Vitamin C and cancer prevention: the epidemiologic evidence”2 Gladis

Block

ABSTRACT

Epidemiologic

of vitamin the

46

evidence

such

studies

in which

compared

with

intake,

esophagus, tective and

low intake.

2 1 found larynx,

effect

cervix

oral For

0f29

there

is also

Of

C index

studies

protection. and

was

for a pro-

rectum,

Several

is strong

breast,

recent

lung

cancer

of fruits

and

Am J C/in Nuir

WORDS

studies,

Ascorbic

epithelial

cancers,

acid,

vitamin

cancer,

C,

epidemiologic

Ascorbic

acid

is increasingly

function synthesis

chrome pounds.

P-450 activity and carnitine synthesis as its well-known

results

that

may

thntis,

and

aging.

sively elsewhere dominant role

negatively

within intake

detoxification and cholesterol

with

coronary

possible

with artery

mechanisms

prevention

have

(3-5). It plays a major in free-radical scavenging

broad

functions cyto-

of exogenous metabolism

functions

to cancer,

Several

in cancer

as an agent

Well-established and neurotransmitters,

antioxidant

extend

important

antioxidants

C in the immune

detail

to their from

and

been and and

com-

( 1 , 2), protective

disease,

ar-

of action described perhaps protection

of

exteneven preagainst

system of leukocyte

(7). have

Several

been

functions

described

of vitamin

(1 5, 16), including

( 1 7), stimulation

chemotaxis

of in-

terferon production ( 1 8), and complement Clq activity (19). Its role in collagen synthesis and basement membrane integrity and in hyaluronidase inhibition (20-22) may iting tumor spread and micrometastases.

be important

elsewhere

nutrient

the

positively

populations ofa nutrient

(4,

23).

intake,

Briefly, by at of in-

2) errors

fact

that

nutrients

are

with

other

nutrients,

and

that are quite homogeneous may be unable to detect

of in-

correlated

3) studies

with an effect

respect ofhigh

to or

intake. Misclassification

errors

cause

a bias

toward the null, making the observed than it really is and making it more significance. of the

Studies

that

sessment long-term

probably dietary

inherent

may

rarely

have

of the

show

investigators one because,

be calculated,

other

and

does

studied

the joint

not

Some

below,

the

effect

but

Epidemiologic The ologic

of low

studies

studies

reported

studies

the index mcvi-

necessarily

effects

of these the

levels

cannot

by cancer below

in humans-that

are

a low

may

produce

For example, in in the population nutrient, control

are

problem

re-

systems it and very

ofhaving

simultaneously. populations

highlighted may

spread. The same situation may exist in the if all in a study group are very well nourished nutrient,

nutrients

true

food and are correlated with it in the is calculated reflects the interests and

investigator

as cases.

cancer,

as-

into identifying although an

negative results that are difficult to interpret. studies in very high risk populations everyone may have a very low intake of a protective as well

face

effect if the be known.

causal agent. Furthermore, in biological nutrients do not act singly but jointly investigators

esophageal

in the

or biochemical

even stronger status could

intake of two or more nutrients Finally, studies in homogeneous

subjects

risk estimates

an effect

in dietary

indicate an or biochemical

nutrient

ofobserved

risk estimate appear weaker difficult to achieve statistical

nevertheless

misclassification

fleet the true is likely that

lipid peroxidation (6, 7). It appears to have a role in sparing or reconstituting the active forms of vitamin E (8- 14), and spares

enhancement

respect

tably accompany it in the plasma. The nutrient that

recognized

and importance. of hormones

as well

acid

in some

of nutrients in disease are hampered of error: 1) error in the classification

arising

presuppositions

biologic include

other

with

terpretation

for a certain

review

Introduction

ascorbic

discussed

Correlated variables mislead wrong nutrient as the effective

199 1;53:270S-82S. KEY

been

dividuals

low

and

studies found significant protective effects of vitamin C or of foods that are better sources of vitamin C than of /3-carotene. It is likely that ascorbic acid, carotenoids, and other factors in fruits and vegetables act jointly. Increased consumption vegetables in general should be encouraged.

have

studies of the role least three sources

both

of the

in fruit

stomach,

evidence.

assessed

cancers

evidence

component

ofthe

that

For

pancreas,

C or some

strong

vitamin

additional

cavity.

cancers

effect

is strong.

significant protection, with high a twofold protective effect

significant

of vitamin

consistent.

cancers

a dietary

calculated, 33 found statistically intake conferring approximately fruit

of a protective

C for non-hormone-dependent

under

be more

opposite with

be assessed

wide-

direction; respect to a well.

site limited

is, case-control

to analytic and

epidemiprospective

in inhib-

Before an examination ofthe epidemiologic evidence that cxists regarding ascorbic acid and cancer prevention, it is important

I From the Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, MD. 2 Address reprint requests to G Block, National Cancer Institute, FPN

to consider

Room

2705

several

sources

ofpotential

misinterpretation. Am J C/in Nutr

These l99l;53:270S-82S.

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3 13, 9000 Printed

Rockville

in USA.

Pike,

Bethesda,

© 1991 American

MD 20892. Society

for Clinical

Nutrition

ASCORBIC studies. any

No

international

studies

region

that

with

same

mortality

individuals

and

risk

included intake

rates

all at the individual are identified and Such

RR

The

generally risk

high

in this

intake).

For

direction

simplicity,

so that

all risks

a relative

risk of the cancer among relative risk (RR) = 2.0 vitamin C are estimated

risk

in the

have

been

is rich in vitamin C, usually raw vegetables. Studies that

fruit simply

are not vitamin

although content

impossible

because, carotenoid

to attribute

expressed

either an actual on a food that

to vitamin

C with

any

confidence.

Non-hormone-dependent C’ancers

oJt/ie

Oral most

cancer of them

dietary

cancers

oral

factors

cavity,

has been

the subject

large

well

and

(24-30).

tective effects Most ofthese

ofseven

controlled,

All but

for increasing studies included

case-control

per

week

consumed

or less often

one

it seven

times

also found protection whereas in the others Two

studies

had

have

found

of the

significant

of

pro-

lowest quartile of or 2.0 (women). consuming fruit

the risk

or more.

Two

from carotene-containing these foods were weaker

of cancer

the role

C intake or fruit intake. for smoking and alcohol.

I .7 times

a week

studies,

investigating

vitamin control

larynx

et al (34, study

(34)

and

Carotene Ziegler

the

Notani

and

creased

risk

once

Jayant of2.0

a week

consumption Cancer gators

of those of the

who studies

have

examined

(33-44)

compared vitamin

compared

smoking, ratio

observed

associated

and

again,

relationships

examined

tically smoking

(32)

and a risk

the

with

a low of 2.4

a statistically

with

with

least

a vitamin

most with

have

found

vitamin

C index

significant relative risks and alcohol consumption.

of

‘2.0 Brown

Compared

A

for citrus

with

heavy

con-

with

with

quartile

adjustment a risk ratio

fruit

cancer

the role

ofdiet

in the

C intake

among

to

even

third

of

intake. 0.004)

=

adjustment

to be lower

in

et al (44)

in-

Decarli

105 cases

one

after

fruit

, 44).

significant

low

for ethanol of 2.4 (P

or citrus

(38-41

effect.

males who died of of other causes. Vi-

a statistically

being

ofvitamin

weaker questionnaire

ofesophageal

cancer

and hospital controls. Fruit and vegetable questions consisted ofonly three items, carrots, green vegetables, and fresh fruit. All were in the protective direction, but after adjustment for alcohol, smoking, and other factors (RR = 3.3) and statistically

only fruit intake significant (trend

P

Mozaffari

354

esophageal

et al (38)

population

consumption In Japan,

studied

controls

in Iran,

of oranges Hirayama (39)

daily consumption cancer. Bjelke (40, cancer and nonsignificantly

patients

with

an area

ofhigh

remained < 0.001).

strong Cookcancer

esophageal

can-

in-

Vegetable

by several

36,

and

investi-

statistically

intake.

All four

37) found

after adjustment et al (33) found

the most significantly protective food. found a risk ratio of -2.7 for less than

of fruit in a case-control study of esophageal 41), in a study of 52 patients with esophageal

hospital control lower intake

subjects,

but

Some mogeneity

studies represent ofintake that

did

not

impossible

effect

for fruit

statisfor that

with those in the upper third of the distribution for C intake, those in the lower third had a statistically

significant twofold risk ratio. Fiber was also significantly protective but carotenoids were not. Fruits, especially citrus fruits and juices, were the only significantly protective foods or food

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/270S/4691329 by guest on 14 February 2018

and

incidence Risk that

ratios

75%

oral

were patients

of both diets

on a vitamin

and

two portions

and

Jayant

index.

C

classic examples of may make the existence In a region

population hoofa protective

of China

with

Li et al (42) conducted or gastric cardia cancer. consumption.

However,

cancer

in Puerto

Rico,

cancers

is among

the

not specifically and

patients

only

in Minnesota, observed and green salad in case

very

high

a large caseNo protective the authors

note

infrequently eaten in this high-risk area, category consisted ofthose who ate fresh year. Martinez (43) studied risk factors

of these

both

subjects of apples

report

to detect.

was seen

in their strong

34,

of

0.005). less than

a week.

C or fruit (33,

intake
35 times per

C was

35) studied

conducted

significant

of vitamin C (3 1 ) or fruit (32). Graham et al (3 1 ) studied 374 patients with cancer of the larynx and hospital control subjects using the Roswell Park questionnaire. After control for possible vitamin

2715

cer incidence. Low intake of fresh fruit and vegetables was strongly associated with risk ofesophageal cancer. with frequent

McLaughlin et al (25) found that those in the vitamin C intake had a risk ratio of 1.7 (men) Winn et al (28) found that those who reported once

fruit

and

or esophagus

larynx,

Tuyns

case-control

elevation

those foods may contain is usually such that it is effect

groups.

tamin

an elevated

but occasionally tomatoes or reported on green vegetables

a protective

PREVENTION

investigate esophageal

those with low intake. For example, a indicates that those with low intake of to have twice the risk of that cancer

compared with those with high intake. Studies are described below if they reported vitamin C score or estimate or if they reported

included C. their

or

group

C or foods (here, those

1 .0 means

>

ratio

CANCER

statistically

result

risk

exposed to a risk factor (here, low intake of vitamin rich in it) is expressed as a ratio ofthose not exposed with

nor in a

in a region.

termed

or OR).

IN

level: mdidietary intake

studies

(occasionally

abbreviated

are nutrient

or morbidity

is assessed.

of relative

ratio

studies to relate

reported below are and without cancer

in estimates odds

attempt

population

The studies viduals with in those

correlation

simply

ACID

(32)

87%

control and

reported. subjects

control

of both

or less ofvegetables studied

esophageal

in which

highest

in the

but the author were

subjects

patients

an area

and

chronically never

the

world. reported

deficient:

had

control

fresh

fruit

subjects

had

per week.

Similarly,

and

cancer

oral

and fruit for

Notani in regions

of India where incidence of these diseases is among the in the world. Fruit consumption showed a nonsignificant

highest effect,

but was so infrequent that the distribution was dichotomized into those who ate it once a week and those who ate it less often. Vegetable consumption, dichotomized on daily rather than weekly

consumption,

In summary,

C index one

was ofeight

significant.

studies

that

in cancer ofthe oral cavity. has found a statistically significant

have

reported

on a vitamin

larynx, or esophagus, every elevation in risk associated

BLOCK

2725 with

low

weak

and

found

to be significant

studies

intake.

Three

of foods

nificant

risk

for

low

fruit

weaker

than

intake,

1 found

carotene

vitamin

2 found

also

Of the

C.

6 found

to be

A was

vitamin

nutrients,

significance, and control

and

found

in two

12

statistically

suggestive

sig-

results

3 found extremely subjects in extremely

or low high-

no effect.

Of

the

‘-30

relationship

epidemiologic

between

focused on many cases assess

any

of vitamin

and

foods

nonsmokers were adjusted day

those

intake,

Koo and

(46)

who

after

cancer

studied

88 subjects never

have

parity,

and

of2.4

Kong

to examine

risk

Risk

education.

with

those

although may have

with

lung

fruit

mdi-

fresh

it five to seven

fish

times

score yielded a risk effect was strongest for C

the number ofsquamous cell cancers been too small for a stable risk esti-

mate. In a study 49 lung

justment

conducted in the Netherlands, cancer patients in a case-control

for smoking

tamin

C index

a risk

4.3

result