vitamin c and cancer prevention: the epidemiologic evidence”2 · several functions of vitamin c...
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2705 Am J C/in Nutr l99l;53:270S-82S. Printed in USA. © 1991 American Society for Clinical Nutrition
Vitamin C and cancer prevention:the epidemiologic evidence”2
Gladi�s Block
ABSTRACT Epidemiologic evidence of a protective effect
of vitamin C for non-hormone-dependent cancers is strong. Of
the 46 such studies in which a dietary vitamin C index was
calculated, 33 found statistically significant protection, with high
intake conferring approximately a twofold protective effect
compared with low intake. 0f29 additional studies that assessed
fruit intake, 2 1 found significant protection. For cancers of the
esophagus, larynx, oral cavity. and pancreas, evidence for a pro-
tective effect of vitamin C or some component in fruit is strong
and consistent. For cancers ofthe stomach, rectum, breast, and
cervix there is also strong evidence. Several recent lung 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 of fruits and
vegetables in general should be encouraged. Am J C/in Nuir
199 1;53:270S-82S.
KEY WORDS Ascorbic acid, vitamin C, epidemiologic
studies, epithelial cancers, cancer, review
Introduction
Ascorbic acid is increasingly recognized as an agent with broad
biologic function and importance. Well-established functions
include synthesis of hormones and neurotransmitters, cyto-
chrome P-450 activity and detoxification of exogenous com-
pounds. carnitine synthesis and cholesterol metabolism ( 1 , 2),
as well as its well-known antioxidant functions with protective
results that may extend to cancer, coronary artery disease, ar-
thntis, and aging. Several possible mechanisms of action of
ascorbic acid in cancer prevention have been described exten-
sively elsewhere (3-5). It plays a major and perhaps even pre-
dominant role in free-radical scavenging and protection against
lipid peroxidation (6, 7). It appears to have a role in sparing or
reconstituting the active forms of vitamin E (8- 14), and spares
other important antioxidants (7). Several functions of vitamin
C in the immune system have been described (1 5, 16), including
enhancement of leukocyte chemotaxis ( 1 7), stimulation 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 be important in inhib-
iting tumor spread and micrometastases.
Before an examination ofthe epidemiologic evidence that cx-
ists regarding ascorbic acid and cancer prevention, it is important
to consider several sources ofpotential misinterpretation. These
have been discussed in some detail elsewhere (4, 23). Briefly,
studies of the role of nutrients in disease are hampered by at
least three sources of error: 1) error in the classification of in-
dividuals with respect to their nutrient intake, 2) errors of in-
terpretation arising from the fact that nutrients are correlated
both negatively and positively with other nutrients, and 3) studies
within populations that are quite homogeneous with respect to
intake ofa nutrient may be unable to detect an effect ofhigh or
low intake.
Misclassification errors cause a bias ofobserved risk estimates
toward the null, making the observed risk estimate appear weaker
than it really is and making it more difficult to achieve statistical
significance. Studies that nevertheless show an effect in the face
of the misclassification inherent in dietary or biochemical as-
sessment probably indicate an even stronger effect if the true
long-term dietary or biochemical status could be known.
Correlated variables mislead investigators into identifying the
wrong nutrient as the effective one because, although an index
for a certain nutrient may be calculated, other nutrients mcvi-
tably accompany it in the food and are correlated with it in the
plasma. The nutrient that is calculated reflects the interests and
presuppositions of the investigator and does not necessarily re-
fleet the true causal agent. Furthermore, in biological systems it
is likely that nutrients do not act singly but jointly and very
rarely have investigators studied the joint effects ofhaving a low
intake of two or more nutrients simultaneously.
Finally, studies in homogeneous populations may produce
negative results that are difficult to interpret. For example, in
studies in very high risk populations everyone in the population
may have a very low intake of a protective nutrient, control
subjects as well as cases. Some of these are highlighted under
esophageal cancer, below, but the problem may be more wide-
spread. 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 of low levels cannot be assessed well.
Epidemiologic studies by cancer site
The studies reported below are limited to analytic epidemi-
ologic studies in humans-that is, case-control and prospective
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
Room 3 13, 9000 Rockville Pike, Bethesda, MD 20892.
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ASCORBIC ACID IN CANCER PREVENTION 2715
studies. No international correlation studies are included nor
any studies that simply attempt to relate nutrient intake in a
region with population mortality or morbidity rates in a region.
The studies reported below are all at the individual level: mdi-
viduals with and without cancer are identified and dietary intake
in those same individuals is assessed. Such studies generally result
in estimates of relative risk (occasionally termed risk ratio or
odds ratio and abbreviated RR or OR). The risk in the group
exposed to a risk factor (here, low intake of vitamin C or foods
rich in it) is expressed as a ratio ofthose not exposed (here, those
with high intake). For simplicity, all risks have been expressed
in this direction so that a relative risk > 1 .0 means an elevated
risk of the cancer among those with low intake. For example, a
relative risk (RR) = 2.0 indicates that those with low intake of
vitamin C are estimated to have twice the risk of that cancer
compared with those with high intake.
Studies are described below if they reported either an actual
vitamin C score or estimate or if they reported on a food that
is rich in vitamin C, usually fruit but occasionally tomatoes or
raw vegetables. Studies that simply reported on green vegetables
are not included because, although those foods may contain
vitamin C. their carotenoid content is usually such that it is
impossible to attribute a protective effect to vitamin C with any
confidence.
Non-hormone-dependent cancers
C’ancers oJ�t/ie oral cavity, larynx, or esophagus
Oral cancer has been the subject ofseven case-control studies,
most of them large and well controlled, investigating the role of
dietary factors (24-30). All but one have found significant pro-
tective effects for increasing vitamin C intake or fruit intake.
Most ofthese studies included control for smoking and alcohol.
McLaughlin et al (25) found that those in the lowest quartile of
vitamin C intake had a risk ratio of 1.7 (men) or 2.0 (women).
Winn et al (28) found that those who reported consuming fruit
once per week or less often had I .7 times the risk of those who
consumed it seven times a week or more. Two of the studies
also found protection from carotene-containing vegetables,
whereas in the others these foods were weaker or nonsignificant.
Two studies of cancer of the larynx have examined the role
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
confounding by alcohol intake and smoking, a low intake of
vitamin C was associated with a risk ratio of 2.4 (P < 0.005).
Notani and Jayant (32) observed a statistically significant in-
creased risk of2.0 associated with consumption offruit less than
once a week compared with at least once a week. Vegetable
consumption was also a significant factor.
Cancer of the esophagus has been studied by several investi-
gators (33-44) and again, most have found strong and statistically
significant relationships with vitamin C or fruit intake. All four
that examined a vitamin C index (33, 34, 36, 37) found statis-
tically significant relative risks of ‘�2.0 after adjustment for
smoking and alcohol consumption. Brown et al (33) found that
compared with those in the upper third of the distribution for
vitamin C intake, those in the lower third had a statistically
significant twofold risk ratio. Fiber was also significantly pro-
tective but carotenoids were not. Fruits, especially citrus fruits
and juices, were the only significantly protective foods or food
groups. Tuyns et al (34, 35) studied esophageal cancer in a large
case-control study conducted in a high-risk region of France. A
statistically significant protective effect was observed for citrus
fruit (34) and for vitamin C (35). Compared with heavy con-
sumers of vitamin C, light consumers had a risk ratio of 2.6
after adjustment for age, smoking. and alcohol consumption.
Carotene also had a significant but somewhat weaker effect.
Ziegler et al (36) used a 3 1-item next-of-kin questionnaire to
investigate the role of diet among 120 black males who died of
esophageal cancer and 250 others who died of other causes. Vi-
tamin C was the only nutrient with a statistically significant
elevation in risk associated with being in the low one third of
the distribution, RR = 1 .8 after adjustment for ethanol intake.
Finally, Mettlin et al (37) found a risk ratio of 2.4 (P = 0.004)
for low vs high quartile ofvitamin C intake even after adjustment
for smoking and alcohol.
Four studies have found fruit or citrus fruit to be lower in
cases with esophageal cancer (38-41 , 44). Decarli et al (44) in-
vestigated the role ofdiet among 105 cases 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 only fruit intake remained strong
(RR = 3.3) and statistically significant (trend P < 0.001). Cook-
Mozaffari et al (38) studied 354 patients with esophageal cancer
and population controls in Iran, an area ofhigh esophageal can-
cer incidence. Low intake of fresh fruit and vegetables was
strongly associated with risk ofesophageal cancer. with frequent
consumption of oranges the most significantly protective food.
In Japan, Hirayama (39) found a risk ratio of -��2.7 for less than
daily consumption of fruit in a case-control study of esophageal
cancer. Bjelke (40, 41), in a study of 52 patients with esophageal
cancer and hospital control subjects in Minnesota, observed
nonsignificantly lower intake of apples and green salad in case
subjects, but did not report on a vitamin C index.
Some studies represent classic examples of population ho-
mogeneity ofintake that may make the existence ofa protective
effect impossible to detect. In a region of China with very high
esophageal cancer rates, Li et al (42) conducted a large case-
control study ofesophageal or gastric cardia cancer. No protective
effect was seen for fruit consumption. However, the authors note
that fruit is very infrequently eaten in this high-risk area, and
the highest intake category consisted ofthose who ate fresh fruit
> 35 times per year. Martinez (43) studied risk factors for
esophageal and oral cancer in Puerto Rico, an area in which the
incidence of these cancers is among the highest in the world.
Risk ratios were not specifically reported. but the author reported
that both patients and control subjects were chronically deficient:
75% of both patients and control subjects never had fresh fruit
in their diets and 87% of both patients and control subjects had
only two portions or less ofvegetables per week. Similarly, Notani
and Jayant (32) studied esophageal and oral cancer in regions
of India where incidence of these diseases is among the highest
in the world. Fruit consumption showed a nonsignificant 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, was significant.
In summary, ofeight studies that have reported on a vitamin
C index in cancer ofthe oral cavity. larynx, or esophagus, every
one has found a statistically significant elevation in risk associated
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with low intake. Three of these studies found carotene to be
weak and nonsignificant, whereas in two vitamin A was also
found to be significant but weaker than vitamin C. Of the 12
studies of foods rather than nutrients, 6 found statistically sig-
nificant risk for low fruit intake, 2 found suggestive results or
did not report statistical significance, 3 found extremely low
intakes in both patients and control subjects in extremely high-
risk populations, and 1 found no effect.
Lung cancer
Of the �‘��-30 epidemiologic studies that have examined the
relationship between dietary factors and lung cancer, most have
focused on vitamin A or carotenoids. Because of this focus, in
many cases the diet questionnaire food list was not designed to
assess vitamin C well and the investigators did not attempt to
draw any conclusions about the role ofvitamin C. A few inves-
tigators have examined the role ofvitamin C, however, and these
are reported below, as well as investigations in which the role
of vitamin C-rich foods could be separately assessed.
Fontham et al (45)examined 1253 lung cancer cases and 1274
age-. sex-, and race-matched controls in the New Orleans area.
Approximately 3 1% ofthe study group was black and 26% were
nonsmokers or former smokers who had quit for � 3 y. Results
were adjusted for smoking, income, and other confounders.
Compared with those who consumed 140 mg or more of vitamin
C per day (as estimated by the questionnaire), those who con-
sumed < 90 mg had a risk estimate of 1.5 (P < 0.001). The
vitamin C effect became stronger (RR 1.9) after adjustment
for carotene intake, whereas the apparent protection due to car-
otene disappeared after adjustment for vitamin C intake.
Koo (46) studied 88 Hong Kong women with lung cancer
and 1 37 control subjects to examine risk factors among mdi-
viduals who have never smoked. Risk estimates were adjusted
for age, parity, and education. Only fresh fruit and fresh fish
consumption were found to be significantly related to a reduction
in lung cancer risk. Leafy green vegetables and carrots were in
the protective direction but nonsignificant. By contrast, those
who consumed fresh fruit less than once a week had a risk ratio
of2.4 compared with those who consumed it five to seven times
a week (trend P < 0.002). A vitamin C score yielded a risk
estimate of 2. 1 (trend P < 0.01 5); the effect was strongest for
adenocarcinoma, although the number ofsquamous cell cancers
in these women may have been too small for a stable risk esti-
mate.
In a study conducted in the Netherlands, HoIst et al (47) stud-
ied 49 lung cancer patients in a case-control study. After ad-
justment for smoking and other risk factors, persons with a vi-
tamin C index < 50 mg/d (as estimated by questionnaire) had
a risk 4.3 times greater than those with a higher intake. This
result was highly statistically significant. No effect ofa /3-carotene
score was seen.
Le Marchand et al (48) studied 230 male and 102 female lung
cancer cases and population-based controls in Hawaii. Among
males, both total vitamin C and vitamin C from foods alone
was significantly protective, RR = 2.0 for the contrast between
lowest and highest quartile, a stronger effect for vitamin C con-
trolled for 13-carotene than was seen for /3-carotene controlled
for vitamin C. However, among females a nonsignificant effect
in the protective direction was seen only for intake from foods,
not supplements, whereas a /3-carotene effect was stronger andsignificant. Vegetables were strongly protective, whereas fruit
was not.
Kromhout (49) analyzed the results of a prospective study in
which a dietary history interview was completed in 1960 on 870
men aged 40-59 y; 63 subsequently died of lung cancer over
the 25-y follow-up. Compared with men consuming � 100 mg
vitamin C/d in 1960 (as estimated by the diet history interview),
those consuming < 60 mg had a 2.8-fold increased risk (age but
not smoking adjusted, P < 0.01). Dietary vitamin C intake re-
mained a statistically significant protective factor after appro-
priate multivariate adjustment for age, cigarette smoking, and
vitamin supplement use. A 55-y-old, male, one-pack-a-day
smoker with low dietary and supplement vitamin C had a 25%
chance ofdying from lung cancer in the 25-y follow-up, whereas
the same smoker with high dietary and supplement vitamin C
had only a 7% chance oflung cancer mortality. Fruit intake was
also significantly and inversely related to subsequent lung cancer
mortality, after age and smoking adjustment. /3-carotene intake
was not related to lung cancer mortality.
The above five recent studies of diet in lung cancer have all
found a statistically significant protective effect of vitamin C.
Four of them have found a weak and nonsignificant effect of /3-
carotene; the fifth (48) found an equal effect of 13-carotene and
vitamin C from foods in men, and a stronger effect of /3-carotene
in women. The comparison with vitamin C from foods is the
appropriate one since the 13-carotene is all from foods and since
supplement use is a behavior commonly increased in prodromal
states, particularly among women.
Four additional studies have reported on a vitamin C index
from the diet (50-52) or in plasma (53) and have found suggestive
but nonsignificant results. Investigators in Hawaii (50, 54) con-
ducted a retrospective study in Hawaii of 26 1 male and 103
female patients, including all five ethnic groups of Hawaii, and
population control subjects. The effect of vitamin C was in the
protective direction, RR = 1.6 for males, but was not statistically
significant. The effect of vitamin C from foods alone was not
reported; instead, vitamin C intake included supplements used
in the 3 mo preceding recognition of lung cancer symptoms.
Supplement use is generally much greater for vitamin C than
vitamin A, greater for women than men, and greater for Cau-
casians than other ethnic groups (55). Consequently, inclusion
of supplement use introduces difficulties of interpretation since
individuals may start taking supplements when they experience
malaise or other prodromal symptoms. This may explain why
in LeMarchand’s study in Hawaii vitamin C from supplements
was in the harmful direction, but only among Caucasian women.
In all ethnic and sex groups, vitamin C from foods alone appeared
to reduce the risk of lung cancer.
Kvale et al (5 1) and Bjelke (56) conducted a prospective study
ofrespondents to a mailed diet questionnaire that included 10
ascorbic acid-rich foods. They observed I 53 subsequent lung
cancer deaths and found no effect for a vitamin C score. To-
matoes, however, rich in vitamin C but not /3-carotene, were
one ofonly two foods that approached significance as individual
items (trend P = 0.07 for squamous and small-cell carcinomas).
Shekelle et al (52) also conducted a prospective study and oh-
served a total of 33 lung cancer cases. Unlike the 13-carotene
score, the vitamin C score was based on a 24-h recall. Considering
the limitations ofthat method for vitamin C and the small num-
ber of cases, the P value of 0.20 for the difference between the
mean of 9 1 .8 mg of vitamin C per day among those who later
developed lung cancer and the mean of 10 1.0 mg among those
who did not is suggestive.
St#{228}helinet al (53, 57) collected plasma from respondents in
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ASCORBIC ACID IN CANCER PREVENTION 2735
197 1- 1973 and followed them for mortality through 1980. In
that time there were 35 lung cancer deaths for which baseline
plasma vitamins could be analyzed. Persons who subsequently
died of lung cancer had lower plasma ascorbate (0.79 mg/dL)
than control subjects (0.90 mg/dL.), P = 0.2. Plasma /3-carotene
was significantly different. Subsequent analyses by St#{228}helin(58)
of more recent cancer deaths did not reveal any differences in
mean plasma ascorbate between lung cancer patients and control
subjects.Finally, two studies have reported no effect ofa dietary vitamin
C index. Two reports using the 1957 Roswell Park questionnaire
(59, 60) found no effect of vitamin C after control for other
factors. The instrument was not welldesigned to assess vitamin
C as noted by the authors (6 1). Byers et al (62) found no effect
for vitamin C in a 1987 study in upstate New York; however,
three fourths of the eligible cases could not be interviewed be-
cause ofillness or death. Thus, it is possible that a nutrient effect
could be missed if low intake had the effect of increasing the
severity or progression of disease.
Although numerous investigators have studied the role of car-
otene-containing vegetables, in relatively few could the role of
fruits, especially vitamin C-rich fruits or raw vegetables, be cx-
amined separately. These are reported below. Long-dc and
Hammond (63) examined data from a prospective study in which
1 36 000 white males in the United States provided information
on their frequency ofconsumption offruit and green salad; 671
lung cancer deaths were seen over the subsequent 1 1-y follow-
up. Men who consumed fruit less than three times per week had
1 .7 times the lung cancer risk ofthose who ate it 5-7 times per
week, a statistically significant increase. Green salad showed a
lower effect in the same direction. Bond et al (64) reported on
a carotenoid and not a vitamin C index. However, of the six
food items found to be individually significant, five (tomatoes,
melon, pasta with sauce, broccoli, and fortified cereals) are rich
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 gen-
erally assumed to be a carotenoid, it is worth noting that many
green vegetables are rich in vitamin C.
Ofthe 1 1 lung cancer studies that have specifically mentioned
a vitamin C score, 5 have found a statistically significant pro-
tective effect, 4 have found effects in the protective direction but
not significant, and 2 have reported no effect. In two of the
studies that found suggestive but nonsignificant results (52, 57),
the lack of statistical significance was based on I tests involving
small numbers oflung cancer cases, n = 33 and 35, respectively.
Of two additional studies that assessed fruit intake, both have
found significant protective effects. Four studies have found
stronger effects for vitamin C than for carotenoids. Whereas a
large body of evidence suggests an important effect for carot-
enoids in lung cancer protection, the recent data reported above
suggest that there may also be an independent protective effect
of vitamin C intake. The role of vitamin C not only as an an-
tioxidant and free-radical scavenger in its own right (6, 7) but
also in enhancing the action of vitamin E (8-14) is well estab-
lished.
Pancreatic cancer
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 in Louisiana. The questionnaire was designed to assess
a wide range ofnutrients and asked about usual adult diet. Those
who consumed less than ‘-70 mg vitamin C/d (as estimated by
the questionnaire) had a relative risk of 2.6 for males, or 1 .8 for
females compared with those who consumed � I 59 mg/d (in
both cases, trend P < 0.05). Fruit consumption (based on fre-
quency of consumption of six fruits, three of which are rich in
vitamin C) conferred a 1.6-fold protective effect after adjustment
for multiple confounding factors.
Norell et al (68), in a case-control study in Sweden of 99
patients and matched hospital and population control subjects,
found a highly significant protective effect both for carrots and
for citrus fruits. For citrus fruits there was a two- to threefold
protective effect for those who ate them daily compared with
those who ate them less than weekly. Mack et al (69) studied
490 pancreas cancer patients and matched neighborhood con-
trols. For those who consumed fresh fruit or vegetables less than
five times a week there was a statistically significant elevated
risk, RR = 1 .4 compared with those who ate them more often.
The diet instrument included only very broad food categories,
the only relevant one here being “fresh fruit or raw vegetables.”
Considering the obvious crudity of the instrument, the obser-
vation of a significant effect is striking. Finally. Gold et al (70)
studied 201 persons with pancreatic cancer and both hospital
and neighborhood control subjects. Adjusted for several con-
founding factors, frequent consumption of raw fruits and veg-
etables was highly protective, RR = 1 .8 for those who ate them
less than five times a week compared with those who ate them
five or more times (P < 0.02).
A prospective study among Seventh Day Adventists (7 1) oh-
served 40 deaths from pancreatic cancer ( 1 7 men and 23 women).
The intake distributions of dietary variables were divided into
thirds and risk within each third was adjusted for age and sex,
a process which, although appropriate, results in small numbers
and reduced statistical power. Frequent consumption of dried
fruit was significantly protective; use of tomatoes, fresh citrus
fruit, and fresh winter fruit showed a “suggestive, though non-
significant, protective relationship.”
Pancreatic cancer is the fifth most common cause of cancer
mortality in the United States (72) and is a disease with extremely
poor prognosis. In the current state of our ability to treat this
disease, prevention is of primary importance. All five pancreas
cancer studies have found statistically significant protective ef-
fects for fruit, and in some instances for vegetables as well. The
one study that calculated a vitamin C index found a significant
twofold reduction in risk associated with high intake.
Stomach cancer
Several studies of an ecological nature have been conducted
(73-75) that suggested a protective role for fruit or for vitamin
C intake in stomach cancer. Ascorbic acid has recently been
demonstrated to be concentrated at three times the plasma level
in the gastric juice of persons with normal gastric histology, but
not in those with chronic gastritis (76). Moreover, in normal
persons it is predominantly in the reduced form, ascorbic acid,
the form required for the antinitrosation reaction; in gastritis
patients, by contrast, it is predominantly in the oxidized form,
dehydroascorbic acid. A similar pattern is seen for gastric 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
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ascorbic and dehydroascorbic acid or considered the conversion
of ascorbic to dehydroascorbic acid during cooking, and that
furthermore the correlation between vitamin C intake and gastric
ascorbic acid was low, only r = 0.22 (77).
Several studies have found a statistically significant protective
effect of vitamin C or fruit in gastric cancer. Bjelke (40, 41, 78)
found vitamin C to be “the dietary variable which discriminated
most strongly between the total group of stomach cancer cases
. . . and the controls” (40). The effect was particularly strong
for gastric carcinomas ofthe diffuse and intestinal types. For the
combined group ofdiffuse and intestinal carcinomas, the relative
odds for low vitamin C intake were 1.8 (40). In Norway, a sta-
tistically significant difference was seen in both males and females
(41) and a strong effect was also observed in Minnesota (40).
No effect of vitamin A was seen for stomach cancer. The author
notes (40) that “the data for stomach cancer are consistent with
an increased risk being associated with a classical deficiency af-
fecting a minority of the population.”
In a study ofdietary factors and gastric cancer in Louisiana,
Correa et al (79) found fruits as a group and dietary vitamin C
to be statistically significantly protective in both blacks and whites
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
the upper quarter. A nonsignificant protective effect for carot-
enoids disappeared after control for vitamin C, whereas the vi-
tamin C effect remained after control for carotenoids and other
risk factors.
In a high-risk region ofChina, You et al (80) observed a sta-
tistically significant twofold relative risk of stomach cancer for
the lowest quartile ofvitamin C intake after control for sex, age,
and income. A similar effect was also seen for carotene. Fruit
was also significantly protective among those who ate > 5 kg/y.
A stronger effect was seen for fresh vegetables where the lowest
intake quartile was � 73 kg/y.
La Vecchia et al (8 1 ) conducted a case-control study in Italy
of206 gastric cancer patients and hospital control subjects. Those
in the bottom one third of the distribution of vitamin C intake
had a 2.5-fold elevated risk, P < 0.001 . The effect of /3-carotene
was similar in multiple regression analysis. In Canada, Risch et
al (82) studied 246 gastric cancer patients and population control
subjects. Although the questionnaire included 1 5 good veg-
etable sources ofvitamin C and three fruit sources, two important
sources, citrusjuices and tomatoes, were either omitted or com-
bined with poor vitamin C sources. a characteristic that may
have generated imprecision in the vitamin C estimate. Citrus
fruit, excluding juice. was highly significant, whereas the overall
vitamin C estimate was significant only at P < 0. 10. However,
when ascorbate was examined just from the 2 1 nitrate-containing
vegetables, a strongly protective and statistically significant effect
was seen for increasing ascorbate intake. This analysis tends to
confirm the hypothesis of an antinitrosation mechanism for
protection by ascorbic acid in stomach cancer. Similarly,
Meinsma (83) found strong increased risk with high bacon intake
and a strong protective effect (P < 0.01) of high consumption
ofcitrus fruit and vitamin C.
In a prospective investigation of the relationship between
plasma levels of nutrients and subsequent cancer, St#{228}helinet al
(53, 57, 58) observed lower levels ofvitamin C in the plasma of
20 persons who later developed stomach cancer (42.6 �zmol/L)
than those who did not (52.8 �mol/L). An examination of their
dietary intake (83) revealed approximately a threefold risk of
subsequent stomach cancer among those who reported infre-
quent citrus fruit consumption in 1971-1973 (P = 0.07).
Several investigators did not report a vitamin C index but did
report specifically on fruit intake. In a study ofgastric cancer in
Japan, Kono et al (85) found a significant twofold elevation in
risk for those who consumed fruit less often than daily, after
adjustment for smoking and other dietary factors. Jedrychowski
et al (86), in Poland, found a statistically significant relative risk
of 3.2 for those who ate fruit less often than twice a week com-
pared with those who ate it daily. In Greece, Trichopoulos et al
(87) observed a statistically significant protective effect of fre-
quent consumption of citrus fruits and of raw salad-type vege-
tables in 1 10 patients with adenocarcinoma of the stomach.
Graham et al (88), in a matched-pair reanalysis ofa previously-
reported negative study (8�), observed a reduced risk of gastric
cancer associated with consuming various vegetables in the Un-
cooked state. Coggon et al (90) in a study of 95 patients and
population control subjects in England found statistically sig-
nificant reductions in risk, twofold or greater, for fruit and for
salad vegetables. For fruit intake, the high-consumption category
consisted of those consuming it six or more times per week. In
1972 Haenszel et al (9 1) reported effects for several vegetables,
but only tomatoes (a source ofvitamin C but not of /3-carotene)
showed protective effects in both Issei and Nisei. No effect of
fruit was seen in this Japanese American population. A study
in Japan (92) found no effect of orange consumption. Finally,
in 1966 Higginson (93) found less frequent consumption of fresh
fruit and raw vegetables among stomach cancer patients than
matched hospital controls. Fontham 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 high-
risk black population in Louisiana. In a negative study of pre-
cursor lesions, however, Haenszel et al (95) found no difference
between the mean plasma levels of total ascorbate in persons
with atrophic gastritis and control subjects in Colombia.
In summary, seven investigators have reported on vitamin C
dietary intake and stomach cancer risk. All seven have found
statistically significant protective effects of approximately two-
fold, usually in the overall vitamin C score although in one in-
stance statistical significance was limited to the vitamin C con-
tamed in nitrate-containing vegetables. One prospective study
found lower plasma vitamin C levels in those who subsequently
developed stomach cancer, nearly significant at P = 0.06 despite
having only 19 cases. In two studies that also examined 13-car-
otene, that factor was also significantly protective; in two other
studies that simultaneously examined 13-carotene and vitamin
C in multivariate models both remained significant in one study,
whereas the effect of 13-carotene disappeared in the other (79).
Eight studies have reported on the role of fruit intake; seven
have found lower fruit consumption in those who developed
stomach cancer, in most instances a statistically significant two-
to threefold effect. Consumption ofraw salad vegetables is often
found to be protective as well.
Cervical cancer
The role of ascorbic acid in the precancerous condition, cer-
vical dysplasia, was examined by Wassertheil-Smoller et al (96)
and by Romney et al (97). Plasma ascorbic acid levels were 0.36
mg/dL in women with the precursor lesion and 0.75 mg/dL in
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ASCORBIC ACID IN CANCER PREVENTION 2755
control subjects, (P < 0.000 1 ) even after control for factors such
as multiple partners, multiple pregnancies, early onset of sexual
activity, and socioeconomic status (97). Dietary factors were
also examined in a different case-control series of 87 women
with cervical dysplasia and matched control subjects (96). Com-
pared with those above the median intake of 88 mg/d, those
below that median had a significant excess risk (RR = 4.35) for
severe dysplasia or carcinoma in situ. Vitamin C intake remained
a significant factor even after control for age and sexual activity.
Brock et al (98) studied 1 17 in situ cervical cancer patients
and matched community controls in Australia. Those in the
lowest quarter of the distribution of intake of vitamin C had a
significantly elevated risk (RR 2.5). After control for eight
sexual activity and dietary variables, including carotene, the risk
estimate was still ‘�2.0, although this was no longer statistically
significant. In contrast, carotene no longer appeared to be pro-
tective after control for vitamin C and the other variables. Fruit
intake more than once per day remained significantly protective
(RR = 2.5). Plasma 13-carotene was significantly protective;
plasma ascorbic acid was not measured.
Verreault et al (99) examined 1 89 women with invasive cer-
vical cancer and population controls. Low intake of vitamin C
was associated with a statistically significant twofold increased
risk. The effect of fruit juices was even stronger (OR = 3, P
< 0.0 1 ). The effect of carotene and dark green vegetables was
in the same direction, although weaker.
Marshall et al (6 1) failed to observe a protective effect of vi-
tamin C in a study of 5 1 3 cervical cancer patients and hospital
control subjects. An effect was seen for the carotene index. The
authors point out that the Roswell Park instrument was “cx-
tremely imprecise in the measurement ofa key source of vitamin
C, fresh fruits.”
Co/orecial cancer
The role of vitamin C in the occurrence of rectal polyps is
unclear. Sporadic or nonsignificant polyp regression (100), re-
ductions in polyp area (101), or nonsignificant reductions in
recurrence rate (102, 103) have been reported. In the latter study,
35% ofpatients who had been receiving vitamins for 2#{189}y were
polyp free compared with 23% of those on placebo, an effect
that the study had insufficient power to detect as significant. A
recent report found minimal effect of vitamin C alone on oc-
currence of polyps in familial polyposis patients (104), whereas
cereal fiber was effective; the most striking effects were seen in
those who had a high compliance to both fiber and vitamin
supplements. Such studies have been quite small and effects of
such manipulations on actual progression to cancer have not
been observed.
A possible role of vitamin C in prevention or reduction of
fecal mutagens in stool has been observed in two studies (105,
106). In a study of diet and fecapentaene levels conducted by
the National Cancer Institute (106), a strong protective effect
was observed for both dietary and supplemental vitamin C in-
take. Consumption of citrus fruit and of supplemental vitamin
E was also significantly negatively associated with fecapentaene
levels. Thus, if fecal mutagens are associated with colon carci-
nogenesis, vitamin C may play an independent role or may act
synergistically with vitamin E in blocking their effect.
Several studies have examined rectal and colon cancer sepa-
rately. An examination ofthese data suggest that vitamin C may
act differently at these two sites. Rectal cancer will be discussed
first below followed by colon cancer and studies addressing only
the combined group, colorectal cancer.
Seven studies have reported on the association of a vitamin
C index, fruit or raw vegetable intake with rectal cancer, often
with statistically significant results. Kune et al (107. 108) cx-
amined rectal and colon cancer separately in a large case-control
study in Australia. A statistically significant protective effect (OR
= I .7) was seen for high intake of dietary vitamin C as well as
for vitamin supplements in rectal cancer. Tuyns et al ( 109-1 1 1)
conducted a study in Belgium of 365 persons with rectal cancer
and population controls. Vitamin C was significantly protective
(RR = 1.5, P < 0.03) after adjustment for age, sex, province,
and total calorie intake (109, 1 1 1). Total fiber was also protective
but 13-carotene was not. Vegetables. both cooked and raw, were
also found to be highly protective ( 1 10) with lesser effects for
fruit. Potter and McMichael (1 12) found a protective effect of
vitamin C in a study of 124 male and 75 female cases of rectal
cancer and appropriate control subjects. The relative risk asso-
ciated with being in the lowest quintile of intake compared with
the highest was 1 .7 among men, 3.3 among women, the latter
being statistically significant. The role of 13-carotene and fiber
was weak and inconsistent.
Heilbrun et al (1 1 3) compared the baseline 24-h recalls of 60
Japanese men in Hawaii who subsequently developed rectal
cancer and control subjects who did not. Vitamin C intake was
generally quite high, and although lower in patients (105 mg/d)
than in control subjects ( 1 16 mg/d), it was not statistically sig-
nificant. No effect was seen in a quintile analysis among the 60
patients and their control subjects, nor was an effect of dietary
fiber or /3-carotene observed. La Vecchia et al (1 14) studied 236
rectal cancer patients and hospital control subjects and observed
an effect in the protective direction but that effect was nonsig-
nificant. Several vitamin C-rich foods were significantly protec-
tive. Bjelke (40) reported data for rectal cancer cases separately
in studies conducted both in Norway and in Minnesota using a
nutrient index based on l00-g portions. For rectal but not for
colon cancer, patients had “a lower consumption of fruits and
berries and, in particular, of vitamin C” in Norway (40). The
same was true in Minnesota where the vitamin C difference
between rectal cancer patients and control subjects achieved sta-
tistical significance.
Finally, Graham et al (1 15) found a significantly increased
risk (RR = 1 .6) among men eating raw vegetables infrequently
and an even stronger effect among women. The role offruit was
not examined.
Thus, there have been four statistically significant and two
suggestive results for vitamin C in rectal cancer and an additional
significant result for raw vegetables. 13-Carotene effects were
weaker and nonsignificant in all but one study.
Numerous studies have examined colon cancer or a combined
category. colorectal, that generally would contain predominantly
colon cancer cases. A few have found a statistically significant
protective effect of vitamin C. Heilbrun et al ( I 1 3) examined
102 colon cancer patients in Hawaii. Vitamin C intake was sig-
nificantly lower among those who developed colon cancer over
the subsequent 16-y period (92 mg/d by 24-h recall) compared
with those who did not (1 16 mg/d). Those in the lowest quintile
of intake had 1 .9 times the risk of those in the upper quintile
(P = 0.01). In Australia, Kune et al(l07, 108)conducted a large
study of 7 15 colorectal cancer patients and matched community
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2765 BLOCK
control subjects. Both dietary and supplemental vitamin C were
significantly protective with a threefold risk associated with the
low quintile ofdietary vitamin C after adjustment for other di-
etary factors. Consumption ofa high-fiber diet was also protective
provided that vegetable intake was also high. Macquart-Moulin
et al ( I 16) examined 399 cases ofcolorectal cancer in Marseilles
and matched injury controls. After adjustment for age, sex, ca-
brie intake, and body weight, a highly significant protective effect
was seen for vitamin C intake (RR = 1 .8 for low vs high quartile
of intake). A similar protective effect was seen for several mi-
cronutrients and minerals and for fiber from vegetables, but not
for vitamin A or fiber from flour.
Some investigators have found suggestive results in colon
cancer. La Vecchia et al ( I 14) observed a protective but non-
significant effect ofdietary ascorbic acid in colon cancer adjusted
for age and sex. However, tomatoes, green peppers, and melon
were highly significantly protective. The cutpoint for low intake
suggests a very high intake even in the lower tertile and little
dispersion between the low and high tertile. Bjelke (40, 41, 78)
found no effect for a vitamin C index in Norway. In Minnesota
he found vitamin C to be significantly lower not only in patients
with rectal cancer but also in patients with cancer of the left
colon (40). Although preliminary results by Tuyns (109) mdi-
cated a significant protective effect, a later analysis revealed no
consistent effects of a vitamin C index (1 1 1). Several foods rich
in vitamin C were, however, significantly protective (1 10).
Of the eight groups of investigators who have reported on a
dietary vitamin C index, two have found no evidence of pro-
tection for colon cancer. Potter and McMichael ( 1 12) found no
relationship with colon cancer in a study of 220 patients and
community control subjects in Australia. Canadian investigators
( 1 1 7, 1 1 8) found no evidence of a protective effect of either a
vitamin C index or of citrus fruit in a case-control study of 348
colon cancer patients and control subjects in Canada. Average
vitamin C intake among male cases in that study was 170 mg/
d as estimated by questionnaire. Fiber intake was also not pro-
tective.
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
of vegetables, but evidence for an effect of fruit in colon cancer
is inconsistent. Modan et al (1 19) found that several vitamin C-
rich foods, including oranges. tomatoes, and green peppers, were
highly significantly protective. Slattery et al (120) also found
protection conferred by fruit as well as vegetables. Higginson
(92), in 1966, found a lower consumption offresh fruit in co-
lorectal cancer patients than in control subjects (not statistically
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
5 legumes. Some fruits were protective in a study of colorectal
cancer in Hawaiian Japanese ( 122). In a large case-control study
in Wisconsin, Young and Wolf (123) found a significant pro-
tective effect for vegetables and for vitamin supplements, but
not for fruit. Similarly. Manousos et al (1 24) found significant
protection conferred by high intake of vegetables, but found no
effect of fruit. Graham et al (1 1 5) found a significant protective
effect for raw and cooked vegetables.
Finally, in a very small study which examined baseline plasma
ascorbate levels, St#{228}helinet al (53, 57, 84) found no difference
between I 4 colorectal cancer patients and their 32 control sub-
jects in the ascorbic acid level in plasma collected in 1965-1966
or 1971-1973. A later analysis of colorectal cancer patients
found lower plasma ascorbate in patients than in control subjects
(P = 0.06).
For colon cancer, as distinct from rectal cancer, the existing
evidence is less consistent. Four groups found a statistically sig-
nificant protective effect of vitamin C, two found suggestive but
nonsignificant effects, two found no effect ofthe nutrient index,
but one of these observed a significant effect of vitamin C-rich
foods. Overall, for both colon and rectal cancer, of the nine
groups that have reported on a vitamin C index, six have found
statistically significant results in one or the other site, two were
nonsignificant but in the protective direction, and one reported
no effect.
B/adder cancer
Several investigators demonstrated that ascorbic acid inhibits
nitrosation in humans and animals and inhibits carcinogen-in-
duced bladder tumors in animals (125-127). Following up on
this lead, Kolonel et al (54) examined 123 male and 41 female
patients with bladder cancer and population control subjects in
two ethnic groups in Hawaii. Vitamin C intake from supplements
was lower in patients than in control subjects in all four ethnic-
sex groups. The same was true for food sources among females
but not males. For the combined total intake from both sources,
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
comparison was not reported. No effects were found for a vitamin
A index. La Vecchia et al (128) examined 163 bladder cancer
patients and hospital control subjects in northern Italy. The
questionnaire included three fruit/vegetable items: carrots, green
vegetables, and fruit. Although there was a significant association
with the former, there 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
subjects, and thus the possible effects of low intake cannot be
examined. Mettlin and Graham (129) and Paganini-Hill et al
(1 30) found an effect for vitamin A, but did not report on the
role ofvitamin C. Table I summarizes the epidemiologic studiesofvitamin C and cancer prevention for non-hormone-dependent
cancer sites.
Childhood brain tumors
and other nonepithelial cancers
Only one study has been conducted on dietary factors in this
cancer. Thomas Sinks and John R Wilkins III (personal corn-
munication, 1989) interviewed parents of 100 children with brain
tumors and 200 matched control subjects, regarding the mothers’
diets during pregnancy. A statistically significant threefold in-
creased risk of delivering a child who later developed brain tu-
mors was associated with low maternal intake ofvitamin C dur-
ing pregnancy, an effect that remained after adjustment for other
factors.
Breast, ovary, endometrium and prostate cancer
For ovarian, endometrial and prostate cancer, the little cvi-
dence that exists does not support an important role for vitamin
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ASCORBIC ACID IN CANCER PREVENTION 2775
TABLE ISummary of epidemiologic studies of vitamin C and cancer prevention �
Non-hormone-dependent cancer sites References No of studies
No of statistically
significantly protective
Median
relative risk
All sites in this category See below Vitamin C index: 46
Fruit: 29
33
21Oral cavity (24-26)
(27 29, 32)
Vitamin C index: 3
Fruit: 4
3
3
2.0
1.7Larynx (31)
(32)
Vitamin C index: I
Fruit: 1
1
1
2.4
2.0
Esophagus (33, 35-37)(38-40, 32, 42-44)
Vitamin C index: 4Fruit: 7
4
3t
2.2
IDjLung (45-52, 60, 62)
(63, 64)
Vitamin C index: 10
Fruit: 2St2
1.6l.7�
Pancreas (67)
(68-7 1)
Vitamin C index: 1
Fruit: 4
1
4
2.2
1.6Stomach or precursors (40, 41, 78-83, 94)
(84-87, 90)
Vitamin C index: 7
Fruit: 5
7
5 II2.0�
2.5
Cervix or precursors (61, 96, 98, 99) Vitamin C index: 4 3 2.0Rectum (40, 107, 108) Vitamin C index: 6 4 1.5Colon or colorectal (40, 107, 1 1 1-1 14, 1 16,
(119, 120, 122-124)
1 17) Vitamin C index: 8
Fruit:543
1.11.7
Bladder (54)(128)
Vitamin C index: 1Fruit: I
00
IDID
Brain (Sinks, personalcommunication, 1989)
Vitamin C index: I I 3.0
S Studies that assessed the role of a dietary vitamin C index or of fruit intake. Studies that 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 data.
§ Estimate based on only those for which relative risk was reported.
II In one study, P = 0.07, n = 19.
C, whereas recent analyses suggest an important role in breastcancer. Slattery et al (13 1) studied 85 women with ovarian cancer
and population control subjects. An effect in the protective di-
rection was observed for those in the lower one-third of the
distribution (OR = 1.4). However, this did not achieve statistical
significance. La Vecchia et al (132, 133) have reported two studies
of ovarian cancer in Italy. Both found a statistically significant
protective effect for more frequent consumption oftwo vegetable
items, but no effect of reported consumption of a single item,
fruit. In a study in China, Shu 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
C 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
ofa role for vitamin C in ovarian cancer. It is notable, however,
that two of these studies appeared to be in populations with a
very high intake of this nutrient: in Slattery et al (13 1), the low
intake category was defined as vitamin C < 98 mg/d, and in La
Vecchia et al (1 32) the study group consumed an average of 12
servings of fruit per week.
In a single study ofendometrial cancer, La Vecchia et al (136)
investigated 206 patients and age-matched hospital control sub-
jects in Italy. Patients reported significantly lower intake of green
vegetables than control subjects, and lower intake of fruit, al-
though not significantly so. Consumption of fruit in this pop-
ulation appears to be high with both patients and control subjects
averaging 1 #{189}servings/d.
Several investigations have suggested an increased risk for
prostate cancer associated with increased vitamin A and in some
instances vitamin C intake. Reports using the Roswell Park 1957questionnaire and the same study population (I 37, 138) found
an increased risk for increasing vitamin A and vitamin C intake,
trend significant for men aged > 70 y. Investigators in Hawaii
(54, 139, 140) have also reported in the same case series a sig-
nificantly increased risk associated with vitamin A, and the same
direction ofeffect for vitamin C, but not statistically significant.
Two similar studies in Washington, DC (141 , 142) assessed diet
from the distant past (when the patients and control subjects
were aged 30-49 y, and � 50 y). The results suggested an elevated
risk for increasing vitamin A intake, but not for vitamin C. A
prospective study ofJapanese men in Hawaii (143) found similar
results. Two analyses ofa case-control study in Japan (144, 145)
have found a protective effect of 13-carotene in contrast to the
above studies, but no evidence of an effect of vitamin C.
Other studies have found protective effects for increasing con-
sumption of fruits or vegetables or of carotenoid indices calcu-
lated from them, but either did not report on vitamin C or did
not use food lists designed to assess it (146- 148). Thus, with
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regard to prostate cancer and vitamin C or foods rich in vitamin
C. the evidence is meager and conflicting with little evidence of
an effect.
For breast cancer, Howe et al ( I 49- 154) recently examined a
series of studies in a major meta-analysis of the role of dietary
factors. Saturated fat was positively associated with breast cancer,
but in addition “vitamin C intake had the most consistent and
statistically significant inverse association with breast cancer
risk.” When 13-carotene, fiber, and vitamin C were examined
simultaneously. only the latter remained significant, and the au-
thors consequently used vitamin C as the marker for the effective
agent(s) in fruit and vegetables. The results for vitamin C re-
mained after control for fat intake. In terms ofattributable risk,
the authors conclude that “ifall postmenopausal women in the
population modify their saturated fat intake to (that ofthe lower
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 in-
crease fruit and vegetable intakes to reach an average daily con-
sumption of vitamin C (equivalent to that of the highest one-
fifth of the population), risk of breast cancer . . . would be re-
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
therefore of the attributable risk. Thus, for breast cancer the
protective effect of vitamin C appears to be very consistent in
the studies examined by Howe et al ( 149- 1 54), and of a mag-
nitude at least equal to that ofsaturated fat. Table 2 summarizes
the epidemiologic studies of vitamin C and cancer prevention
for hormone-dependent cancer sites.
Summary
In the I 1 non-hormone-dependent cancer sites described
above, 46 studies have specifically reported on a vitamin C index
or plasma ascorbate values; 33 of these found statistically sig-
nificant protective effects, and several more were in the protective
direction but did not achieve significance. None has found el-
evated risk with increasing intake. In addition to those, 29 studies
reported on the effect of fruit consumption, 2 1 of which found
significant protection associated with frequent consumption or
high risk associated with low consumption. For oral, esophageal,
gastric, and pancreatic cancer, the evidence is extremely strong,
with virtually all studies showing a significant protective effect.
The cervical and rectal cancer data are also very strong, with
only a few studies failing to find significant protection. In lung
cancer, five recent studies observed statistically significant pro-
tection, although several earlier studies found nonsignificant re-
sults. In breast cancer, there appears to be a very consistent
protective effect, in the meta-analysis by Howe et al (149). How-
ever, none ofthe studies ofovarian or prostate cancer have found
a statistically significant protective effect of vitamin C.
Dietary estimates involve uncertainties in nutrient content of
foods, in degree of nutrient destruction in cooking and storage,
in portion size quantification, and in the individual’s ability to
estimate his or her frequency of consumption, as well as sub-
sequent altering of blood and tissue levels by host factors. All
ofthese result in substantial misclassification ofthe individual’s
true nutrient status. Misclassification results in a severe bias of
risk estimates toward the null. A great deal has been made of
this problem in discussions of the effects of fat intake, in which
risk estimates have frequently been found to be low and non-
significant. In studies reported here for several cancer sites, how-
ever, particularly the epithelial cancers, the risk estimates have
frequently been substantial and statistically significant. The fact
that misclassification undoubtedly exists can only mean that the
observed effects reported here are underestimates of the true
risk.
These results appear suggestive enough to warrant more in-
tensive investigations in the future. Few studies have examined
plasma vitamin C values and none has examined leukocyte vi-
tamin C values and their relationships with cancer. Leukocyte
values would be preferable because they represent a target tissue
for ascorbate concentration and they are not affected by very
recent dietary intake. Such analyses are needed in prospective
studies or case-control studies nested in a prospective cohort.
These values represent what is actually available to the body for
TABLE 2Summary of epidemiologic studies of vitamin C and cancer prevention
Hormone-dependent
cancer sites References No studies
No statistically
significantly protective
Medianrelative risk
All sites in this category See below Vitamin C index: 9
Fruit: 3
Ot
1
Ovary (131, 134, 135)(132)
VitaminCindex:3Fruit: 1
0j
0
1.3
ID.
Endometrium (136) Fruit: 1 1 1.8
Prostate (137, 139, 141-144) VitaminCindex:6 0� 0.8
Breast (149-154) VitaminCindex:9 Seetextt 1.4
6 Studies that assessed the role of a dietary vitamin C index or of fruit intake. Studies that 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 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.
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ASCORBIC ACID IN CANCER PREVENTION 2795
antioxidant or other functions. Dietary data, on the other hand,
are severely hampered by inaccuracies in food table values, loss
of ascorbate in foods as a result of storage and cooking. and
other factors comprising the chasm ofassumptions between the
estimates of dietary intake and the level of ascorbate actually
reaching the tissues. Very important among these is the role of
other characteristics ofthe individual that alter blood and tissue
levels after the food is consumed. Smoking dramatically lowers
blood ascorbate levels, as does aspirin consumption, oral con-
traceptives, acute and chronic diseases, and a variety of other
stresses. The fact that smoking is usually included in multivariate
models adds another complication to the interpretation, since
they may be in the same causal pathway-smoking may exert
part of its effect by virtue of its reduction of plasma ascorbate
levels. Because of factors such as these, it would appear that
clarification ofthe role ofvitamin C in cancer prevention would
be greatly enhanced by studies that examine blood levels, care-
fully prepared and stored, in relation to cancer outcome.
In addition to assessing blood levels, some additional meth-
odologic features might be considered in future investigations.
First, sample size has been inadequate in several studies described
here; even when apparently adequate, investigators often divide
their sample into quartiles or quintiles and then impose control
for numerous confounders [eg, eight in Brock et al (98). each
with several levels] on each of the quantiles. The result is cx-
tremely unstable estimates and poor statistical power. Prestudy
sample size and power calculations should be based on the real
analyses that will be performed. Second, estimates of the mean
nutrient intake and standard deviation based on several 24-h
recalls or records should be collected in a subset of the study
population. This would permit correction of the mean and dis-
tribution obtained in the food frequency questionnaire so that
the nutrient intake corresponding to the quantile cutpoints could
be more accurately estimated. If this were done, it might ulti-
mately be possible to compare studies in different populations
and with different instruments and to estimate risks for levels
of actual nutrient intake. Third, analyses should take into ac-
count effect modification rather than simply confounding by
other factors. For example, the effect ofvitamin C (or /3-carotene)
may only exist when fat (or meat) intake is high or low. Ross et
al ( 147) found a suggestion that 13-carotene was only protective
for prostate cancer when fat intake was low, and Heilbrun et al
(1 1 3) found similar results with regard to the protective effect
ofdietary fiber in colon cancer at different fat levels. Joint effects
oftwo variables and effect modifications such as these have rarely
been examined, but may explain some ofthe differences in results
seen in different population groups. Future investigators may
wish to design their studies with sample sizes adequate to examine
their data in this way.
Because other nutrients, especially carotenoids and folic acid,
often are obtained in the same foods, with dietary data we cannot
be completely certain that the effect is due to vitamin C and not
to other factors. Nevertheless, the strength and consistency of
the results reported here for several sites suggests that there may
be a real and important effect ofascorbic acid in cancer preven-
tion. It may be more productive to stop thinking in terms of
“or”-”Is it vitamin C or carotenoids?” It is very likely that
both are needed, that all the nutrients packaged together in fruitsand vegetables are synergistic and provide optimal benefit when
all are present in optimal quantities. Vitamin C is apparently
the first line ofantioxidant defense (7), spares vitamin E (8-14),
may be an effective radical scavenger under different partial
pressures of oxygen than those that are optimal for 13-carotene.
and may act synergistically with other biologic antioxidants and
radical scavengers in quenching different elements of a radical
cascade ( 1 55). Future research should focus on analyses of risks
in individuals in which two or more nutrients are low or high.
Public health action should be directed towards increasing the
consumption of fruit, as well as vegetables, in which nature has
packaged a variety of protective nutrients.
I am indebted to the following people for their skillful and committedassistance and support for this paper Lisa Carter, Susana Rosales. VickiHoffman, and Marilyn Apfel.
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