plant phenolic compounds, flavonoids, conjugated linoleic acid, ω-3 (n3) fatty acids, cyclo-oxygenase-2 inhibitorsAlter enzyme actionAlter enzyme detoxificationModified carcinogenic metabolites in biological fluids, urineIsothiocyanates, dithlolthiones, flavones, indoles, sulphur compoundsIndole 3 carbinolIncrease 2 OH-oestradiol oxidationIncreased urinary 2-OH/16-OH oestradiol ratiod-giucaratesInhibit glucuronidaseIncreased urinary glucuronide excretion (eg, oestrogens)Calcium, vitamin DReduce bile acid, fatty-acid irritation in colon, proliferationModified gene expression, reduced hyperproliferation, cytotoxicity, increased serum 25-OH-vitamin D3DifluoromethylomithineInhibit ODCReduced ODC levels associated with cell proliferationDehydroeplandrosteroneReduce G-6PDH activityReduced carcinogen activation, cell proliferationRetinoidsInduce cell differentiationReverse squamous metaplasia, modulate cell differentiation markers, leukoplasiaTerpenesReduce oncogene iseprenylation and ubiquinone synthesisModulations of HMG-CoA metabolic pathways and productsAntioestrogens (eg, tamoxifen)Reduce oestrogen-stimulated proliferationModulate proliferation, oestrogen metabolism and gene expressionNSAID=non-steroidal anti-inflammatory agents, ODC=ornithine decarboxylase, G-6PDH=glucose-6-phosphate dehydrogenase, HMG-CoA=3 - hydroxyl-3-methylglutaryl coenzyme A. Open table in a new tab NSAID=non-steroidal anti-inflammatory agents, ODC=ornithine decarboxylase, G-6PDH=glucose-6-phosphate dehydrogenase, HMG-CoA=3 - hydroxyl-3-methylglutaryl coenzyme A. Human epidemiological studies have largely centred around associations with fat and vitamin intake. A summary of the epidemiological situation is likely to be contentious. Present evidence indicates that an increased intake of fat, and also red meat, is associated with an higher risk of colorectal cancer and probably prostate cancer. High consumption of fruits and vegetables is associated with a reduced risk of several cancers, including lung, oral, pancreas, larynx, oesophagus, bladder, and stomach. The major exceptions have been the lack of strong association with hormonally-related forms of cancer such as prostate, breast, ovary, and endometrium.18Steinmetz K.A. Potter J.D. Vegetable, fruit, and cancer I: epidemiology.Cancer Causes Control. 1991; 2: 325-358Crossref PubMed Scopus (1290) Google Scholar The relation appears to be a general effect and consistently found with many different groups of fruits and vegetables. Many candidate mechanisms (and molecules) have been put forward and probably multiple components of diet are responsible. Implementation of a randomised trial of increased consumption of fruits and vegetables is underway and the search continues for the molecule(s) in fruits and vegetables responsible for the apparent protection.23Greenwald P Clifford C Pilch S Heimendinger J Kelloff G New directions in dietary studies in cancer: the National Cancer Institute.in: Longnecker JB Nutrition and biotechnology in heart disease and cancer. Plenum Press, New York1995: 229-239Crossref Scopus (5) Google Scholar, 24Weisberger JH Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids.Am J Clin Nutr. 1995; 53: 226sGoogle Scholar, 25Wattenberg L Lipkin M Boone CW Kelloff G Chemoprevention of cancer. CRC Press, Boca Raton1992Google Scholar, 26Kelloff G Boone C Cancer chemopreventive agents: drug development status and future prospects. J Cell Biochem. S20. 1994: 1-303Google Scholar The demonstration of a reduction in mortality in a randomised intervention trial in China is of considerable significance and gives hope for a potentially successful future for chemoprevention19Blot WJ J-Y Li Taylor P et al.Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.J Natl Cancer Inst. 1993; 85: 1483-1492Crossref PubMed Scopus (1505) Google Scholar, notwithstanding that this was a special population with high cancer rates and a long history of low dietary intakes of several important micronutrients. Indeed, the failure of recent major studies to demonstrate any beneficial effect of β-carotene supplementation on cancer risk in populations with essentially normal intakes20The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study GroupThe effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.N Engl J Med. 1994; 330: 1029-1035Crossref PubMed Scopus (4333) Google Scholar, 21Hennekens CH Buring JE Manson JE et al.Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease.N Engl J Med. 1996; 334: 1145-1149Crossref PubMed Scopus (2117) Google Scholar, 22Omenn GS Goodman GE Thornquist MD et al.Effects of combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease.N Engl J Med. 1996; 334: 1150-1155Crossref PubMed Scopus (3062) Google Scholar poses key strategic questions for future directions in chemoprevention studies. Cancer prevention programmes involving dietary factors have encompassed two broad categories: analyses of the effects of entire diets23Greenwald P Clifford C Pilch S Heimendinger J Kelloff G New directions in dietary studies in cancer: the National Cancer Institute.in: Longnecker JB Nutrition and biotechnology in heart disease and cancer. Plenum Press, New York1995: 229-239Crossref Scopus (5) Google Scholar, 24Weisberger JH Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids.Am J Clin Nutr. 1995; 53: 226sGoogle Scholar and chemopreventive approaches with individual dietary constituents.25Wattenberg L Lipkin M Boone CW Kelloff G Chemoprevention of cancer. CRC Press, Boca Raton1992Google Scholar, 26Kelloff G Boone C Cancer chemopreventive agents: drug development status and future prospects. J Cell Biochem. S20. 1994: 1-303Google Scholar, 27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google Scholar Whole dietary regimens directed at tumour inhibition have involved lowering dietary fat content, increasing intake of fibre, fruit, and vegetables,23Greenwald P Clifford C Pilch S Heimendinger J Kelloff G New directions in dietary studies in cancer: the National Cancer Institute.in: Longnecker JB Nutrition and biotechnology in heart disease and cancer. Plenum Press, New York1995: 229-239Crossref Scopus (5) Google Scholar, 24Weisberger JH Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids.Am J Clin Nutr. 1995; 53: 226sGoogle Scholar, 27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google Scholar, 28Armstrong B Doll R Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices.Int J Cancer. 1975; 15: 617-631Crossref PubMed Scopus (1865) Google Scholar, 29Hursting S Thornquist M Henderson M Types of dietary fat and the incidence of cancer at five sites.Prev Med. 1990; 19: 242-253Crossref PubMed Scopus (181) Google Scholar, 30Rose D Goldman M Connolly J Strong L High-fiber diet reduces serum estrogen concentrations in premenopausal women.Am J Clin Nutr. 1991; 54: 520-525PubMed Google Scholar, 31Henderson M Kushi L Thompson D et al.Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women's Health Trial vanguard study.PrevMed. 1990; 19: 115-133PubMed Google Scholar, 32White T Shattuck A Kristal A et al.Maintenance of a low-fat diet: follow-up of the Women's Health Trial.Cancer Epidemiol Biomark. 1992; 1: 315-322PubMed Google Scholar and the administration of specific micronutrients, including most of the naturally occurring nutrients listed in the panel. Studies of low-fat diets include the Women's Health Trial Vanguard Study which evaluated the feasibility of lowering fat content in postmenopausal women;31Henderson M Kushi L Thompson D et al.Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women's Health Trial vanguard study.PrevMed. 1990; 19: 115-133PubMed Google Scholar, 32White T Shattuck A Kristal A et al.Maintenance of a low-fat diet: follow-up of the Women's Health Trial.Cancer Epidemiol Biomark. 1992; 1: 315-322PubMed Google Scholar the National Institute of Health's Women's Health Initiative examining the effects of modified diet, calcium and vitamin D supplementation, and hormonal replacement therapy on breast and colon cancer, coronary heart disease, and osteoporosis in postmenopausal women; the Women's Intervention Nutrition Study of dietary fat reduction in women with previous breast cancer; and the Polyp Prevention Trial with low-fat, high-fibre, and high fruit and vegetable intake.23Greenwald P Clifford C Pilch S Heimendinger J Kelloff G New directions in dietary studies in cancer: the National Cancer Institute.in: Longnecker JB Nutrition and biotechnology in heart disease and cancer. Plenum Press, New York1995: 229-239Crossref Scopus (5) Google Scholar Dietary regimens are generally tested in human populations for potential chemopreventive efficacy with many of the same steps that are described below for pharmaceutical agents. However, when studying natural dietary regimens, the preclinical studies and phase I toxicology studies can generally be omitted. Nevertheless, when individual nutrients are isolated from natural foods, they may require testing in preclinical and phase I studies. Many individual nutrients and pharmaceutical compounds are now in trials to elucidate tumour inhibitory activity. The larger studies include the Linxian study of oesophageal and stomach cancer,19Blot WJ J-Y Li Taylor P et al.Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.J Natl Cancer Inst. 1993; 85: 1483-1492Crossref PubMed Scopus (1505) Google Scholar the α-tocopherol, β-carotene (ATBC) study of lung cancer prevention,20The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study GroupThe effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.N Engl J Med. 1994; 330: 1029-1035Crossref PubMed Scopus (4333) Google Scholar, the β-carotene and retinol efficacy trial (CARET) in lung cancer,33Omenn G Goodman G Thornquist M et al.The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations; smokers and asbestos-exposed workers.Cancer Res. 1994; 54: 2038s-2043sPubMed Google Scholar and the Physician Health Study.34Hennekens C Issues in the design and conduct of clinical trials.J Natl Cancer Inst. 1984; 73: 1473-1476PubMed Google Scholar New compounds developed for chemoprevention efficacy studies have to undergo preclinical safety and efficacy testing before being approved for clinical trials. Agents under study in the USA are being evaluated at the National Cancer Institute's Division of Cancer Prevention and Control. The chemoprevention branch there provides scientific and administrative oversight for drug development, ranging from drug discovery and preclinical testing to the conduct of clinical trials.26Kelloff G Boone C Cancer chemopreventive agents: drug development status and future prospects. J Cell Biochem. S20. 1994: 1-303Google Scholar We have listed the chemopreventive agents now in clinical studies in the National Cancer Institute's programme (table 1). These studies include most of the categories of agent shown in the panel. Studies are also underway with combinations of these agents (eg, calcium with vitamin D, tamoxifen with 4-HPR), and others are planned. These studies will test the efficacy of lower doses of agents with complementary mechanisms of action, with the hope of providing equal or greater efficacy with reduced risk of side-effects.Table 1Chemoprevention trials underway and planned26Kelloff G Boone C Cancer chemopreventive agents: drug development status and future prospects. J Cell Biochem. S20. 1994: 1-303Google Scholar, 27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google Scholar, 35Kelloff G Johnson J Crowell J et al.Approaches to the development and marketing approval of drugs that prevent cancer.Cancer Epidemiol Biomark. 1995; 4: 1-10PubMed Google Scholar, 36Kelloff G Crowell J Boone C et al.Strategy and planning for chemopreventive drug development: clinical development plans.J Cell Biochem. 1994; S20: 55-299Crossref Scopus (31) Google ScholarTrialOrgan site(s)Nutritional supplements and modified dietsCalciumBreast, colon, oesophagusβ-carotene and other carotenoidsBreast, cervix, colon, oesophagus, lung, oral, skin, stomachDietary modificationsBreast, colon, skinIndole-3-carbinolCervix, larynxSeleniumLiver, lung, skinVitamin ALung, oral, skinVitamin CColon, stomachVitamin D3 (and analogues)Colon, breastVitamin EBreast, colon, oesophagus, oral, prostateVitamins, combinedCervix, colon, oesophagus, lung, oral, stomachVitamins and minerals combinedColon, oesophagus, lung, oralPharmaceutical agentsAspirinBreast, colon, lungAntibioticsStomachDehydroepiandrosterone (DHEA) analogue 8354Breast, prostate2-difluoromethylomlthine (DMFO)Bladder, cervix, colon, oral prostateFinasterideProstate18β-glycyrrhetinic acidLiverN acetyl I cyeteine (NAC)Bladder, lungN(4-hydroxyphenyl) retinamide (4-HPR)Bladder, breast, cervix, lung, oral, prostate, skinNSAIDS (ibuprofen, piroxicam, sulindac, COX-2 inhibitors)Bladder, colonOltiprazBladder, breast, liver, lung, prostateRetinoids, syntheticBreast, cervix, head and neck, lung, skinSunscreensSkinTamoxifenBreastVaccinationsLiver Open table in a new tab Specific requirements have to be fulfilled to evaluate the efficacy of new pharmaceutical compounds for tumour inhibitory activity in human populations. The requirements in the USA have been described by Kelloff et al35Kelloff G Johnson J Crowell J et al.Approaches to the development and marketing approval of drugs that prevent cancer.Cancer Epidemiol Biomark. 1995; 4: 1-10PubMed Google Scholar and are summarised here. Other countries follow the same principles. After phase I studies, in phase II trials, the dose of the agent that inhibits established surrogate biomarkers is established. If a surrogate marker has not been identified, a randomised trial is done to attempt to identify a suitable biomarker. A further randomised placebo-controlled study is then carried out to establish associations between dose, response of the surrogate endpoint biomarkers, and toxicity. Then a randomised, double-blind placebo-controlled trial can be started to demonstrate whether significant modulation occurs in surrogate endpoint biomarkers. Larger randomised studies can eventually be carried out for much longer durations to evaluate whether reduction of cancer incidence or mortality, or delay in the onset of cancer, occurs and can be attributed to the agent under study35Kelloff G Johnson J Crowell J et al.Approaches to the development and marketing approval of drugs that prevent cancer.Cancer Epidemiol Biomark. 1995; 4: 1-10PubMed Google Scholar, 36Kelloff G Crowell J Boone C et al.Strategy and planning for chemopreventive drug development: clinical development plans.J Cell Biochem. 1994; S20: 55-299Crossref Scopus (31) Google Scholar Numerous cancer prevention trials have been done or are underway to assess intervention strategies, both during the period before initial turnouts have developed and after the formation of neoplasms. Either the general population or those at increased risk for neoplasia have been studied. The high-risk groups include individuals who have had high exposures to adverse risk factors and others who have developed preneoplastic or neoplastic lesions and therefore are assumed to be at increased risk. These clinical trials have been summarised.26Kelloff G Boone C Cancer chemopreventive agents: drug development status and future prospects. J Cell Biochem. S20. 1994: 1-303Google Scholar, 27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google Scholar Large studies have also been carried out on cardiovascular disease prevention, which have included cancer-related intermediate endpoints or biomarkers. Various regimens have included smoking cessation and dietary fat modification, and other clinical trials have been done with defined dietary regimens or specific chemopreventive agents as noted above. Cancer prevention intervention trials are underway in Africa, Australia, Canada, China, European countries, South America, USA, and the countries of the former USSR (table 2).Table 2Countries with chemoprevention intervention trials27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google ScholarCountryOrgan site studiedUSABreast, cervix, colon, prostate, head and neck, lung, oropharynx, skinEuropeBreast, colon, cervix, head and neck, lung, stomachAustraliaColon, lungAfricaSkin, liverCanadaBreast, colon, oropharynxChinaOesophagus, lung, liver, oropharynxIndiaOralSouth AmericaStomachUSSROropharynx, oesophagus, lung Open table in a new tab When assessing the utility of surrogate endpoint biomarkers in clinical trials, the closer the association to the development of cancer the more useful the endpoint will be. Endpoints describing late stages of disease (eg, dysplasias) are most closely associated with the evolution of cancer; however, modulation of early-stage endpoints (eg, cell proliferation or arachidonic-acid metabolites) can give useful information, identifying mechanisms of activity of the chemopreventive agents in human beings and whether or not this activity is similar to mechanisms found in preclinical models. Intermediate endpoints under study in clinical trials include: late-stage precancerous lesions (in studies of breast, cervix, oesophagus, lung, oropharynx, skin, and stomach); recurrence of precancerous lesions (in cervix, colon, and oral mucosa); micronuclei (in oesophagus, lung, and oral mucosa); cell proliferation (in oesophagus and colon); and cancer development (in breast, colon, oesophagus, lung, liver, and skin).27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google Scholar Chemopreventive agents under study in clinical trials (table 2) now include vitamin A in lung, oral mucosa, and skin cancer; vitamin C in colon and stomach cancer; synthetic retinoids in breast, cervix, head and neck, lung, and skin cancer; β-carotene and other carotenoids in breast, cervix, colon, lung, skin, and stomach cancer; fibre in colon cancer; selenium in liver, lung, and skin cancer; calcium in oesophagus and bladder and colon cancer; NSAIDs in bladder and colon cancer; tamoxifen in breast cancer; vaccination in liver cancer; and dietary regimens in breast, colon, and skin cancer.26Kelloff G Boone C Cancer chemopreventive agents: drug development status and future prospects. J Cell Biochem. S20. 1994: 1-303Google Scholar, 27Buiatti E Intervention trials of cancer prevention: results and new research programmes.Lyon: IARC Technical Report no 18. 1994; Google Scholar Our studies cited above were done at the Strang Cancer Research Laboratory and the Anne Fisher Nutrition Center.