Vitamin C and cancer prevention:

the epidemiologic
evidence2
Gladis

Block

ABSTRACT

Epidemiologic

of vitamin
the

46

evidence

such

studies

in which

compared

with

intake,

esophagus,
and

larynx,
effect

cervix

For

there

is also

0f29

additional
and

strong

was

of the
for a pro-

in fruit

stomach,

evidence.

assessed

cancers

evidence

component

ofthe

that

For

pancreas,

C or some

cancers

C index

studies

protection.

cavity.

of vitamin

consistent.

vitamin

Of

significant
protection,
with high
a twofold
protective
effect

significant

oral

effect

is strong.

rectum,

Several

is strong

breast,

recent

lung

and
cancer

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.

of fruits

and

Am J C/in Nuir

WORDS

studies,

Ascorbic

epithelial

cancers,

acid,

vitamin

cancer,

C,

epidemiologic

acid

is increasingly

function
synthesis

chrome
pounds.

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

thntis,
ascorbic

and aging.
Several
possible
acid in cancer
prevention

sively elsewhere
dominant
role

extend

as an agent

with

Well-established
and
neurotransmitters,

detoxification
and cholesterol

results

may

antioxidant

broad

functions
cyto-

of exogenous
metabolism

functions

to cancer,

coronary

with
artery

mechanisms
have been

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

and
and

com-

( 1 , 2),
protective

disease,

ar-

of action
of
described
extenperhaps
protection

even preagainst

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

antioxidants

C in the immune

in some

with

terpretation
both

low

respect

to their

arising

negatively

within
intake

detail

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

(4,

23).

Briefly,

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

and

positively

populations
ofa nutrient

nutrient

the

intake,

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

fleet the true

is likely that
rarely

have

of the

show

in the

even stronger
status
could

into identifying
although
an

be calculated,

other

nutrients

investigator

studied

as cases.

true
the
index
mcvi-

food and are correlated

with it in the
is calculated
reflects
the interests
and
and

does

not

the joint

necessarily

effects

Some

of these

re-

systems
it
and very

ofhaving

simultaneously.
populations

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

as-

effect if the
be known.

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

face

or biochemical

investigators
one because,

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

tably accompany
it in the
plasma.
The nutrient
that

recognized

and importance.
of hormones

as well

enhancement

dividuals

presuppositions

biologic
include

other

discussed

for a certain

review

Introduction
Ascorbic

been

Correlated
variables
mislead
wrong
nutrient
as the effective

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

have

studies
of the role
least three
sources

a low

may

produce

For example,
in
in the population
nutrient,
control

are

highlighted

under

esophageal
cancer,
below,
but the problem
may be more widespread.
The same situation
may exist in the opposite
direction;
if all in a study group
are very well nourished
with respect
to a
nutrient,

the

effect

Epidemiologic
The
ologic

of low

studies

studies

reported

studies

levels

cannot

by cancer
below

in humans-that

are

be assessed

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.

3 13, 9000
Printed

Rockville

in USA.

Pike,

Bethesda,

1991 American

MD 20892.
Society

for Clinical

Nutrition

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

tective

low intake.

2 1 found

cancers

a dietary

calculated,
33 found
statistically
intake
conferring
approximately
fruit

of a protective

C for non-hormone-dependent

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

fruit
simply

are not
vitamin

although
content

impossible

because,
carotenoid

to attribute

expressed

C with

any

confidence.

Non-hormone-dependent
Cancers

oJt/ie

Oral
most

oral

cancer
of them

dietary

cancers
cavity,

has been

the subject

large

well

factors

and

(24-30).

tective
effects
Most ofthese

ofseven

controlled,

All but

for increasing
studies
included

one

case-control

have

per

week

consumed

or less often

it seven

times

also
found
protection
whereas
in the others
Two

studies

found

patients
using

of cancer

with
the

cancer

Roswell

confounding
C was

Notani

and

creased
once

risk

consumption
Cancer

Two

Graham

larynx

(32)

intake

with
with

at

hospital

and

again,

relationships

most
with

control

vitamin

studies

ratio

found

for

age,

and

the

only

the distribution,
Finally,
Mettlin

quartile

esophageal
the role

adjustment
a risk ratio

fruit

cancer
ofdiet

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-

in the

C intake

of 2.6

weaker
questionnaire

a statistically

being

ofvitamin

for smoking
and alcohol.
Four studies
have found
vestigated

with

with

RR = 1 .8 after
et al (37) found

for low vs high

with

120 black
who died

con-

ratio

consumption.

but somewhat
next-of-kin

nutrient

associated

heavy

a risk

alcohol

for citrus

with

had

smoking.

in a large

of France.

observed

Compared

the role of diet among

cancer
and 250 others
in risk

cancer
region

was

consumers

also had a significant

et al (36) used a 3 1-item

C was

cases

effect

C (35).

C, light

adjustment

Carotene
Ziegler

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

Mozaffari

354

esophageal

et al (38)

population

studied

controls

in Iran,

patients

with

an area

ofhigh

remained
<
0.001).

strong
Cookcancer

esophageal

can-

offruit

C or fruit

and
intake.

hospital
control
lower intake

but

Some
mogeneity

studies
represent
ofintake
that

>

of
in-

less than
Vegetable

by several
strong

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

subjects,

did

not

impossible

that fruit
the highest

significant
a week.

cancer
and
nonsignificantly

effect

0.005).

<

of oranges
Hirayama
(39)

daily consumption
cancer.
Bjelke (40,

374

intake

(P

consumption
In Japan,

role

investi-

statistically
All four

that examined
a vitamin
C index
(33, 34, 36, 37) found
statistically
significant
relative
risks of 2.0
after adjustment
for
smoking
and alcohol
consumption.
Brown
et al (33) found
that
compared
vitamin

for vitamin

report

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

35

for fruit

is very
intake

times

and

year.
oral

incidence

of these

Risk

were

that

ratios
both

In a region

only

two portions
Jayant

in the

(43)

Rico,

cancers

is among

the

control

reported.

the authors

risk

an area
highest

were

note

where

studied

esophageal

factors

for
the

in the

chronically

world.
reported

deficient:

incidence

of these

Fruit

consumption

per week.

Similarly,

and

cancer

diseases
showed

oral

and
fruit

in which

but the author

subjects

high

high-risk
area,
who ate fresh

studied

in Puerto

or less ofvegetables

(32)

world.

Martinez

in this
ofthose

very

a large caseNo protective

patients
and control
subjects
never had fresh
and 87% of both patients
and control
subjects

and

of India

with

However,

eaten
consisted

cancer

and

population
hoofa protective

of China

consumption.

not specifically

patients

75% of both
in their diets

index.

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

infrequently
category

per

esophageal

in Minnesota,
observed
and green
salad in case

on a vitamin

to detect.

was seen

subjects
of apples

classic
examples
of
may make the existence

esophageal
cancer
rates,
control
study ofesophageal

for possible

of 2.4

once

and

protective

of vitamin

effect

subjects

a low

consumption

have

who

the

control

a statistically
least

of the

examined

smoking,

a risk

of those

et al (3 1 ) studied
After

and

with

associated

compared

and

observed

pro-

vegetables,
or nonsignificant.

have

was also a significant

factor.
of the esophagus
has been studied

(33-44)

significant

larynx

(32).

questionnaire.

associated

of2.0

a week

gators

Park

Jayant

the risk

or more.

of the

of the

by alcohol

vitamin

I .7 times

a week

significant

of

lowest quartile
of
or 2.0 (women).
consuming
fruit

from
carotene-containing
these foods were weaker

C (3 1 ) or fruit

of vitamin

had

studies,
the role

C intake
or fruit intake.
for smoking
and alcohol.

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

(34)

esophageal

in a high-risk

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

investigating

vitamin
control

35) studied

conducted

significant

sumers

and

or esophagus

larynx,

et al (34,
study

elevation

either
an actual
on a food that

to vitamin

fruit

tamin

an elevated

those
foods
may contain
is usually
such that it is
effect

Tuyns

case-control

investigate
esophageal

but occasionally
tomatoes
or
reported
on green vegetables

a protective

groups.

2715

fruit
had

Notani
in regions

is among

the

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

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

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

group

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

PREVENTION

after

or

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

BLOCK

2725
with

low

weak

and

found

to be significant

studies

intake.

Three

of foods

nificant

risk

for

low

fruit

weaker

than

nutrients,
intake,

1 found

carotene

vitamin

2 found

to be

A was

vitamin

also

Of the

C.

6 found

significance,
and control

and

found

in two

12

statistically

suggestive

sig-

results

3 found
extremely
subjects
in extremely

or
low
high-

Of

the

-30 epidemiologic
between

focused
on
many
cases

vitamin
the diet

vitamin

draw

any

of vitamin

foods

those

intake,

(46)

who

after

studied

88
subjects
never

have

parity,

and

of2.4

women
risk

Risk

education.

with

those

although
may have

who

1274
were

who

due

with

lung

factors

fresh

con-

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.
ied

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

<

times

result

was highly

score

was

was

cases
both

50 mg/d
greater

risk

factors,

(as estimated

than

statistically

those

persons

with

significant.

a higher
No effect

intake.
ofa

et al (48)
and
total

significantly

studied

230

population-based
vitamin
C and
protective,

and

highest

trolled

for

13-carotene

quartile,

C. However,

than

RR

2.0

a stronger
was
among

male

and

controls
vitamin

not.

carotene;
vitamin

seen
females

for the contrast

for vitamin

for /3-carotene
a nonsignificant

dietary
cancer

the fifth (48) found

from foods in men,
The

comparison

one

since

vitamin
C
intake
was
lung

cancer
intake

cancer

have

all

of vitamin
C.
effect of /3-

an equal
effect of 13-carotene
and
and a stronger
effect of /3-carotene
with

vitamin

the 13-carotene

studies

a 25%

/3-carotene

in lung

and

whereas

to subsequent

adjustment.

C from

is all from

supplement
use is a behavior
commonly
states,
particularly
among
women.
additional

had

and supplement
mortality.
Fruit

related

appro-

follow-up,

significant
protective
effect
found
a weak and nonsignificant

in women.

Four

after

but
re-

smoking,
one-pack-a-day

vitamin

in the 25-y

smoking

appropriate

have

reported

foods

foods

increased

is the

and

since

in prodromal

on a vitamin

a retrospective
study
in Hawaii
patients,
including
all five ethnic

population

control

protective

direction,

significant.

lung

between
C concontrolled
effect

subjects.

The

RR

C index

effect

The

vitamin

A, greater

of 26 1 male and
groups
of Hawaii,

effect

of vitamin

1.6 for males,

of vitamin

for women

or other

prodromal

in LeMarchands
was in the harmful
In all ethnic

the

than

men,

deaths

Shekelle
score,

the vitamin

the limitations
ber of cases,
mean

Bjelke

(56)

greater

may

found

foods
0.07

not

for Cau-

explain

why

no effect

that approached
for squamous

and

C score
P

conducted

cases.

was based

57)

C per

collected

mean

study

included

not

10

C score.

day

as individual
carcinomas).
the

recall.

and

oh-

13-carotene
Considering

C and the small numdifference

between
the
among

those

who

of 10 1.0 mg among
plasma

Towere

study

Unlike

on a 24-h

lung

/3-carotene,

significance
small-cell

method
for vitamin
value of 0.20 for the
the

that

a prospective

cancer

lung cancer
and
not is suggestive.

St#{228}helinet al (53,

appeared

a prospective

for a vitamin
C but

of 33 lung
ofthat

alone

I 53 subsequent

in vitamin

also

foods

conducted
observed

of 9 1 .8 mg of vitamin

developed
who did

from

They

rich

the

foods.

et al (52)
a total

was

cancer.
questionnaire

two

served

and

This

diet

and

alone

Consequently,
inclusion
of interpretation
since
when they experience

to a mailed

however,

one ofonly
items (trend

vitamin

of lung

acid-rich

cancer

foods

symptoms.

sex groups,

risk

et al (5 1) and

ascorbic

in the

not statistically

study in Hawaii
vitamin
C from supplements
direction,
but only among
Caucasian
women.

and

to reduce

103
and

included
supplements
used
of lung cancer
symptoms.
greater
for vitamin
C than

casians
than other
ethnic
groups
(55).
of supplement
use introduces
difficulties
individuals
may start taking
supplements
malaise

C was

but was

C from

reported;
instead,
vitamin
C intake
in the 3 mo preceding
recognition
Supplement
use is generally
much

had
This

in the protective
direction
was seen only for intake
from foods,
not supplements,
whereas
a /3-carotene
effect was stronger
and
significant.
Vegetables
were strongly
protective,
whereas
fruit
was

found
a statistically
Four of them have

Kvale

in Hawaii.
Among
C from
foods
alone

effect

supplement

cancer

risk (age
C intake

factor
cigarette
male,

not related
to lung cancer
mortality.
The above
five recent
studies
of diet

ofrespondents

/3-carotene

102 female

protective

inversely

age and

increased
vitamin

for age,
55-y-old,

and

lung

and

after

a vi-

by questionnaire)
with

dietary
from

significantly

matoes,

lowest

for vitamin

other

et al (47) studstudy.
After ad-

seen.

Le Marchand
cancer
males,

and

HoIst

low

smoker
with high
a 7% chance
oflung

mortality,
was

significant
adjustment
use. A

over

100 mg
interview),

ducted
female

related
to a reduction
and carrots
were in

consumed

cancer

cancer
adjusted

and

of lung

in

on 870

to car-

among
were

died

study

in 1960

from the diet (50-52)

or in plasma
(53) and have found suggestive
but nonsignificant
results.
Investigators
in Hawaii
(50, 54) con-

By contrast,
those
a week had a risk ratio

A vitamin
0.01 5); the

<

also

C intake.

estimates

Only

to

0.001).
The
adjustment

protection

to examine

the same
had only

of vitamin

those

for vitamin
Kong

in
to

3 y. Results
confounders.

1.5 (P <
1.9) after

the apparent

smoked.

(trend
P
<
0.002).
of 2. 1 (trend
P

adenocarcinoma,
in these women

with

area.

26%

140 mg or more

direction
but nonsignificant.
fresh fruit less than once

compared

a week
estimate

and

questionnaire),

Hong

and

Orleans

was black

consumption
were found to be significantly
in lung cancer
risk. Leafy green
vegetables
the protective
who consumed

cases

New

had quit for

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y; 63 subsequently

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those consuming
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viduals

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sumed
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history

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respondents

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those
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and

Compared

lung

investigators

et al (45)examined

Approximately

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the

about

C-rich

sex-,

have

and

examined
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age-.

and

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tigators
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are reported

that

factors

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Because
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questionnaire
food list was not designed

well

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dietary

(49)

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priate
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ASCORBIC
197 1 - 1973
that

time

and

followed

there

plasma

were

vitamins

could

died

of lung

cancer

than

control

subjects

was significantly
of more
mean

them

35 lung

plasma

mortality
deaths

for which

Persons

who

lower

(0.90

cancer

plasma

ascorbate

did

between

0.2.

Subsequent

deaths

through

reveal

lung

cancer

two studies

C index.

Two

C as noted

reports

by the

for vitamin

have

reported

using

the

authors

and

no effect

1957

ofa

Roswell

fourths

cause
could

ofillness
or death.
be missed
if low

of the

in

control

Park

Thus,
intake

not

those

have

studied

the role of car-

few

could

Men

who

ofconsumption
were seen

consumed

1 .7 times the lung

week,
a statistically
effect

in the

a carotenoid

and

items

melon,

same
not

found

pasta

less than

cancer
risk
significant

direction.

sauce,

be cxand

study in which
information

times

per week

who ate it 5-7

Green
salad

Bond

et al (64)

C index.

to be individually

with

three

ofthose
increase.

a vitamin

of

offruit
and green salad; 671
the subsequent
1 1-y follow-

over

fruit

role

fruits or raw vegetables,

reported
below.
Long-dc

(63) examined
data from a prospective
white males in the United
States provided

on their frequency
lung cancer
deaths

the

broccoli,

and

times per
showed
a

reported

However,

significant,

had

of the

cereals)

erally

assumed

to be a carotenoid,

a vitamin

C score,

tective
effect,
not significant,
studies

that

5 have

4 have
and
found

found
stronger

suggestive

additional
significant
effects

found

but

of vitamin
tioxidant

that

studies

that

protective
for vitamin

there

Pancreatic

may

also

C intake.
The
and free-radical

also in enhancing
lished.

noting

the

that

many

specifically

mentioned

significant

direction
but
In two of the

nonsignificant

action

assessed

results

fruit

intake,

(52,

both

Four
studies
for carotenoids.

57),

be an independent

protective

role of vitamin
C not only
scavenger
in its own right
E (8-14)

effect
as an an(6, 7) but

is well

estab-

The

questionnaire

was

designed

fresh

among

of dietary
each

third

protective;
fruit

winter

protective
cancer

and

reduction

Stomach

cancer

the

obser-

et al (70)

those

and vegate them

who

ate them

variables
was

current

(7 1) oh-

and

23 women).

were

adjusted

divided

for age

of tomatoes,

a suggestive,
common

and

state

of our

sex,

numbers
of dried
fresh

citrus

though

non-

cause

is a disease

into

and

results
in small
consumption

use

(72)

Adventists

of cancer

with

ability

extremely

to treat

this

is of primary
importance.
All five pancreas
found
statistically
significant
protective
efin some

calculated

twofold

vegetables.

and both hospital

for several
con-

Day

showed

States

In the

that

often.

categories,

Gold

( 1 7 men

relationship.
is the fifth most

in the United

for fruit,

more

food

or raw

with

cancer

fresh

study

conless than
elevated

instrument,

cancer
Adjusted

Seventh

pancreatic

significantly

fects

and

studied

consumption
of raw fruits
RR = 1 .8 for those who

and

one

ate them

Finally.

pancreatic
subjects.

was

prevention
studies
have

et al (69)

fruit

of the

a week compared
<
0.02).

within

prognosis.

of 99
subjects,

(P

in risk

instances

for vegetables

a vitamin

C index

associated

with

Several
studies
of an ecological
(73-75)
that suggested
a protective

C intake

in stomach

cancer.

to be concentrated
juice of persons

not

with

in those

persons
form

chronic

it is predominantly
required

for

as well.

found
high

The

a significant

intake.

to assess

gastritis

have been conducted

for fruit or for vitamin
acid

at three
with normal
in the

the

nature
role

Ascorbic

demonstrated
in the gastric

patients,
by contrast,
dehydroascorbic
acid.

cancer

in Louisiana.

with
control

fruit,

disease,
cancer

in

for carrots

broad

is striking.

fruit

significant,
Pancreatic

both

who
very

a process
which,
although
appropriate,
and reduced
statistical
power.
Frequent

the

Five studies
have examined
the risk of pancreatic
cancer
in
relation
to either
a vitamin
C index
(67) or fruit (68-7 1 ). Falk
et al (67) investigated
363 cases and matched
hospital
control
subjects

being

effect

from

risk

are rich
adjustment

in Sweden

Mack

those

crudity

distributions

and

fre-

have

have
found
Whereas
a

an important
effect for carotthe recent
data reported
above

of vitamin

intake

poor
pro-

here

study

40 deaths

mortality

a statistically

effects.
C than

A prospective

(in

on

control

effect

only

frequent
protective,

less than five times

five or more times

study

weekly.

with

obvious

founding
factors,
etables
was highly

The

significance
was based on I tests involving
cancer
cases, n = 33 and 35, respectively.

large body of evidence

suggests
enoids
in lung cancer
protection,
suggest

C.
have

found
effects in the protective
2 have reported
no effect.

the lack of statistical

small numbers
oflung
Of two

it is worth

are rich in vitamin

cancer
studies
that

one

the

studied
201 persons
and neighborhood

thirds

are rich

relevant

1 .8 for

I 59 mg/d

and matched
neighborhood
fresh fruit or vegetables
a statistically
significant

included

of a significant

served

than

1 .4 compared

Considering
vation

less

instrument

the only

on

in vitamin
C as well as (or in some cases instead
of) carotenoids.
Others
have reported
protective
effects
of green
(65) or green
and yellow (66) vegetables.
Whereas
the protective
factor is gengreen vegetables
Ofthe
1 1 lung

RR
diet

six

five (tomatoes,

fortified

risk,
The

by

or

fruits there
was a two- to threefold
who ate them
daily compared
with

490 pancreas
cancer
patients
trols. For those who consumed
five times
a week there
was

them

Those

(based

population

protective

For citrus
for those

no effect

effect
the

consumed
consumption

and

however,

it is possible
that a nutrient
had the effect of increasing

in relatively

hospital

found

ate

diet.

(as estimated

factors.

York;

who

who
Fruit

in a case-control

significant

fruits.
effect

adult

C/d

of six fruits,
three of which
a 1.6-fold protective
effect after

matched

a highly

usual

risk of 2.6 for males,

those
0.05).

confounding

for citrus
protective

about

mg vitamin

a relative

<

et al (68),
and

found

be-

especially
vitamin
C-rich
separately.
These
are

Hammond
1 36 000

questionnaire

asked

-70

with

trend

of consumption
C) conferred

patients

be interviewed

of disease.
investigators

vegetables,

New

could

vitamin

had

compared
cases,

quency
vitamin

and

less than

for multiple

control
for other
to assess vitamin

et al (62)

in upstate

cases

dietary

ofnutrients

has

(76).

Moreover,

reduced

form,

antinitrosation

it is predominantly
A similar
pattern

recently

times the plasma

gastric
histology,

reaction;

been
level
but

in normal
ascorbic

acid,

in gastritis

in the oxidized
is seen for gastric

form,
tissue

ascorbic
acid, which
often
falls to immeasurable
levels
(77)
in patients
with chronic
gastritis.
The focus below
is on studies
at the individual
level,
but it should
be noted
that indices
of
vitamin
C intake
have
heretofore
not differentiated
between

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

otene-containing

study

eligible

severity
or progression
Although
numerous

food

(6 1). Byers

in a 1987

three

lower

both

by St#{228}helin(58)

patients

range
consumed

females

mg/dL)

differences

a wide

2735

the questionnaire)

/3-carotene

any

PREVENTION

who

baseline

(0.79

(59, 60) found

no effect
of vitamin
C after
factors.
The instrument
was not welldesigned

up.

In

CANCER

Norell

subjects.
Finally,

fruits,
amined

1980.

Plasma

analyses

not

IN

subsequently

ascorbate

mg/dL.),

different.

recent

for
cancer

be analyzed.

had

ACID

2745

BLOCK

ascorbic
and dehydroascorbic
of ascorbic
to dehydroascorbic
furthermore

the correlation

ascorbic

acid

was

low,

Several
studies
effect of vitamin
found

vitamin

most
.

strongly
and

acid or considered
the conversion
acid during
cooking,
and that

the

between
only

vitamin

0.22

C intake

and

C to be the

dietary
total

the

controls

for gastric

carcinomas

combined

group

(40).

The

ofthe

ofdiffuse

and

which

protective
(40, 41, 78)
discriminated

of stomach

effect

diffuse

was

and

intestinal

cases

particularly

strong

types.

carcinomas,

For

the relative

In Norway,
males and

a stafemales

(41) and a strong effect was also observed

in Minnesota

No effect

cancer.

of vitamin

(40)

that

an increased

A was

the
risk

data

being

seen

for stomach

for stomach

cancer

associated

with

fecting
a minority
of the population.
In a study ofdietary
factors
and
Correa

et al (79)

found

a classical

gastric

as a group

significantly

The

af-

in Louisiana,

dietary

in both

with

deficiency

cancer
and

protective

author

are consistent

blacks

and

report
Japan,

Kono
for

consumption

tables

in

enoids

disappeared

tamin

C effect

risk

after
remained

factors.
In a high-risk

tistically

control
after

region

significant

control

effect

was seen

had
was

bottom

one

third

a 2.5-fold
elevated
similar
in multiple

the
and

observed

of stomach

vi-

et al (88),

reported

negative

for fresh

vegetables

where

a case-control
hospital
control

of the

distribution

risk, P <
regression

the

cancer

associated

study
subjects.

of vitamin

in Italy
Those
C intake

cooked

state.

et

sources

sources,
bined
have

ofvitamin

C and

citrusjuices

and

three

tomatoes,

with poor vitamin

generated
imprecision

ascorbate

vegetables,
was

seen

confirm
protection
Meinsma
and

the

(83)

found
and

strong
vitamin

57, 58) observed

20 persons
than those

lower

(P

important

omitted

or com-

whereas
the overall
<
0. 10. However,

This

analysis

0.01)

effect
tends

to

high

of high

bacon

intake

daily,
relative

twice

in a study

For

fruit

intake,

et al
of frevege-

ofa

stomach.
previously-

risk

of gastric

vegetables

in England
twofold

com-

salad-type

a reduced

et al (90)

risk

a week

of the

reanalysis

observed

after

Jedrychowski

of raw

various

fruit

tomatoes

(a source

protective

effects

was

seen

in this

(92)

in the

of 95

found

Un-

patients

and

statistically

or greater,

for fruit

sigand

the high-consumption

for

category

matched

Japanese

found

hospital

ofvitamin

but

in both

Issei

and

American

no effect

of orange

Fontham

No

effect

population.

of

A study

consumption.

found
less frequent
among
stomach

controls.

not of /3-carotene)
Nisei.

Finally,

consumption
of fresh
cancer
patients
than

et al (94) found

a statistically

significant
2.5-fold
elevation
in risk of gastric
cancer
precursor
lesions
for those below the median
intake
ofvitamin
C in a highrisk

black

population

in Louisiana.

In a negative

cursor
lesions,
however,
Haenszel
between
the mean
plasma
levels
with atrophic
gastritis
and control
In summary,
seven investigators
intake

and

stomach

significant

tamed

in nitrate-containing

found

lower

developed
having
otene,

plasma
stomach

that
the

Eight

studies

have

found

risk.

All

effects

seven

have

found

of approximately

vegetables.

cancer,

levels

nearly

simultaneously

One

two-

prospective

in those

significant

In two studies
also significantly

that

examined

who
at

study

subsequently
0.06

despite

also examined
13-carprotective;
in two other

13-carotene

and

vitamin

models
both remained
significant
in one study,
effect of 13-carotene
disappeared
in the other
(79).
have
lower

reported
fruit

on

consumption

stomach
cancer,
in most instances
to threefold
effect. Consumption
found

of pre-

vitamin
C score although
in one inwas limited
to the vitamin
C con-

vitamin

only 19 cases.
that factor
was

study

et al (95) found
no difference
of total ascorbate
in persons
subjects
in Colombia.
have reported
on vitamin
C

cancer

protective

fold, usually
in the overall
stance
statistical
significance

C in multivariate

mechanism
for
cancer.
Similarly,

risk with
<

only

whereas

significant

and

in

consisted
of those consuming
it six or more times per week. In
1972 Haenszel
et al (9 1) reported
effects for several
vegetables,

studies

the 2 1 nitrate-containing

statistically
intake.

increased

effect

to be protective

the

role

of fruit

in those
a statistically
ofraw
salad

intake;
who

seven

developed

significant
twovegetables
is often

as well.

consumption

C.

In a prospective
investigation
plasma
levels of nutrients
and
(53,

of an antinitrosation
acid
in stomach

protective

fruit

from

and

ascorbate

hypothesis
by ascorbic

either

two

a characteristic
that may
vitamin
C estimate.
Citrus

significant,
only at

just

protective

for increasing

a strong

ofcitrus

was examined

a strongly

sources,

were

C sources.
in the

fruit, excluding
juice.
was highly
vitamin
C estimate
was significant
when

fruit

than

than

in

elevation

factors.

consuming

in risk,

vegetables.

fruits

subjects

reductions

statistically

al (82) studied
246 gastric cancer
patients
and population
control
subjects.
Although
the questionnaire
included
1 5 good vegetable

Coggon
control

nificant

dietary

0.001 . The effect of /3-carotene

analysis.
In Canada,
Risch

often

adenocarcinoma

(8),

with

a sta-

lowest

but did
cancer

significant

in a matched-pair
study

in 1966 Higginson
(93)
fruit and raw vegetables

for

less
dietary

less often

with

in Japan

cancer

0.07).

C index

twofold

a statistically
fruit

of citrus

other

C intake
after control
for sex, age,
was also seen for carotene.
Fruit
among
those who ate > 5 kg/y.

intake
quartile
was
73 kg/y.
La Vecchia
et al (8 1 ) conducted
of206
gastric cancer
patients
and
in the

et al (80)
risk

for carot-

whereas

C,

for carotenoids

You

relative

the lowest quartile

ofvitamin
and income.
A similar
effect
was also significantly
protective
A stronger

for vitamin

ofChina,

twofold

effect

ate

1 10 patients

Graham

showed

protective

found

who

quent

but

A nonsignificant

fruit
other

of

infre-

ofgastric

a significant

and

in Poland,

(P

a vitamin

In a study

consumed

risk

reported

pared
with those who ate it daily.
In Greece,
Trichopoulos
(87) observed
a statistically
significant
protective
effect

the

quarter.

who

found

who

1971-1973

not report
intake.

for smoking

of 3.2 for those

salad

whites

et al (85)

a threefold

those

in

did
on fruit

those

adjustment

approximately
among

consumption

specifically

after multivariate
control
for smoking
and other
factors.
Those
in the lower quarter
ofthe
intake
distribution
had twice the risk
(whites)
or three times the risk (blacks)
compared
with those in
upper

fruit

population

vitamin

cancer

Cervical cancer
of the
subsequent

levels

ofvitamin

relationship
between
cancer,
St#{228}helinet al
C

in the

who later developed

stomach
cancer
(42.6
who did not (52.8 mol/L).
An examination

plasma
zmol/L)
of their

of

The role of ascorbic

acid
vical dysplasia,
was examined

in the precancerous
by Wassertheil-Smoller

condition,
ceret al (96)

and by Romney
et al (97). Plasma
ascorbic
acid levels
mg/dL
in women
with the precursor
lesion
and 0.75

were 0.36
mg/dL
in

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

to be statistically

fruits

(40).

revealed

investigators

et al (86),

the

(83)
stomach

citrus

risk

cancer

intestinal

odds for low vitamin

C intake
were
1.8 (40).
tistically
significant
difference
was seen in both

notes

quent

Several

variable
group

intake

subsequent

(77).

have found
a statistically
significant
C or fruit in gastric
cancer.
Bjelke
between

gastric

dietary

control
subjects,
(P
as multiple
partners,
activity,

and

ASCORBIC

ACID

control
early

for factors
such
onset of sexual

0.000 1 ) even after

multiple
pregnancies,

<

socioeconomic

also
with

examined
cervical

pared

with

those

above

below

that

median

had

severe

dysplasia

status

(97).

Dietary

in a different
case-control
dysplasia
and matched
control
the

median

or carcinoma

of 88

excess

in situ.

factors

risk

Vitamin

(RR
intake

matched

lowest

community

quarter

of the

controls

in Australia.

distribution

activity.
patients

Those

in the

after

control

intake

more

than

(RR

2.5).

plasma

cancer
associated

and

The

effect

same

tamin

examined

authors

point

juices

tremely

imprecise

C, fresh

fruits.

was

was

the

intake

cer-

of vitamin

twofold

increased

stronger

(OR

green

vegetables

was

effect

of vi-

dark

3,

cancer

seen

patients

and

for the carotene

Roswell

Park

in the measurement

The

role

of vitamin

ductions
recurrence

in polyp
area (101),
rate (102, 103) have

35%

ofpatients

polyp

free

who

currence

hospital

was
had

been observed.
A possible
fecal mutagens

take.

also

levels.

Thus,

role of vitamin
in stool has

rately.

of diet

of vitamin

vitamin
with

and

an

studies

An examination

(104),

whereas

were seen in
and vitamin

small and
to cancer

and

effects of
have not

with

fecapentaene

data

and

suggest

colon

role
their

carci-

or may

act

effect.

colon
that

effect
C invitamin

with

an independent
rectal

by

protective
vitamin

associated

E in blocking

examined

conducted

of supplemental

associated
are

play

ofthese

levels

(106),
a strong
and supplemental
fruit

vitamin
have

effect

as significant.
A
C alone
on oc-

patients

fecapentaene

mutagens
C may

is
re-

for 2#{189}
y were

placebo,

striking
effects
to both
fiber

negatively

if fecal

polyps
(100),

C in prevention
or reduction
of
been observed
in two studies
(105,

of citrus

significantly

synergistically
Several

and

ciated

with

cancer
vitamin

sepaC

may

after

adjustment

(109,

1 1 1). Total

Vegetables.
protective

appropriate
being

highest

was

control

Heilbrun

1 .7 among

and

generally

in

both

control
quite

in control

cancer

was

who

patients

and

protective

nificant.

Several

vitamin

and

fiber

24-h

recalls

Vitamin
not

index

colon

cancer,

berries

and,

same

on

patients

l00-g

had

true
rectal

an even

not

examined.
Thus,
there

suggestive
significant
weaker
and
Numerous

been

subjects
that

and

effect

were

category.
colorectal,
colon
cancer
cases.
protective
102 colon

effect
cancer

nificantly

lower

the subsequent
with those who

nonsig-

significantly

protec-

For

rectal

separately
using
but

consumption

for

of fruits

and

(40).

The

the

vitamin

C difference

subjects

achieved

control

among
four

women.
statistically

in rectal
vegetables.
C

The

offruit

significant

in all but one

examined
colon

study.
cancer

sta-

increased
infrequently

role

cancer
and
13-Carotene

not

where
and

that generally
A few have

was

and

two

an additional
effects
were
or a combined

would
contain
predominantly
found
a statistically
significant

of vitamin
C.
Heilbrun
et al ( I 1 3) examined
patients
in Hawaii.
Vitamin
C intake
was sigamong

those

who

developed

colon

cancer

over

16-y period
(92 mg/d by 24-h recall)
compared
did not (1 16 mg/d).
Those
in the lowest quintile

of intake
had 1 .9 times
(P = 0.01).
In Australia,
study

observed

was

in Norway

for vitamin
for raw

nonsignificant
studies
have

60

effect

have

results
result

the

of vitamin

patients

stronger

sig-

among

tistical
significance.
Finally,
Graham
et al (1 15) found
a significantly
risk (RR = 1 .6) among
men eating
raw vegetables
and

mg/d)

was an effect of dietary

et al (1 14) studied
236

portions.

in Minnesota
cancer

was

(105

statistically

analysis

but

a lower

in particular,

was

between

based

rectal
intake

in patients

tive. Bjelke (40) reported

data for rectal cancer
cases
in studies
conducted
both in Norway
and in Minnesota
nutrient

of 60

developed

it was

foods

with

of 13-carotene

control

C-rich

assolatter

not.

direction

risk
the

in a quintile

hospital

effect of
of rectal

women,

lower

control
subjects,
nor
observed.
La Vecchia

in the

raw, were
effects
for

compared

baseline

did

although

seen

an effect

and
lesser

subsequently

( 1 16 mg/d),

subjects

No effect

province,
protective

relative

among

the

who

and

cancer

protective
sex,

The

role

(OR

was also

of intake

3.3

The

subjects

high,

rectal

age,

cooked

subjects.

men,

Hawaii

for

( 1 10) with

et al (1 1 3) compared
men

with

significantly
fiber

quintile

being
statistically
significant.
was weak and inconsistent.
Japanese

effect

(1 12) found
a protective
male and 75 female
cases

in the lowest

patients
and their
fiber or /3-carotene

on

studies
have been quite
on actual
progression

Consumption

nogenesis,

polyposis

Cancer
Institute
for both dietary

E was

cancer

protective

persons

0.03)

cx-

case-control

vitamin
C as well as
Tuyns
et al ( 109-1 1 1)

C was

intake

<

cx-

reductions
in
In the latter study,

power
to detect
effect of vitamin

calorie

of 365

108)

in a large

significant

Vitamin

often

et al (107.

separately

in Belgium

but 13-carotene
was not.
also found
to be highly

than

vitamins

of those

effective;
the most
a high compliance

In a study

the National
was observed

receiving

in familial

1.5,

rectal

Kune

intake
of dietary
in rectal cancer.

controls.

was

regression

cancer

a study

nificant.

of rectal

polyp

23%

had insufficient
found
minimal

of polyps
fiber
who

occurrence

colon

results.

A statistically

The

key source

or nonsignificant
been reported.

been

with

supplements.
Such
such manipulations

106).

had

compared

that the study

recent
report
cereal
those

C in the

or nonsignificant

and

population

rectal

Sporadic

significant

conducted

Co/orecial cancer

unclear.

cancer,

index.

instrument

ofa

of a vitamin

with

seen for high

supplements

cancer
a protective

association

intake

in Australia.

the

weaker.

of 5 1 3 cervical
that

even

and
to observe

An effect
out

Low

invasive

on the

fruit. Potter
and McMichael
vitamin
C in a study
of 124

protective;

with

significant

although

C in a study
subjects.

1 89 women

of carotene

et al (6 1) failed

control

Fruit

protective

significantly

controls.

of fruit

direction,

Marshall

was

a statistically

effect

variables.

significantly

measured.

population
with

< 0.0 1 ). The

not

to be pro-

reported

I .7) was
for vitamin

only

vegetable

study

total

be discussed

addressing

have

rectal

and

will

studies

or raw

amined

(RR

eight

cancer

and

cancer.

statistically

and

Rectal

cancer

colorectal

studies
fruit

sites.

of 7 15 colorectal

the risk of those

Kune et al(l07,
cancer

patients

and

in the upper
108)conducted
matched

quintile
a large

community

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

vical

in the

was

for

appeared

the other

remained

13-carotene

acid

et al (99)

was

C and

per day

Plasma

Verreault

risk.

for vitamin
once

ascorbic

no longer

control

and dietary
variables,
including
carotene,
the risk
still 2.0,
although
this was no longer
statistically
carotene

After

C had

two

by colon

group,

elevated

tective

2.5).

for

sexual activity
estimate
was

In contrast,

(RR

with

remained

of vitamin

combined
Seven

significantly

significant.

risk

of intake

at these
followed

C index,

those

4.35)

a significant
factor even after control
for age and sexual
Brock
et al (98) studied
1 17 in situ cervical
cancer
and

the

2755

PREVENTION

first below

were

mg/d,

CANCER

act differently

series
of 87 women
subjects
(96). Com-

intake

a significant

IN

BLOCK

2765
control

subjects.

Both

dietary

and

significantly

protective

with

low quintile
etary factors.

ofdietary
Consumption

vitamin
ofa

vegetable

intake

provided

that

et al ( I 16) examined

399 cases

and

matched

controls.

brie

intake,

was seen

injury
and

body

cronutrients

and

for vitamin

minerals

Some

investigators

cancer.

for fiber

a very

dispersion

high

(40).

cated

a significant

consistent
in vitamin

even
and

high

index

preliminary
protective

results

for colon
with

community

control

( 1 1 7, 1 1 8) found
vitamin

not

0.06).
For colon

cancer,

Bjelke

nificant

protective

(40,

little

41,

78)

In Minnesota

one

effects,

of these

foods.
groups

Potter

and

in a study

in Australia.

Several
nitrosation
duced

investigators
in humans

bladder
lead,

mdino

foods rich
(1 10).

( 1 12) found

no

patients

and

investigators

lower

but

not

Modan
including

highly
significantly
protection
conferred
(92),

in 1966,

lorectal

et al (1 19) found
oranges.
protective.
by fruit

found

cancer

tomatoes,

a lower

patients

than

that

in colon

several

and

green

consumption
in control

vitamin

C-

were

fruit

males.

5 legumes.

Some

fruits

were

tective
effect
not for fruit.
protection
effect

by high

Graham

effect for raw and cooked

Finally,
in a very small
ascorbate
between

Wolf

(not

in a study

(123)

for vegetables
and
Similarly.
Manousos

conferred

of fruit.

protective

( 122). In a large
for

intake

found

statistically

comparison

of vegetables,

vegetables.
study which

but

a significant

examined

or the

index,

of vitamin

C-rich

other

direction,

site,

and

two

one

were

reported

For

that ascorbic
acid inhibits
and inhibits
carcinogen-in(125-127).

examined

in control

was

Following

123 male

and population
Vitamin
C intake
true

total

and

up on
41 female

control
subjects
from supplements

subjects

for food

the combined

was not reported.

A index.

La Vecchia
and

intake

in

in all four

ethnic-

among

females

sources

questionnaire
vegetables,
with

the

No effects

et al (128)

hospital

from

former,

there

were

both

found

examined

control

included
three
and fruit. Although

sources,

subjects

163

for a vitamin
bladder

in northern

cancer
Italy.

The

fruit/vegetable
items: carrots,
green
there was a significant
association

appeared

to be no association

between

case-control
status and intake ofthis
fruit item in this population.
It is notable
that this population
reported
a high intake
of fruit,
averaging
more
than once a day in both patients
and control

(1 30)

and thus
Mettlin

found

ofvitamin

and

effects
of low intake
cannot
be
(129)
and Paganini-Hill
et al

for vitamin

C. Table
C

cancer

the possible
and Graham

an effect
cancer

A, but

I summarizes

did

not

report

on the

the epidemiologic

studies

prevention

for non-hormone-dependent

and other

nonepithelial

sites.

study
pro-

baseline

found

Childhood
Only
cancer.

brain

no

protective
plasma

levels,
St#{228}helinet al (53, 57, 84) found
no difference
I 4 colorectal
cancer
patients
and their 32 control
sub-

1989)

tumors
and
diets during
creased

conducted
on dietary
factors
John
R Wilkins
III (personal

interviewed

200 matched
pregnancy.

risk

cancers

tumors

one study has been

Thomas
Sinks and

munication,

of colorectal

case-control
a significant

vitamin
supplements,
but
et al (1 24) found
significant

et al (1 1 5) found

than

same

in co-

significant).
Dales et al ( 12 1) found
nonsignificant
effects in the
protective
direction
for persons
above
the median
on a fiber
index consisting
of6 fruits,
14 vegetables,
3 grain products,
and
cancer
in Hawaiian
Japanese
in Wisconsin,
Young
and

but

nutrient

also found
Higginson

offresh
subjects

cancer

peppers,

Slattery
et al (120)
as well as vegetables.

sig-

patients
averaged
389 mg/d and control
subjects
5 13 mg/d. None
of the differences
within
the four individual
ethnic-sex
groups
was statistically
significant;
significance
ofthe
overall case-control

patients

Average
170 mg/
not pro-

The

role ofvitamin

foods,

existing

suggestive

ofthe

effect

in one

in animals

et al (54)

in patients

sex groups.

of vegetables,
rich

the

a statistically

found

no effect

demonstrated
and animals

tumors

Kolonel

subjects,
examined.

is inconsistent.

cancer,

C, two

in the protective

was

of fruit

subjects

cancer

Several
investigations
have reported
protective
effects of fruit
or vegetables
but have not specifically
reported
on risks associated
with low vitamin
C intake.
Many
have found
protective
effects
for an effect

results

but

(109)

Canadian

patients

in control

found

a significant

revealed

of 220

in 1965-1966
cancer

colon
and rectal
cancer,
of the nine
on a vitamin
C index,
six have found

analysis

tective.

evidence

observed

significant

rectal

groups

found

by Tuyns

colon
cancer
patients
and control
subjects
in Canada.
vitamin
C intake
among
male cases in that study was
d as estimated
by questionnaire.
Fiber intake
was also

but

two

patients
with bladder
cancer
two ethnic groups
in Hawaii.

McMichael

than

from

of vitamin

Overall,
for both
that have reported

B/adder

this

who have reported

on a
found
no evidence
of pro-

cancer

collected
colorectal

in patients

Four

effect

nonsignificant

no effect.

and

(1 1 1). Several
protective

colon

of

as distinct

in patients
of the left

a later

cancer.

ascorbate

is less consistent.

but

non-

in plasma

analysis

nonsignificant

no evidence
of a protective
effect of either
a
or of citrus
fruit in a case-control
study of 348

index

plasma

but

mi-

level

adjusted

tertile

in Norway.

C index
significantly

subjects

(P

lower

in colon

cancer

lower

tertile.

groups
of investigators
C index,
two have

relationship

a protective
in colon

results
effect,

effects of a vitamin
C were, however,

Of the eight
dietary
vitamin

quartile
but

to be significantly
lower not only
but also in patients
with cancer

Although

effect

several

suggestive

in the

low

found

acid

A later

parents

of 100 children

control
subjects,
regarding
A statistically
significant

of delivering

a child

who

mors was associated

with low maternal
ing pregnancy,
an effect that remained

later

in this
corn-

with

brain

the mothers
threefold
in-

developed

brain

intake
ofvitamin
after adjustment

tu-

durfor other
C

factors.

Breast,
For
dence

ovary,

endometrium

ovarian,

endometrial

that

exists

does

and prostate

cancer

and

cancer,

not support

prostate

an important

the
role

little

cvi-

for vitamin

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

colon

for

ca-

green peppers,
and melon
The cutpoint
for low intake

for a vitamin

he found
vitamin
with rectal
cancer

seen

vegetables,

acid

tomatoes,
protective.

the

1971-1973.

statistically

found

intake

between
no effect

protective

from

ascorbic

suggests

tection

was

et al ( I 14) observed

sex. However,
significantly

sex,

1 .8 for low vs high

effect

for age and

were highly

for age,

in the ascorbic

or

evidence

flour.

have

ofdietary

in Marseilles

significant

effect

jects

Macquart-Moulin
cancer

adjustment

La Vecchia

significant

found

high.

also

(RR

and

the

was

a highly

from

with

adjustment
for other didiet was also protective

protective

A or fiber

were

associated

C after
high-fiber

After

intake

A similar

vitamin

risk

ofcolorectal

weight,

for vitamin

of intake).

supplemental

a threefold

ASCORBIC
TABLE
Summary

IN

CANCER

PREVENTION

2775

I
of epidemiologic

Non-hormonedependent
cancer

studies

of vitamin

sites

Esophagus
Lung
Pancreas
or precursors

Bladder
Brain

that

Vitamin
C index:
Fruit: 29
Vitamin
C index:
Fruit: 4
Vitamin
C index:
Fruit: 1
Vitamin
C index:
Fruit: 7
Vitamin
C index:
Fruit: 2
Vitamin
C index:
Fruit: 4
Vitamin
C index:
Fruit: 5
Vitamin
C index:
Vitamin
C index:
Vitamin
C index:
Fruit:5
Vitamin
C index:
Fruit: I
Vitamin
C index:

assessed

the role of a dietary

vitamin

index

or of fruit intake.

Studies

46

Median
relative risk

33
21
3
3
1
1
4

3
I
4

3t
St
2
1
4
7
5 II
3
4
4
3
0
0
I

10
1
7
4
6
8
1
I

that

2.0
1.7
2.4
2.0
2.2
IDj
1.6
l.7
2.2
1.6
2.0
2.5
2.0
1.5
1.1
1.7
ID
ID
3.0

reported

on the role of both

are included

only

under

Vitamin
C Index, even ifthe fruit effect was stronger or more statistically
significant.
Because sample sizes in subgroups
were sometimes
small, in
some cases results are classified as statistically
significant
ifa major subgroup
(eg, males) produced
significance.
Significance
is defined as P < 0.05;
in many studies levels of P < 0.01 or stronger were observed,
and some of these are noted in the text. Median relative risk refers to the median over
all studies in the group, not simply the statistically
significant
ones.
t See text.
t ID, Insufficient
Estimate based

data.
on only those

II In one study,

C, whereas

recent

cancer.
Slattery
and population
rection

was

0.07,

for which

analyses

suggest

et al (13 1) studied
control
subjects.
observed

distribution
significance.

(OR

of ovarian

cancer

for

in the

=
1.4). However,
La Vecchia
et al (132,

Both

In a study

in China,

Shu

role in breast

with ovarian
cancer
in the protective
di-

lower

one-third

of the

this did not achieve

statistical
133) have reported
two studies
found

protective
effect for more frequent
items,
but no effect of reported
fruit.

risk was reported.

an important
85 women
An effect

those

in Italy.

relative

19.

a statistically

consumption
consumption

significant

oftwo
vegetable
of a single
item,

et al (1 34) found

no relationship

between
vitamin
C intake
and ovarian
cancer,
although
it is
notable
that the lowest quartile
consisted
ofthose
who consumed
68 mg. Finally,
Byers et al (I 35) found
no effect of vitamin

vegetables

instances

intake
category
was defined
as vitamin
C <
Vecchia
et al (1 32) the study group
consumed
servings
of fruit per week.
In a single study ofendometrial
investigated

206

jects

Patients

in Italy.

patients

and

reported

98 mg/d,
and
an average

in La
of 12

age-matched
significantly

La Vecchia
hospital
lower

et al (136)
control

intake

sub-

of green

patients

and

suggested

with

Reports

for men aged

have also reported

increased
ofeffect

for

results.

of fruit,

an

in this

control

risk

A and

using the Roswell

for

in some

Park 1957

(I 37, 1 38) found

vitamin
C intake,

70 y. Investigators
in the same case

>

subjects

increased

vitamin

alpop-

in Hawaii
series a sig-

risk associated
with vitamin
A, and the same
for vitamin
C, but not statistically
significant.

increasing

vitamin

study

ofJapanese

Two
found

above

analyses

ofa

a protective

studies,
studies

but

A intake,
men

no evidence

have

found

use

food

lists

designed

but

not

in Hawaii

case-control
effect

study

of an effect

for

vitamin

(143)

C. A

found

in Japan

of 13-carotene

protective

sumption
of fruits or vegetables
lated from them,
but either
did
not

intake
of fruit

similar
studies
in Washington,
DC (141 , 142) assessed
diet
the distant
past (when
the patients
and control
subjects
aged 30-49
y, and
50 y). The results suggested
an elevated

Other
cancer,

lower

and the same study

population
risk for increasing
vitamin
A and

prospective
have

C intake.

vitamin

nificantly
direction

risk

however,

associated

trend
significant
(54, 139, 140)

two of these studies

appeared
high intake
of this nutrient:

It is notable,

cancer

questionnaire
an increased

role

to be in populations
with a
in Slattery
et al (13 1), the low

and

so. Consumption

increased

that
very

cancer.

subjects,

prostate

ofa

C in ovarian

control

significantly

both

Two
from
were

for vitamin

not

ulation
appears
to be high with
averaging
1 #{189}
servings/d.
Several
investigations
have

as calculated
from the 1957 Roswell
Park questionnaire,
but
did find a protection
from vitamin
A calculated
from fruits and
vegetables.
Thus,
the existing
studies
do not provide
evidence
C

than

though

similar

(144,

in contrast
of vitamin

effects

145)
to the

C.

for increasing

con-

or of carotenoid
indices
calcunot report
on vitamin
C or did

to assess

it (146-

148).

Thus,

with

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

Cervix or precursors
Rectum
Colon or colorectal

No of statistically
significantly
protective

No of studies

(24-26)
(27 29, 32)
(31)
(32)
(33, 35-37)
(38-40,
32, 42-44)
(45-52,
60, 62)
(63, 64)
(67)
(68-7 1)
(40, 41, 78-83, 94)
(84-87,
90)
(61, 96, 98, 99)
(40, 107, 108)
(40, 107, 1 1 1-1 14, 1 16, 1 17)
(119, 120, 122-124)
(54)
(128)
(Sinks, personal
communication,
1989)

Larynx

Studies

prevention

See below

Oral cavity

Stomach

and cancer

References

All sites in this category

ACID

BLOCK

2785
regard

to prostate

C. the evidence
an effect.
For breast
series

and

Howe

et al ( I 49meta-analysis

Saturated

When

fat was positively

after

the authors
population

with

rich

in vitamin

little

reported

evidence

inverse
fiber,

only the latter

used vitamin
and vegetables.

control

154) recently

of

role

with

had the
association
and

examined

of the

associated

C intake

13-carotene,

simultaneously.
thors consequently
agent(s)
in fruit
mained

C or foods

conflicting

in a major

cancer,

but in addition
vitamin
statistically
significant
risk.

vitamin

and

most
with

vitamin

of dietary

breast

cancer,

consistent
and
breast
cancer
were

examined

remained
significant,
and the auC as the marker
for the effective
The results
for vitamin
C re-

for fat intake.

conclude
that ifall
modify
their saturated

In terms

ofattributable

risk,

postmenopausal
women
fat intake
to (that ofthe

in the
lower

on the

significant
high

of studies

factors.

cancer
is meager

risk associated

The

cervical

and

only

a few

studies

cancer,

five recent

tection,

although

sults.
In
protective
ever,

none

Dietary

result

sumption
of vitamin
fifth of the population),

C (equivalent

risk

of breast

to that
cancer

of the
.

daily
highest
would

cononebe re-

therefore
protective

of the
effect

attributable
of vitamin

the studies
examined
nitude
at least equal
the

epidemiologic

risk. Thus,
for breast
cancer
C appears
to be very consistent

the
in

by Howe
et al ( 149- 1 54), and of a magto that ofsaturated
fat. Table 2 summarizes
studies

for hormone-dependent

of vitamin
cancer

C and

cancer

direction
evated

but

did

risk with

not

TABLE 2
Summary
of epidemiologic
Hormone-dependent
cancer sites
All sites in this category

Endometrium
Prostate
Breast
Studies

intake.

studies

that assessed

nutrient

risk

estimates

this
risk

problem
estimates

ever,
that

significance.

of vitamin

has

to those,

C and cancer

found

involve

very

strong,

protection.
significant
nonsignificant

or prostate
effect

cancer

in substantial

tissue

content

null.

and

by

host

results
deal

in a severe
has

reported

the

been

substantial

effects

here

epithelial
and
here

are

can

only

of

in which
and nonsites,

how-

estimates

have
The

mean

underestimates

of

made

significant.

exists

bias

been

cancer

the risk

statistically

undoubtedly
reported

for several

cancers,

All

individuals

in discussions
of the effects of fat intake,
have frequently
been found
to be low
In studies

as sub-

factors.

ofthe

A great

of

storage,
ability
to

as well

levels

Misclassification

found

C.

in nutrient

misclassification

the

re-

have

of vitamin

of consumption,
and

pro-

to be a very consistent
by Howe et al (149). How-

uncertainties

frequency

with
In lung

found

destruction
in cooking
and in the individuals

of blood

toward

also

strong,
effect.

statistically

studies

ofovarian

results

appear

suggestive

enough

investigations
in the future.
vitamin
C values
and none
C values
and their
would
be preferable

for ascorbate
recent
dietary

fact

that

of the

the
true

studies
These

or case-control
values
represent

to warrant

Few studies
has examined

more

in-

have examined
leukocyte
vi-

relationships
with cancer.
Leukocyte
because
they represent
a target tissue

concentration
intake.
Such

and they are not affected

by very
analyses
are needed
in prospective

studies
nested
what is actually

in a prospective
cohort.
available
to the body for

No statistically
significantly
protective

No studies
Vitamin
C index:
Fruit: 3
VitaminCindex:3
Fruit: 1
Fruit: 1
VitaminCindex:6
VitaminCindex:9

See below

vitamin

or

esophageal,

prevention

References

the role of a dietary

el-

29 studies

observed

protective

misclassification

tamin
values

statistically
sigin the protective

None

In addition

are

significant

earlier

studies

particularly

frequently

data

to find

studies

status.

significant.

These

cancer
sites described
on a vitamin
C index

(131, 134, 135)

(132)
(136)
(137, 139, 141-144)
(149-154)

Ovary

achieve

increasing

true

tensive
plasma

or plasma
ascorbate
values;
33 of these
found
nificant
protective
effects, and several
more were

For oral,

risk.

prevention

sites.

reported

cancer

failing

his or her

observed

Summary
In the I 1 non-hormone-dependent
above,
46 studies
have specifically

found

consumption

C index

or of fruit intake.

Studies

Median
relative risk

Ot
1
0j
0
1
0
Seetextt
that

reported

on the role of both

1.3
ID.
1.8
0.8
1.4
are included

only under

Vitamin
C Index, even ifthe fruit effect was stronger or more statistically
significant.
Because sample sizes in subgroups
were sometimes
small, in
some cases results are classified as statistically
significant
if a major subgroup
(eg, males) produced
significance.
Significance
is defined as P < 0.05;
in many studies levels of P < 0.0 1 or stronger were observed,
and some of these are noted in the text. Median relative risk refers to the median over
all studies in the group. not simply the statistically
significant
ones.
t Howe et al ( 149), in a meta-analysis,
found vitamin
C to be consistently
inversely associated
with breast cancer risk, in nine studies examined.
See text.
None were significant
in either the protective
or harmful
direction.
Two studies found significantly
elevated risk with high intake, in some age subgroups
or control comparisons.

Downloaded from ajcn.nutrition.org by guest on June 6, 2015

duced
by 16%. The effects
were approximately
additive,
and
simultaneously
making
both changes
would
reduce
the risk by
24%. The authors
also point out that misclassification
of dietary
intake
would
lead to underestimation
of the relative
risk and

rectal

estimates

ofthese

an average

2 1 of which

frequent

low consumption.

foods,
in degree
of nutrient
in portion
size quantification,

crease

to reach

with

significant

altering

intakes

with

cancer,
there
appears
in the meta-analysis

ofthe

a statistically

sequent

vegetable

consumption,

several

breast
effect,

estimate

and

of fruit
associated

gastric,
and pancreatic
cancer,
the evidence
is extremely
with virtually
all studies
showing
a significant
protective

one-fifth
of the population),
the current
rate of breast
cancer
would
be reduced
by 10% in postmenopausal
women
in North
America.
.
.
.
If all postmenopausal
women
.
.
. were
to infruit

effect

protection

ASCORBIC
antioxidant

or other

are severely

hampered

of ascorbate
other

factors

comprising

characteristics

levels

after

blood

ascorbate

traceptives,

food

models

fact that

adds

another

part of its effect

levels.
Because
clarification
be greatly

same

ofthe
enhanced

In addition

and

to the

sample

when

for numerous
with several
tremely

adequate,

quartiles

or quintiles

size

analyses
nutrient

estimates

and

power

or

records

population.

obtained

mately
of actual

frequency

corresponding
estimated.

nutrient

intake.

rather

than

For example,

the effect

fat (or meat)

similar

variables

and

effect

seen
wish

in different
population
to design their studies

but may

some

with

groups.
sample

be a real

and

important

tion.
It may be more
or-Is
it vitamin
both
and

here

to the

into

acby

or low.

Ross

the

for several
effect

protective

fat levels.
such

ofthe

et

effect

Joint

as these

effects

have

differences

rarely

in results

Future
investigators
may
sizes adequate
to examine

especially

Nevertheless,

reported

for levels

take

C (or /3-carotene)

is high

regard

explain

in this way.
other nutrients,

factors.

populations

confounding

ofvitamin

at different

often are obtained

in the same foods,
be completely
certain
that the effect
results

simply

modifications

examined,

the

dis-

so that

risks

should

intake

with

cancer

been

to other

and

that 13-carotene
was only protective
fat intake
was low, and Heilbrun
et al

results

in colon

study

in different

modification

fiber

of the
mean

to estimate

analyses

when

mean
24-h

questionnaire

Third,

exist

(1 1 3) found

of the

real

of the
several

to the quantile
cutpoints
could
If this were done,
it might
ultiand

al ( 147) found
a suggestion
for prostate
cancer
when

their data
Because

in a subset

food

Prestudy
on the

estimates
based
on

correction

studies

factors.

oftwo

control

power.
be based

Second,
deviation

to compare

other

ofdietary

divide

impose

statistical

instruments

effect
only

meth-

often

then

should

different

count
may

poor

permit

in the

be possible
with

and

be collected

would

the nutrient
intake
be more
accurately
and

and

should

This

tribution

investigators

calculations

that will be performed.

intake
and standard

recalls

additional

confounders
[eg, eight in Brock
et al (98). each
levels]
on each of the quantiles.
The result
is cx-

unstable

sample

outcome.

in future
investigations.
in several studies
described

apparently

into

exert

prevention
would
blood
levels, care-

some

carotenoids

and

with dietary
data
is due to vitamin
strength
sites

and

ofascorbic

acid

acid,

we cannot
C and not

consistency

suggests

productive
to stop
C or carotenoids?

folic

that
in cancer

there

of
may

preven-

thinking
in terms
of
It is very likely
that

are needed,
that all the nutrients
packaged
together
in fruits
vegetables
are synergistic
and provide
optimal
benefit
when

all are

present

in optimal

quantities.

Vitamin

is apparently

radical

be an

of oxygen

may

defense
radical

than

act synergistically
scavengers

cascade
( 1 55).
in individuals
health

consumption

(7), spares

scavenger

those

that

with

in quenching

are

other

action

should
as well

biologic

E (8-14),

different

optimal

different

Future
research
should
in which
two or more
of fruit,

vitamin

under

partial

for 13-carotene.
antioxidants

elements

focus on analyses
nutrients
are low

be directed
as vegetables,

towards

and

of a radical
of risks
or high.

increasing

in which

nature

the
has

packaged
a variety
of protective
nutrients.
I am indebted to the following
people for their skillful and committed
assistance
and support for this paper Lisa Carter, Susana Rosales. Vicki
Hoffman,
and Marilyn
Apfel.

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