THE LANCET
Cancer prevention
Michael Osborne, Peter Boyle, Martin Lipkin
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.
Avoiding risky exposures
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
Tobacco smoking remains the largest single avoidable
cause of premature death internationally and the most
important known carcinogen to human beings. 1 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
Lancet 1 9 9 7 ; 3 4 9 (suppl II): 27-30
Strang Cancer Prevention Center and the New York Hospital-
Cornell Medica! Center, New York, New York, USA (M Osborne MD,
M Lipkin MD); and Division of Epidemiology and Biostatistics,
European Institude of Oncology, Milan, Italy (Prof P Boyle PhD)
Correspondence to: Dr Martin Lipkin, Strang Cancer Research
Laboratory, Rockefeller University, 1230 York Avenue, Room 136B,
New York, NY 10021, USA (e-mail lipkin@rockvax.rockefelter.edu)
Vo1349 • May • 1997
ages. In countries of central and eastern Europe,
including the former USSR, there were 441 200 deaths in
middle age in m en and 42 100 deaths in women. 2
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. 3"4
There are an estimated 1500 deaths in non-smoking
women due to passive smoking and 500 deaths in non-
smoking 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 countries2 ,6 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
eastem Europe, there are currently more than 400 000
premature deaths each year caused by tobacco smoking?
There are several core strategies for a comprehensive
tobacco-control programme that have the support of the
International Union Against Cancer, the W H O , 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 Committee 7 that deserves the active support of
the international scientific community.
Ethanol drinking
Alcohol drinking is causally associated with cancers at
various sites, mainly in the oral cavity, pharynx, larynx,
and oesophagus." 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. Th e 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?
Sunlight exposure
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 burdenY The important message
is to avoid overexposure to sunlight and, in particular, to
SII27
THE LANCET

avoid sunburns at all times and to be especially careful to Dietary regimens

protect children2°
Cancer-causing viruses
There is strong evidence that h u m a n papillomavirus is
associated with an increased risk of cervix cancer in
women, H Epstein-Barr virus with nasopharyngeal
c a n c e r f hepatitis B virus with primary liver cancer, '~ and
HIV with Kaposi's sarcoma and some forms of
lymphoma34'~5 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. ~8
Chemoprevention
Many classes of chemopreventive agents, including
naturally occurring and pharmaceutical compounds are
being studied for chemopreventive efficacy. 1~ 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 inter-
mediate endpoints for assessing such activities (panel).
H u m a n 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. 18The 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. 23-26The
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
chemoprevention% 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 B-carotene
supplementation on cancer risk in populations with
essentially normal intakes2°-=poses key strategic questions
for future directions in chemoprevention studies.
Cancer prevention programmes involving dietary
factors have encompassed two broad categories: analyses

Chemopreventlve approaches Postulated mechanism Biomarkers

Avoidcancer-related agents in environment Reduce DNA damage and/or promotion Reduced urinary and blood markers that identify
Tobacco products, saecifc agents leg, DNA adducts, oxidation, and
High dietary fat, calories, alkylation Droductsi
Chemicals leg, aflstoxin, heterocyclic amines),
Viruses leg, hepatitis)
Antioxldants Reduce risk of excessive oxidative DNA damage and Reduced DNA oxidative metabolites in blood and urine.
Tocopherots. ascorbate, carotenes, selenium call toxicit~ oroliferation
B-carotene Reduce oxidation reactions Reduced hyperuroliferation, modulate cell differentiatior
Inhibitarochldonic acid or ex'edatlon Inhibit arachidonic acid metabolism, oxidative Reduced lipoxygenase, cyclo-oxygenase activity,
NSAIDs plant phenolic compounds, flavonoids, reactions inflammation, proliferation
conjugated linoleic acid, e-3 (m3) fatty acids,
cyclo-oxygenase-2 inhibitors
Alter enzyme action Alter enzyme detoxiflcetion Modified carcinogenic metabolites in biological fuids,
Isothiocyanates, dithlolthiones, flavones, indoles. urine
SulphUr cempounds
Inddle 3 carbinol increase 2-OH~Oestradioi oxidation increased urinary 2-OH/16-OH oestradiol rauo
d-giucarates inhibit glucuronidase Increased unnary glucuronide excretion
leg, oestrogens)
Calcium. vitamin D Reduce bile acid, fatty-acid irritation in colon. Modified gene expression, reduced hyperproliferation,
proliferation cytotoxicity, increased serum 25-OHwitamin D~
Difluoromethylomlth ne Inhibit ODC Reduced ODC levels associated witl~ cell proliferation
Dehydroeplandrosterone Reduce G-6PDH activity Reduced carcinogen activaton, cell orofiferation
Retlnoids Induce cell differentiation Reverse squamous metaplasia, modulate cell
differentiation markers, leukoplasta
Terpenes Reduce oncogene iseprenylation and ubiqumone Modulations of HMG-CoA metabolic oatbways and
synthesis prOdUCtS
Antioestrogens(ag, tamoxlfen) Reduce oestrogen-stimulatad proliferation Modulate oroliferation, oestrogen metabolism and
gene expression

N #n~steraida[anti-iT)flammatptyagents, ODC=ornithirJedecarboxylase, G-6PDH=glucose-6-phosnhatedehydrogenase RMG~CoA=3.hydroxy-3mothy gtutaryi coenzymeA.

SII28 Vol 3 4 9 • M a y • 1 9 9 7
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of the effects of entire diets 23'z4 and chemopreventive Efficacy and safety testing
approaches with individual dietary constituents.2~-2vWhole New compounds developed for chemoprevention efficacy
dietary regimens directed at tumour inhibition have studies have to undergo preclinical safety and efficacy
involved lowering dietary fat content, increasing intake of testing before being approved for clinical trials. Agents
fibre, fruit, and vegetables,23,24'27-32and the administration under study in the USA are being evaluated at the
of specific micronutrients, including most of the naturally National Cancer Institute's Division of Cancer Prevention
occurring nutrients listed in the panel. and Control. The chemoprevention branch there provides
Studies of low-fat diets include the Women's Health scientific and administrative oversight for drug
Trial Vanguard Study which evaluated the feasibility of development, ranging from drug discovery and preclinical
lowering fat content in postmenopausal women; 3~'32 the testing to the conduct of clinical trials. 26
National Institute of Health's Women's Health Initiative We have listed the chemopreventive agents now in
examining the effects of modified diet, calcium and clinical studies in the National Cancer Institute's
vitamin D supplementation, and hormonal replacement programme (table 1). These studies include most of the
therapy on breast and colon cancer, coronary heart categories of agent shown in the panel. Studies are also
disease, and osteoporosis in postmenopausal women; the underway with combinations of these agents (eg, calcium
Women's Intervention Nutrition Study of dietary fat with vitamin D, tamoxifen with 4-HPR), and others are
reduction in women with previous breast cancer; and the planned. These studies will test the efficacy of lower doses
Polyp Prevention Trial with low-fat, high-fibre, and high of agents with complementary mechanisms of action, with
fruit and vegetable intake. 23 the hope of providing equal or greater efficacy with
Dietary regimens are generally tested in h u m a n reduced risk of side-effects.
populations for potential chemopreventive efficacy with Specific requirements have to be fulfilled to evaluate
many of the same steps that are described below for the efficacy of new pharmaceutical compounds for
pharmaceutical agents. However, when studying natural tumour inhibitory activity in h u m a n populations. The
dietary regimens, the preclinical studies and phase I requirements in the USA have been described by Kelloff
toxicology studies can generally be omitted. Nevertheless, et al3~ and are summarised here. Other countries follow
when individual nutrients are isolated from natural foods, the same principles.
they may require testing in preclinical and phase I studies. After phase I studies, in phase II trials, the dose of the
Many individual nutrients and pharmaceutical agent that inhibits established surrogate biomarkers is
compounds are now in trials to elucidate tumour established. If a surrogate marker has not been identified,
inhibitory activity. The larger studies include the Linxian a randomised trial is done to attempt to identify a suitable
study of oesophageal and stomach cancer, ~9 the c~- biomarker. A further randomised placebo-controlled
tocopherol, [3-carotene (ATBC) study of lung cancer study is then carried out to establish associations between
prevention,2°, the [3-carotene and retinol efficacy trial dose, response of the surrogate endpoint biomarkers, and
(CARET) in lung cancer, 33 and the Physician Health toxicity. Then a randomised, double-blind placebo-
Study. 34 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
Trial Organ site(s)
reduction of cancer incidence or mortality, or delay in the
Nutritional supplements onset of cancer, occurs and can be attributed to the agent
and modified diets
under study35"36
Calcium Breast, colon, oesophagus
13-caroteneand other Breast, cervix, colon, oesophagus, lung, oral,
cerotenoids skin, stomach Cancer prevention trials
Dietary modifications Breast, colon, skin
Indole-3-carbinol Cervix, larynx Numerous cancer prevention trials have been done or are
Selenium Liver, lung, skin underway to assess intervention strategies, both during
Vitamin A Lung, oral, skin the period before initial turnouts have developed and after
Vitamin C Colon, stomach the formation of neoplasms. Either the general population
Vitamin D3(and analogues) Colon, breast
Vitamin E Breast, colon, oesophagus, oral, prostate or those at increased risk for neoplasia have been studied.
Vitamins, combined Cervix, colon, oesophagus, lung, oral, The high-risk groups include individuals who have had
stomach high exposures to adverse risk factors and others who
Vitamins and minerals combined Colon, oesophagus, lung, oral
have developed preneoplastic or neoplastic lesions and
Pharmaceutical agents therefore are assumed to be at increased risk.
Aspirin Breast, colon, lung
Antibiotics Stomach These clinical trials have been summarised. 26'27 Large
Dehydroepiandrosterone(DHEA) Breast, prostate studies have also been carried out on cardiovascular
analogue 8354
2-difluoromethylomlthine (DMFO) Bladder,cervix, colon, oral prostate
Finasteride Prostate Country Organ site studied
1813-gIycyrrhetinic acid Liver
USA Breast, cervix, colon, prostate, head and neck, lung,
N acetyl I cyeteine (NAC) Bladder, lung
N (4-hydroxyphenyl)retinamide Bladder, breast, cervix, lung, oral, prostate, oropha~nx, skin
Europe Breast, colon, cervix, head and neck, lung, stomach
(4-BPR) skin
NSAIDS (ibuprofea, piroxicam, Bladder, colon Australia Colon, lung
sulindac, COX-2 inhibitors) Africa Skin, liver
Oltipraz Bladder, breast, liver, lung, prostate Canada Breast, colon, oropharynx
Retinoids, synthetic Breast, cervix, head and neck, lung, skin China Oesophagus, lung, liver, oropharynx
Sunscreens Skin India Oral
Tamoxifen Breast South America Stomach
Vaccinations Liver USSR Oropharynx, oesophagus, lung
Table 1: Chemoprevention trials underway and planned 26,2~,3~7 Table 2: Countries with chemoprevention intervention trials =7

Vo1349 ° May • 1997 sn29

THE LANCET
disease prevention, which have included cancer-related
intermediate endpoints or biomarkers. Various regimens
have included smoking cessation and d i e t a r y fat
m o d i f i c a t i o n , a n d o t h e r clinical trials h a v e b e e n d o n e w i t h
d e f i n e d d i e t a r y r e g i m e n s o r specific c h e m o p r e v e n t i v e
a g e n t s as n o t e d a b o v e . C a n c e r p r e v e n t i o n i n t e r v e n t i o n
trials are u n d e r w a y in Africa, A u s t r a l i a , C a n a d a , C h i n a ,
E u r o p e a n countries, S o u t h America, USA, a n d the
c o u n t r i e s o f t h e f o r m e r U S S R (table 2).
W h e n a s s e s s i n g t h e utility o f s u r r o g a t e e n d p o i n t
b i o m a r k e r s in clinical trials, t h e c l o s e r t h e a s s o c i a t i o n to
the d e v e l o p m e n t of cancer the m o r e useful the endpoint
will be. E n d p o i n t s d e s c r i b i n g late s t a g e s o f d i s e a s e (eg,
dysplasias) are m o s t closely a s s o c i a t e d w i t h t h e e v o l u t i o n
o f c a n c e r ; h o w e v e r , m o d u l a t i o n o f early-stage e n d p o i n t s
(eg, cell p r o l i f e r a t i o n o r a r a c h i d o n i c - a c i d m e t a b o l i t e s ) c a n
give u s e f u l i n f o r m a t i o n , i d e n t i f y i n g m e c h a n i s m s o f
activity o f t h e c h e m o p r e v e n t i v e a g e n t s in h u m a n b e i n g s
a n d w h e t h e r o r n o t this activity is s i m i l a r to m e c h a n i s m s
f o u n d in preclinical m o d e l s . I n t e r m e d i a t e e n d p o i n t s
under s t u d y in clinical trials include: late-stage
p r e c a n c e r o u s l e s i o n s (in s t u d i e s o f b r e a s t , cervix,
o e s o p h a g u s , l u n g , o r o p h a r y n x , skin, a n d s t o m a c h ) ;
r e c u r r e n c e o f p r e c a n c e r o u s l e s i o n s (in cervix, c o l o n , a n d
oral m u c o s a ) ; m i c r o n u c l e i (in o e s o p h a g u s , l u n g , a n d oral
m u c o s a ) ; cell p r o l i f e r a t i o n (in o e s o p h a g u s a n d c o l o n ) ;
a n d c a n c e r d e v e l o p m e n t (in b r e a s t , c o l o n , o e s o p h a g u s ,
l u n g , liver, a n d skin).27
C h e m o p r e v e n t i v e a g e n t s u n d e r s t u d y in clinical trials
(table 2) n o w i n c l u d e v i t a m i n A in l u n g , oral m u c o s a , a n d
skin c a n c e r ; v i t a m i n C in c o l o n a n d s t o m a c h c a n c e r ;
s y n t h e t i c r e t i n o i d s in b r e a s t , cervix, h e a d a n d n e c k , l u n g ,
a n d skin c a n c e r ; [3-carotene a n d o t h e r c a r o t e n o i d s in
b r e a s t , cervix, c o l o n , l u n g , skin, a n d s t o m a c h c a n c e r ; fibre
in c o l o n c a n c e r ; s e l e n i u m in liver, l u n g , a n d skin c a n c e r ;
c a l c i u m in o e s o p h a g u s a n d b l a d d e r a n d c o l o n c a n c e r ;
N S A I D s in b l a d d e r a n d c o l o n c a n c e r ; t a m o x i f e n in b r e a s t
c a n c e r ; v a c c i n a t i o n in liver c a n c e r ; a n d dietary r e g i m e n s
in b r e a s t , c o l o n , a n d skin c a n c e r . 26'27
Our studies cited above were done at the Strang Cancer Research
Laboratory and the Anne Fisher Nutrition Center.
References
1 Peto R, Lopez AD, Boreham J, Thun M, Heath C. Mortality from
tobacco in developed countries: indirect estimation from national vital
statistics. Lancet 1992; 39: 1268-78.
2 Peto R, Lopez AD, Boreham J, Thun M, Heath C, Doll R. Mortality
from smoking world-wide. B r M e d Bull 1996; 52: 12-21.
3 Centres for Disease Control. Smoking-attributable mortality and years
of potential life lost--United States, 1988. M M W R 1991; 40: 62-71.
4 USDHHS (United States Department of Health and Human
Services). Reducing the health consequences of smoking: 25 years of
progress, a report of the Surgeon General. Washington, DC: US
Government Printing Office, 1989.
5 La Vecchia C, Lucchini F, Negri E, Boyle P, Maisonneuve P, Levi E.
Trends of cancer mortality in Europe, 1955-89: II respiratory tract,
bone, connective and soft tissue sarcomas, and skin. Eur.7 Cancer
1992; 28: 514-99.
6 La Vecchia C, Lucchini F, Negri E, Boyle P, Levi F. Trends in cancer
mortality in the Americas, 1955-1989. E u r J Cancer 1993; 29A:
431-70.
7 Boyle P. Cancer, cigarette smoking and premature death in Europe: a
review including the recommendations of European Cancer Experts
Consensus Meeting. Helsinki, October, 1996. Lung Cancer (in press).
8 IARC (International Agency for Research on Cancer) Monographs on
the evaluation of carcinogenic risk to humans: alcohol drinking. Vol
44. Lyon: IARC, 1988.
9 Parkin DM, Ferlay J, Pisani P. Estimates of the worldwide incidence of
eighteen major cancers in 1985. I n t J Cancer 1993; 54: 594-606.
10 Boyle P, Veronesi U, Tubiana M, et al. European School of Oncology
SII30
advisory report to the European Commission for the "Europe Against
Cancer Programme": European Code Against Cancer. E u r J Cancer
1995; 9:1395 405.
11 IARC (International Agency for Research on Cancer) monographs on
the evaluation of carcinogens to man: human papilloma viruses.Vol
XX. Lyon: IARC, 1996.
12 Epstein MA. Epstein-Barr virus--discovery, properties and
relationship to nasopharyngeal carcinoma. In: De Th~ G, Ito Y, eds.
Nasopharyngeal carcinoma: etiology and control. Lyon: IARC,
Scientific Publication no 20, 1978.
13 Beasley RP, Lin C, Hwang LY and Chien CS. Hepatocelhilar
carcinoma and hepatitis B virus: a prospective study of 22 707 men in
Taiwan. Lancet 1981; ii: 1129-33.
14 Biggar RJ, Rosenberg PS, Cote T. Kaposi's sarcoma and non-
Hodgkin's lymphoma following the diagnosis of AIDS: multistate
AIDS/cancer match study. Intff Cancer 1996; 68: 754-58.
15 Pedersen C, Barton SE, Chiesi A, et al. HIV-related non-Hodgkin's
lymphoma among European AIDS patients. AIDS in Europe Study
Group. EurJHaema~o11995; 55: 245-50.
16 Tomatis L, Day NE, Heseltine E, et al. Cancer: causes, occurrence
and control. Lyon: IARC, Scientific Publication no 100, 1990.
17 Lipkin M. Strategies for colon cancer prevention. Ann N Y A c a d Sci
1995; 768: 129-40.
18 Steinmetz K.A., Potter J.D. Vegetable, fi'nit, and cancer I:
epidemiology. Cancer Causes Control 1991; 2: 325-58.
19 Blot WJ, Li J-Y, 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 N a t l Cancerlnst 1993; 85: 1483-92.
20 The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
Group. The effect of vitamin E and beta carotene on the incidence of
lung cancer and other cancers in male smokers. N E n g l J M e d 1994;
330: 1029-35.
21 Hennekens CH, Bnring ~E, 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.7 Med 1996;
334: 1145-49.
22 Omenn GS, Goodman GE, Thoruquist MD, et al. Effects of
combination of beta-carotene and vitamin A on lung cancer and
cardiovascular disease. N E n g l J M e d 1996; 334" 1150-55.
23 Greenwald P, Clifford C, Pilch S, Heimendinger J, Kelloff G. New
directions in dietary studies in cancer: the National Cancer Institute.
In: Longnecker JB, et al, eds. Nutrition and biotechnology in heart
disease and cancer. New York: Plenum Press, 1995: 229-39.
24 Weisberger JH. Nutritional approach to cancer prevention with
emphasis on vitamins, antioxidants, and carotenoids. A m .7 Clin Nutr
1995; 53". 226s.
25 Wattenberg L, Lipkin M, Boone CW, KelloffG, eds.
Chemoprevention of cancer. Boca Raton: CRC Press, 1992.
26 KelloffG, Boone C, eds. Cancer chemopreventive agents: drug
development status and future prospects..7 Cell Biochem 1994; $20:
1-303.
27 Buiatti E. Intervention trials of cancer prevention: results and new
research programmes. Lyon: IARC Technical Report no 18, 1994.
28 Armstrong B, Doll R. Environmental factors and cancer incidence and
mortality in different countries, with special reference to dietary
practices. I m J C a n c e r 1975; 15: 617-31.
29 Hursting S, Thornquist M, Henderson M. Types of dietary fat and the
incidence of cancer at five sites. Prey Med 1990; 19: 242-53.
30 Rose D, Goldman M, Connolly J, Strong L. High-fiber diet reduces
serum estrogen concentrations in premenopausal women. A m ~ Clin
Nutr 1991; 54: 520-25.
31 Henderson 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: 115-33.
32 White 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: 315-22.
33 Omenn 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-43s.
34 Hennekens C. Issues ha the design and conduct of clinical trials..7 N a d
Cancer Inst 1984; 73: 1473-76.
35 KelloffG, Johnson J, Crowell J, et al. Approaches to the development
and marketing approval of drugs that prevent cancer. Cancer Epidemiol
Biomark 1995; 4." 1-10.
36 Kelloff G, Crowell jr Boone C, et al. Strategy and planning for
chemopreventive drug development: clinical development plans. ~ Cell
Biochem 1994; $20: 55-299.
Vot 349 • May • 1997