Download Intake of Fat, Meat, and Fiber in Relation to Risk

[CANCERRESEARCH54. 2390-2397, May 1, 1994]
Intake of Fat, Meat, and Fiber in Relation to Risk of Colon Cancer in Men'
Edward
Giovannucci,2
Eric B. Rimm,
Meir J. Stampfer,
Graham
A. Colditz,
Alberto
Ascherio,
and Walter
C. Willett
Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital fE. G., M. J. S., G. A. C., W. C. W.], and Departments of
Epidemiology fE. B. R., M. J. S., G. A. C., A. A., W. C. W.J and Nutrition fE. B. R., M. J. S., A. A., W. C. W.J, Harvard School ofPublic Health, Boston, Massachusetts 02115
ABSTRACT
Some evidence suggests that diets high in animal fat or red meat may
increase the risk of colon cancer, whereas high intake of fiber or
vegetables may be protective. Frequently, intake of red meat has been
a stronger risk factor than total fat. Because data from prospective
cohort
studies
are sparse,
we examined
fat, meat, fiber, and vegetable
intake in relation to risk of colon cancer in a cohort of 47,949 U.S. male
health professionals who were free of diagnosed cancer in 1986. At
baseline, these men, 40 to 75 years of age, completed a validated food
frequency questionnaire and provided detailed information on other
lifestyle and health-related factors. Between 1986 and 1992, 205 new
cases of colon cancer were diagnosed in these men. Intakes of total fat,
saturated fat, and animal fat were not related to risk of colon cancer.
However, an elevated risk of colon cancer was associated with red meat
intake
(relative
risk, 1.71; 95% confidence
interval,
1.15—2.55 between
high and low quintiles; P 0.005 for trend). Men who ate beef, pork,
or lamb as a main dish five or more times per week had a relative risk
of 3.57 (95% confidence interval, 1.58—8.06;P
0.01 for trend)
compared to men eating these foods less than once per month. The
association with red meat was not confounded appreciably by other
dietary factors, physical activity, body mass, alcohol intake, cigarette
smoking, or aspirin use. Other sources of animal fat, including dairy
products, poultry, and fish as well as vegetable fat, were slightly
inversely related to risk of colon cancer. No clear association existed
between
fiber
support
the hypothesis
or vegetable
intake
and
risk
of colon
cancer.
that intake of red meat is related
These
data
to an elevated
risk of colon cancer.
INTRODUCTION
Although a genetic component is well established (1), colon cancer
appears to be strongly influenced by environmental factors. The rates
of colon cancer generally increase among migrants from low- to
high-incidence areas (2), and striking secular trends have occurred
within populations, including a sharp increase in Japan after World
War II (3). Doll and Peto (4) have suggested that differences in diet
may account for 90% of the marked variation in rates of this malig
nancy among different countries (5). Studies comparing per capita
national consumption levels of various foods and nutrients with na
tional colon cancer rates have found high correlations with red meat
or animal
fat but not with vegetable
fat (6, 7). With few exceptions
(8—12),a link with fat (13—21)or red meat intake (22—28)has been
supported in numerous case-control studies where recalled past diets
of persons with and without colon cancer are compared. However, in
many of these studies, a positive association between total energy
intake and risk of colon cancer has been observed (13—17,19, 21),
raising the question of whether it is the total amount of food consumed
or the fat composition of the diet that is etiologically important (29).
Prospective studies of colon cancer, less prone to selection and
recall bias, have demonstrated positive (30, 31), inverse (32, 33), and
null associations (34, 35) with fat or meat consumption. However,
much of the earlier prospective data have been limited by the small
number of cases, crude assessments of diet, and lengthy time periods
between assessment of diet and the accrual of cases. A report from the
NHS,3 which avoided these limitations, showed a strong association
between animal fat, principally from red meat, and risk of colon
cancer in women (36). A recent cohort study from the Netherlands
found an association between processed meats and colon cancer, but
no relationship was observed for fresh meats (37).
A second major hypothesis regarding diet and colon cancer was
primarily initiated by Burkitt's observation of low rates of colon
cancer in regions of Africa which had a high fiber consumption level
and a corresponding large stool bulk (38). However, analytical epi
demiological studies have been rather inconsistent in supporting the
fiber-colon cancer hypothesis. Inverse associations between total fiber
intake and risk of colorectal cancer have been observed in some
case-control studies (10, 15, 16, 19, 39, 40) but not all (8, 9, 12—14,
17). Prospective data regarding fiber intake and colon cancer are
scarce and generally null (41). Overall, it appears that factor(s) present
in some vegetables and fruits may be protective (3), but it is unclear
whether fiber, some specific component of fiber, or other factors
common in plants are the relevant compounds.
We examine here the intake of fat, meat, and fiber in relation to the
incidence of colon cancer during 6 years of follow-up in a large cohort
of U.S. male health professionals. Within this cohort, we have re
ported previously that a diet high in animal fat, especially fat from red
meat, and low in dietary fiber was associated with an elevated risk of
colorectal adenomas, precursors of cancer (42).
MATERIALS
AND METHODS
Study Population. The Health Professionals Follow-up Study cohort,
which has been described previously (43), formed the base population for this
analysis. Briefly, this cohort was started in 1986 when 51,529 U.S. male
dentists, optometrists,
osteopaths,
podiatrists,
pharmacists,
and veterinarians
40 to 75 years of age responded to a mailed questionnaire, which included a
semiquantitative
food frequency
questionnaire.
Participants
also provided
in
formation on smoking history, age, weight, height, physical activity, use of
aspirin and other common medications, parental history of cancer, and history
of professionally diagnosed medical conditions. Every 2 years, we mail a
follow-up questionnaire to the men to ascertain newly diagnosed medical
conditions (44).
Semiquantitative
Food-Frequency
Queslionnaire.
The dietary
question
naire used in this study, an expanded version of a previously validated
instrument (45, 46), included 131 food items plus vitamin and mineral sup
plement use that collectively accounted for over 90% of the major nutrients.
For each food or beverage item, a commonly used unit or portion size (e.g., one
egg or slice of bread) was specified, and participants were asked how often, on
average over the past year, they consumed
that amount of each food. Subjects
chose from nine possible responses, which ranged from ne@ierto six or more
times per day. We also inquired about the types of fat used, and we provided
Received 12/6/93; accepted 3/3/94.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
I Supported
by
Grants
CA
55075
and
HL
35464
from
the
NIH
and
Special
Institution
an open-ended section for foods that were not specified on the questionnaire.
We computed nutrient intakes by multiplying the consumption frequency of
each unit of food by the nutrient content of the specified portions (47—49),
also
accounting for the specific types of fat used in food preparation. We adjusted
Grant 18 from the American Cancer Society. G. A. C. is supported by a Faculty Research
Award (FRA-398) from the American Cancer Society.
2 To whom requests for reprints should be addressed, at Channing Laboratory,
Longwood Avenue, Boston, MA 02115.
180
3 The
abbreviations
used
are:
NHS,
Nurses'
Health
Study;
kcal,
kilocalories;
relative risk; CI, confidence interval.
2390
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
RR,
MEAT, FAT, FIBER, AND COLON CANCER
nutrient values for total energy intake using regression analysis (50). Briefly,
after appropriate transformations, the specific nutrient intake is regressed
(using linear regression) on total calories, and the individual's residual is added
to the mean nutrient level at the mean caloric intake to form the energy
adjusted nutrient.
We askedrandomlyselected participantsfromthe Boston areato complete
2 weeks of diet records in order to estimate the true variation in nutrient intakes
within the study population and to evaluate the precision of the questionnaire.
The results have been described in detail previously (51). Briefly, 127 partic
ipants provided complete information for both 1-week detailed weighed diet
records, administered approximately 6 months apart, and a second semiquan
titative food-frequency questionnaire administered by mail after the diet
records were received. Mean intakes for the lowest and highest quintiles
determined by the diet records were 24 and 41% of energy for total fat, 7 and
14% of energy from saturated fat, 85 and 232 mg per 1000 kcal for cholesterol,
and 7.5 and 15.7 g per 1000 kcal for dietary fiber. Pearson correlation
coefficients
between the second questionnaire
and the average of the two
1-week diet records for energy-adjusted nutrients (adjusting for week-to-week
variation in the diet records) were 0.67 for total fat, 0.75 for saturated fat, 0.68
for monounsaturated fat, 0.76 for cholesterol, 0.44 for protein, and 0.68 for
dietary fiber.
Identification of Cases of Colon Cancers. We mailed follow-up question
naires to all study participants
in 1988, 1990, and 1992 and asked them to
report any diagnosis of cancer during the past 2 years. We mailed up to six
questionnaires per follow-up cycle to nonrespondents, including two certified
mailings. For this analysis, the follow-up response rate was 95% of total
possible person-years
through January 31, 1992, the end of the study period.
Most of the deaths in the cohort were reported by family members or the postal
system in response to the follow-up questionnaires. In addition, we used the
National Death Index, a highly sensitive method of identifying deaths among
nonrespondents (52). We expect to capture essentially all of the fatal cancers
during the study period and approximately 95% of the nonfatal cancers as
previous experience suggests that nonresponse is not strongly correlated with
disease status.
When a subject (or next of kin for decedents) reported a diagnosis of cancer
of the colon or rectum on our follow-up questionnaire, we asked him (or next
ofkin) for permission to obtain hospital records and pathology reports. A study
physician, blinded to exposure information, reviewed all medical records and
extracted data on histological type, anatomic location, and stage of the cancer.
Proximal cancers were considered those from the cecum to the splenic flexure,
and distal cancers included those in the descending and sigmoid colon. We
confirmed 251 new cases of colorectal cancer (excluding carcinoma-in-situ),
226 (90%) by medical records, and 25 with corroborating information on
diagnosis and treatment from the cohort member. For the primary analysis, we
did not include 46 cases that occurred in the rectum because rectal cancers
appear to have a different epidemiological pattern and are less clearly associ
ated with dietary variables. This left 205 cases of colon cancer for analyses.
Data Analysis. For these analyses, we excluded men with implausibly high
or low scores for total energy intake (outside the range of 800 to 4200 kcal per
day) or with 70 or more items left blank and men who reported previous cancer
(other than nonmelanoma skin cancer), ulcerative colitis, or a familial polyp
osis syndrome at baseline, leaving 47,949 men. Each man contributed
fol
low-up time beginning on the month of return of the initial questionnaire in
1986 and ending at the month of diagnosis of colorectal cancer, month of death
for other causes of death, or at the end of the study period, January 31, 1992.
We computed relative risks by dividing the incidence rate (cases divided by the
number of person-years) in each category (usually quintile) of intake by the
rate among those in the lowest category. We used stratified analysis to control
for potentially confounding variables including age (five-year categories),
parental
history
of colon or rectal cancer
(yes/no),
obesity
(quintiles
of body
mass index), physical activity (quintiles), smoking (categories of pack-years),
alcohol intake (categories), aspirin use (yes/no), history of polyp (yes/no), or
prior endoscopy (yes/no) as well as other nutrients (quintiles). For the stratified
analyses, we used the Mantel-Haenszel
linear trends using the Mantel Extension
summary estimator (53) and tested for
test (54). To adjust simultaneously
for
two or more covariates, we used proportional hazards regression (55). Criteria
for inclusion into the multivariate model included a priori belief that the factor
was related to colon cancer for biological reasons (e.g., family history) or
diagnostic reasons (e.g., prior screening) and that the factor was related to
colon cancer in this cohort. For nutrients or food groups adjusted by propor
tional hazards regression,
we tested for trend by modeling
the quintile of the
nutrient ordered from 1 to 5 as a continuous variable.
Our primary analyses focused on total fat, types of fat (saturated, monoun
saturated, and polyunsaturated), both crude and dietary fiber, and sources of fat
and protein (vegetable and animal) and fiber (vegetable, cereal, and fruit). We
also evaluated separately sources of animal fats (red meat, chicken, fish, and
dairy) and the red meat to chicken and fish ratio. This ratio, the most
significant
predictor
for colon cancer among women
in the NHS, approximates
the effect of substituting red meat with chicken and fish as often recommended
(56, 57). Becausethis ratio is a meaningfulrepresentationof the substitution
pattern of chicken and fish for red meat mainly among those eating an
appreciable amount of these foods, we limited our analyses to men eating at
least one serving of these foods daily on average.
RESULTS
A slight inverse but nonsignificant association existed between total
energy intake and colon cancer incidence (Table 1). Energy-adjusted
total fat intake was also unrelated to risk of colon cancer. Animal fat
had no clear association with risk of colon cancer; a significantly
elevated risk was evident in the second highest quintile relative to the
lowest, but the rate in the highest quintile was slightly lower than that
in the lowest quintile. Fat from vegetable sources had a modest,
nonsignfficant inverse association with colon cancer. The major types
of fat from animal sources and saturated and monounsaturated fat
were unrelated with risk of colon cancer, and linoleic acid, the major
polyunsaturated fat, was slightly inversely associated with risk. Cho
lesterol intake, exclusively from animal sources, was unrelated to the
risk of colon cancer.
In contrast to the absence of an association between total and
animal fat and risk of colon cancer, a significant association
existed between red meat intake and risk of colon cancer (Table 2).
Beef, pork, or lamb as a main dish was significantly related to risk
of colon cancer; an association also existed with processed meats,
although this did not achieve statistical significance (P = 0.06). Of
the other sources of meat, poultry intake was slightly inversely
related to the risk of colon cancer, and fish intake was unrelated to
risk. The red meat to chicken and fish ratio, representing the
substitution of chicken and fish for red meat, was significantly
related to higher risk of colon cancer.
We conducted multivariate analyses to assess whether other
potentially confounding variables influenced the relation between
red meat consumption and colon cancer. In a multiple logistic
model which included age, body mass index, history of previous
polyp and prior endoscopy, parental history of colon cancer, aspi
rin use, physical activity, and intake of dietary fiber, methionine,
and alcohol, the elevated risk associated with red meat intake (RR
= 1.66;
95%
CI = 1.04—2.65
between
high
and
low
quintiles;
P =
0.02 for trend) and beef, pork, or lamb as a main dish (RR = 3.07;
95% CI = 1.35—6.98between
5 servings per week versus less
than once per month; P = 0.04 for trend) persisted. The modest
degree of confounding, represented by the change in relative risk
in the full multivariate model, was due primarily to physical
activity and cigarette smoking before the age of 30 years. Further
adjustment for folic acid, calcium, and vitamins A, C, D, and E and
multivitamin use did not influence the results.
Because red meat is an important dietary source of both protein and
fat, we examined the association between sources of fat and protein
and the risk of colon cancer in detail. The correlations between intakes
of red meat and total fat (r = 0.51) and animal fat (r = 0.57) were not
so high to preclude our ability to discriminate statistically among the
sources of fat. The combination of the positive association with red
meat and the inverse associations with other major sources of fat
2391
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
MEAT, FAT, FIBER, AND COLON CANCER
Table 1 Relative risk of colon cancer according to quintile of total energy intake and dietary fats
Quintilex
5Total
1
(P)Variable
2820CaseWperson-@ears
energy(mediankcal/day)
2
1229
1586
1884
2308
64/52,871
44/53,126
35/53,134
1.0
1.92 (1.28—2.90)
89.0Cases/person-years
fat (mediang/day)
54.2
1.33 (0.85-2.08)
65.3
28/52,567
1.12 (0.70—1.80)
72.3
55/52,150
55/53,287
27/52,834
1.0
1.80 (1.18—2.74)
1.82 (1.19—2.77)
0.95 (037—1.56)
56Cases/person-years
fat (median g/day)
25
33
40
46
42/55,158
40/50,612
40/56,035
53/52,869
1.0
1.12 (0.73—1.72)
1.06 (0.69—1.63)
131 (1.02—2.24)
(035—1.38)0.42(0.67)Vegetable
(95% Cr)c
46Cases/person-years
fat (median g/day)
20
27
32
37
37/52,304P.R
(0.33)Saturated
(95%Ct)c
54/52,812
40/54,1 14
33/52,593
41/52,865
33.0Cases/person-years
fat (median g/day)
31/52,178RR
17.4
47/53,305
22.2
44/54,212
25.2
44/56,650
28.3
39/52,335
1.0
1.01 (0.67—133)
1.13 (0.75—1.70)
1.07 (0.70—1.63)
19.1
39/53,526
23.8
42/52,838
26.9
48/54,660
29.7
41/52,740
1.0
(036—1.37)—0.27(0.79)Monounsaturated
(95%
@)C
34.2Cases/person-years
fat (median g/day)
35/50,916RR
(0.68)Linoleic
(95%CI)c
1.21(0.78—1.87)
8.0
34/52,762RR
0.87
139 (0.91—2.12)
0.88
1.24(0.80—1.93)
10.1
11.6
13.2
42/52,005
37/52,498
43/52,801
1.0
0.99 (0.66—1.49)
0.87 (037—134)
1.01 (0.67—132)
0.79
198
40/53,188
1.0
262
46/53,320
1.27 (0.83—1.93)
313
37/53,522
0.99 (0.64—135)
369
40/52,570
1.07 (0.69—1.66)
1.07
x-ststi@tic
isequivalent
toZvalue
from
standard
normal
tables
with
anegative
value
representing
aninverse
association.
b Adjusted
analysis.C
for
age
using
1.07(0.68—1.69)0.41
49/54,614
(031—1.22)—0.84(0.40)Cholesterol
(95% C1)c
467Cases/person-years
(median mg/day)
42/52,080RR
(0.70-1.63)—0.07(0.94)a
(95%
@)C
1.19
0.79(032—1.19) 0.70(0.45—1.07) 0.90(0.60—1.35) 0.76(030—1.16)—0.98
1.0
16.2Cases/person-years
acid (median g/day)
0.94
79.0
34/53,278
(0.74—1.90)—0.47(0.64)Animal
(95% Ct)c
30/50,006RR
4
34/52,982
(037—135)—1.42(0.16)Total
RR (95% Cl)
34/53,132RR
fortrend―
3
stratified
Adjusted for age using stratified analysis.Nutrients
analysis.Table are adjustedfor intake of total energy using residual
2 Age-adjustedrelativeriskof coloncanceraccordingtogroupsCategoryx
intakeof variousanimalfood
for trend
5Red
1
(P)Variable
meata(mediang/day)
55/529,689RRC
@b/p@_.@n@years
2
3
18.5
42.9
39/51,897
35/52,448
(95%
CI)
(0.005)Beef,
1.0
5/weekCases/person-years
pork,or lambas maindish(servings)
0.97
0
64.1
(0.62—134)
0.98
44/49,307
(95% Cl)
(0.01)Processed
1.0
1.92 (1.03—3.60)
0
1293
40/52,871
(0.62—136)
1—3/month
12124,870
7/13,305RR
(95% Cl)
(0.06)Poultry
883
32/52,805
16/14,906RR
5/weekCases/person-years
meats (servings)
4
1.21
(0.77—1.88)
1/week
2-4/week
57/85,194
72/88,713
1.69 (0.92—3.10)
2.11 (1.13—3.92)
1-3/month
1/week
2-4/week
52/70,150
63/79,387
41/55,113
39/44,211
1.0
1.25 (0.87—1.80)
63.1Cases/person-years
(median gjthy)d
1.71
1.40 (0.92—2.13)
1.67 (1.06—2.61)
8.8
15.8
29.2
42.2
36/53,532RR
(95% CI)
(0.27)Fish
54/52,186
1.0
39/53,062
0.81 (034—1.23)
36/53,1 10
0.76 (030—1.17)
40/52,790
0.79 (032—1.18)
83.4Cases/person-years
(median g/day)―
51/53,215RR
(95% CI)
(0.79)Ratio
8.4
41/52,817
20.9
35/53,071
31.0
43/52,789
47.8
35/52,788
1.0
0.85 (0.54—1.33)
3.6Cases/person-years
of red meat to chicken and fish (median)'@
49/44,642RR
(95% Cl)
0.20
31/43,534
1.0
1.05 (0.68—1.61)
0.80 (031—1.26)
036
1.0
1.7
31/42,650
1.20 (0.73—1.96)
33/428,232
1.30 (0.80—2.12)
28/44,102
1.09 (0.65—1.82)
(1.15—235)2.83
337 (138—8.06)239
1.16 (0.44—3.04)1.89
0.82 (034—1.24)—1.10
1.06 (0.70—1.60)0.26
1.83 (1.17—2.85)2.43
(0.015)
aData
onred
meat
relate
tothe
following:
beef,
pork,
orlamb
asamain
dish
(e.g.,
steak,
roast,
and
ham);
beef,
pork,
orlamb
asasandwich
oramixed
dish
(e.g.,
stew,
casserole,
and lasagna); hamburger, hot dog; preserved meats (e.g., sausage, salami, and bologna); and bacon.
To@ casesfor food groupsand items may not add up to 205 due to missinginformation on food items.
C Red
meat,
poultry,
and
fish
were
adjusted
for
total
energy
using
residual
analysis
and
beef,
pork,
or
lamb,
and
processed
meats
were
adjusted
by
standard
stratified
analysis
because
of non-normality. Computed from the energy-adjusted values in g/day for red meat and chicken plus fish. The ratio analysis was limited to those who had at least one serving per day
of thesefoods.
d Data on poultry and fish relate to the following:
chicken or turkey with skin, chicken or turkey without skin, canned tuna fish, dark meat fish, other fish, shellfish (e.g., shrimp,
lobster, and scallops).
(poultry, dairy, and vegetable) balanced each other to yield the overall
null association observed between total and animal fat intake and risk
of colon cancer. As seen in Table 1, vegetable fat and the major
lated to the risk of colon cancer. In addition, fat from dairy products
(RR = 0.66; 95% CI = 0.43—1.01between high and low quintiles; P
= 0.23 for trend) and from chicken (RR = 0.60; 95% CI = 0.38—
polyunsaturated fat linoleic acid were nonsignificantly inversely re-
0.95; P = 0.08 for trend) were slightly inversely related to the risk of
2392
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
MEAT, FAT, FIBER, AND COLON CANCER
Table 3 Relative risk of colon cancer according to quintile of total dietary protein and sources of protein
Quintile
12345Total
(P)
protein―
(median g/day)
70
C@sb/permnyears
(0.52—1.17)—1.17(0.24)Animal
RRc (95% CI)
46/46,834
1.080
protein―(median g/day)
48/54,390
1.055
meat proteina (median g/day)
Cases―/person-years
5
40/51,876
RRC (95% CI)
(0.01)Animal
1.010
protein excluding red meata (median g/day)
@@sb/permn@years
1.027
protein―(median g/day)
@@sb/permn@ye@
RRC
(0.45—1.10)—1.48(0.14)a
(95%
CI)
adjusted
for
total
47/59,001
42/52,607
0.88 (0.58—1.33)95
34/50,945
0.71 (0.46-1.10)108
0.78
0.93 (0.61—1.41)63
43/56,165
0.89 (039—1.35)72
36/50,474
0.81 (033—1.25)85
37/51,942
0.76
34/52,295
0.93 (0.59—1.47)16
33/53,05 1
0.97 (0.61—1.53)22
42/52,778
52/52,990
1.25 (0.81—1.92)32 134 (1.03—2.31)2.53
energy
41/51,709
19
56/52,542
RRC
(0.46—1.02)—1.86(0.06)Vegetable
(95%
CI)
Nutrients
36/53,294
0.74 (0.48—1.15)88
44
@sb/p@_,@n.ye@
(0.49—1.16)—1.42(0.16)Red
RRc (95% CI)
@
x for trend
Variable
34/52,580
39/53,139
34/53,168
42/52,253
0.64 (0.42—0.97)33 0.70 (0.47—1.06)40 0.60 (0.40—0.92)54 0.68
18
44/52,804
1.022
using
residual
40/52,776
0.93
49/54,058
(0.61—1.43)25
1.09
(0.73—1.63)28
39/5 1,727
33/53,316
0.88 (037—1.36)33 0.70
analysis.
fornutrients
maynotaddupto205duetomissing
information.
C Relative
risks
adjusted
for
age
using
stratified
analysis.
colon cancer. As expected, fat from red meat sources was related to
colon cancer (RR = 1.39; 95% CI = 0.82—2.36;P = 0.02 for trend).
These data suggest that fat intake, at least that from non-red meat
sources, does not increase the risk of colon cancer.
Despite the strong positive association with red meat consumption,
intake of total protein from both animal and vegetable sources was
inversely associated (nonsignificantly) with the risk of colon cancer
(Table 3). We explored further the association with animal protein
from sources other than red meat in a model that included intake of
energy-adjusted protein from red meat, energy-adjusted protein from
animal sources other than red meat, age, body mass index, history of
previous polyp and prior endoscopy, parental history of colon cancer,
aspirin use, physical activity, and alcohol intake. In this model, animal
protein from sources other than red meat was associated with a
reduced risk of colon cancer (RR = 0.63; 95% CI = 0.41—0.97
between high and low quintiles of intake; P = 0.03 for trend). The
slightly stronger association between non-red meat animal protein and
risk of colon cancer when controlling for red meat protein suggests
that this inverse association may not be due entirely to the displace
cream, P = 0.17; chicken with skin, P = 0.06) or were unrelated to
risk (hard cheese and butter).
We had reported an association between smoking at early ages and
risk of colorectal cancer in this cohort (Ref. 58 and in the NHS, Ref.
59). Based on the age-adjustedrelativerisk of 1.60 among those who
had smoked before the age of 30 years relative to nonsmokers, we
estimated that 38% of the colon cancers diagnosed among smokers
could be attributable to smoking. If colon cancers related to smoking
and those related to red meat occur via different etiological pathways,
smoking-related cancers would attenuate the relative risks associated
with the intake of red meat among smokers. Thus, we examined the
risk of colon cancer in relation to consumption of red meat separately
among smokers and nonsmokers. Among nonsmokers before age 30
years (75 cases of colon cancer among 24,817 men), we found strong
associations between colon cancer and the intake of red meat (RR =
2.18;
95%
CI = 1.14—4.16 between
high and low quintiles;
P =
0.008 for trend) and intake of beef, pork, and lamb as a main dish (RR
= 5.11; 95% CI
1.38—18.9 between
5 servings
per week versus
less than once per month; P
0.008 for trend). Among men who had
smoked before age 30 years (126 cases among 22,812 men) there were
ment of red meat in the diet.
We examined the relationship with red meat by subsite within the considerably weaker associations between colon cancer and the intake
of red meat (RR = 1.38; 95% CI = 0.83—2.30;P = 0.21 for trend)
large bowel (among cases for which subsite information was avail
and the intake of beef, pork, and lamb (RR = 1.60; 95% Cl =
able), including the rectum. The association between red meat intake
0.67—3.85;P = 0.75 for trend).
and large bowel cancer was suggested for the distal colon (89 cases,
Intake of total dietary fiber or of crude fiber was unrelated to risk
age and energy-adjusted RR = 1.78; 95% CI = 0.97—3.25between
of colon cancer (Table 4). For both types of fiber, men in the lowest
high and low quintiles of intake; P = 0.07 for trend) but not in the
quintile of intake appeared to be at the highest risk. However, no
proximal colon (69 cases, RR = 0.87; 95% CI = 0.43—1.76;P = 0.85
obvious trend was evident from quintiles 2 to 5. Furthermore, in the
for trend). There were too few cases of rectal cancer (46) to provide
informative relative risk estimates (RR
1.22; 95% CI = 0.36— full multivariate model, any suggestion of a protective effect of fiber
disappeared. The major contributors to confounding were intake of
4. 14). For total colorectal
cancer, entailing 25 1 cases, associations
red meat and level of physical activity. None of the sources of fiber,
existed with red meat intake (RR = 1.66; 95% CI = 1.14—2.42;P =
fruit, vegetable, or cereal, appeared related to risk. The relation with
0.003 for trend) and the red meat to chicken and fish ratio (RR = 1.81;
fiber intake did not vary appreciably by subsite within the colon.
95% CI = 1.22—2.67;P = 0.02 for trend).
We also examined associations between frequency of total vegeta
Of all the food items included in the questionnaire, beef, pork, and
ble and fruit consumption and risk of colon cancer. Intakes of vege
lamb as a main dish had the strongest positive association with colon
tables (RR = 1.02; 95% CI
0.64—1.63for >5 versus
@2servings
cancer. Other red meat products, processed meats (P = 0.06), ham
per day; P = 0.83 for trend) and fruits (RR = 0.98; 95% CI
burger (P = 0.04), and bacon (P = 0.11) were positively associated
0.54—1.77for >4 versus <1 servings per day; P = 0.52 for trend) were
with the risk of colon cancer, whereas hotdogs and beef and pork or
lamb served as a sandwich or mixed dish were unrelated to risk. In unrelated to risk. Of all fruits and vegetable items examined individ
ually (see footnote for Table 4 for list), none were statistically sig
contrast, other high-fat foods of animal origin had nonsignificant
nificantly related to the risk of colon cancer in an age- and energy
inverse associations with colon cancer (whole milk, P = 0.08; ice
2393
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
MEAT, FAT, FIBER, AND COLON CANCER
Table 4 Relative risk of colon cancer according to quintile of total dietary and crude fiber and dietary fiber from fruits, vegetables, and cereals
Quintile
x for trend
Variable12345Total
(F)
g/day)14.218.321.725.632.8Cases/person-years53/55,56128/52,32225/51,88652/52,15747/52,754Age-adjusted
dietaryfiber(median
(0.36)Multivariate
RR (95% CI)1.0032
(0.68-1.70)137(0.12)Total
RR (95% C])―1.00.63
(0.33—0.81)0.43
(0.39—1.01)039
(0.27—0.68)0.82
(0.36-0.97)1.19
(036—1.19)0.65
(0.78—1.82)1.08
(0.44—0.97)—0.91
(037—1.29)0.69
(0.81—1.98)1.05
(0.45—1.05)—1.13
(0.61—1.63)—0.23
g/day)3.64.65.66.68.6Cases/person-years42/51,58834/53,79434/52,72451/53,41444/53,159Age-adjusted
crude fiber (median
(0.44-1.07)0.64
(032—1.32)0.87
(0.26)Multivariate
RR (95% CI)1.00.68
(0.65—1.71)0.95(0.34)Fruit
RR (95% CI)―1.00.83
(0.41—1.00)0.86
(034—139)1.27
g/day)b1.22.64.15.89.2Cases/person-years33/62,29343/54,28255/52,25038/49,29136/46,564Age-adjusted
fiber (median
(0.82)Multivariate
RR (95% CI)1.01.23
(0.78—1.94)131
(0.99—2.31)1.05
(0.65—1.69)1.00
(0.98—2.81)1.74(0.08)Vegetable
RR (95% CI)―1.01.60
(1.01—235)2.03
(1.29—3.20)1.61
(0.98—2.81)1.66
@@y)C2.8436.07.911.7Cases/person-years43/55,73345/55,15149/54,54330/48,75738/50,496Age-adjusted
fiber (median
(0.63—135)—0.72(0.47)Multivariate
RR (95% CI)1.00.98
(0.71—1.63)0.71
(0.64—130)1.08
(0.74—1.73)1.26
RR (95% CI)―1.01.13
(0.45—1.14)0.99
(032—1.40)1.17
(0.82—1.94)0.86
(0.72—1.90)0.11
Cereal fiber (median g/thy)d
Cases/person-years
2.3
40/50,343
4.4
48/56,520
6.6
38/56,575
9.4
46/55,039
15.3
33/46,205
Age-adjusted RR (95% CI)
Multivariate RR (95% CI)―
1.0
1.0
1.15 (0.75—1.76)
1.27 (0.83—1.96)
0.99 (0.61—139)
1.22 (0.77—1.93)
1.38 (0.89—2.16)
1.63 (1.04—237)
1.06 (0.66—1.73)
1.28 (0.78—2.09)
a RR adjusted
for age, total energy,
previous
polyps,
previous
endoscopic
screening,
parental
history
of colorectal
cancer,
total pack-years
of cigarette
(0.91)
0.35 (0.73)
1.42(0.16)
smoking,
aspirin
use, and
intake of red meat, methionine and alcohol, using the Cox model.
b Includes
raisins,
C Includes
string
avocados,
beans,
bananas,
broccoli,
cantaloupes,
sauerkraut,
watermelon,
coleslaw,
cauliflower,
apples,
brussels
pears,
oranges,
sprouts,
grapefruits,
carrots,
corn,
strawberries,
peas,
mixed
blueberries,
vegetables,
peaches,
beans,
cabbage,
apricots,
lentils,
plums,
alfalfa
and
fruit
sprouts,
juices.
celery,
mushrooms,
yellow squash, eggplant, yams, spinach, iceberg or romaine lettuce, green pepper, garlic, tomatoes, tomato juice and sauce, red chili sauce, and kale or chard greens.
d Includes
cold
breakfast
cereal,
cooked
oatmeal,
other
cooked
breakfast
cereal,
white
bread,
dark
bread,
English
muffins,
bagels,
rolls,
brown
rice,
white
rice,
pasta,
other
grains,
pancakes, crackers, and added bran.
adjusted analysis. The item with the strongest evidence of an inverse
association was garlic intake (RR
0.77; 95% CI
0.51—1.16for
2 servings versus 0 servings per week; P = 0.14 for trend), an
association limited to the distal colon (RR = 0.63; 95% CI =
0.38—1.65;P = 0.07 for trend).
scopic procedures during the study period. Thus, a higher detection
rate for colon cancer among the heavier consumers of red meat is
unlikely to explain the observed associations. Controlling for total
energy, parental history of colorectal cancer, physical activity, body
mass index, aspirin use, smoking, and intake of alcohol and other
nutrients did not alter markedly the association between meat intake
and colon cancer incidence. Because the population consisted of a
DISCUSSION
relatively homogeneous group of male health professionals, any re
sidual confounding from other factors potentially related to socioeco
nomic status was unlikely to be substantial.
While our study does not support a general effect of fat intake on
These data support the hypothesis that high consumption of red
meat increases the risk of colon cancer, particularly of the distal colon,
but do not provide evidence for a protective effect of dietary fiber. In
contrast to the findings for red meat, fat from dairy, poultry, and
vegetable sources tended to be inversely associated with the risk of
colon cancer. No overall relationship existed between total or satu
colon cancer risk, it is still plausible that the fat content of red meat
is deleterious. It has been hypothesized that diacylglycerides aris
ing from the incomplete breakdown of dietary triglycerides induce
mitogenesis of adenoma and some carcinoma cells but not normal
cells in primary culture (60). Conceivably, fat from red meat may
rated fat and this malignancy, despite a marked range in fat intake
(means of 24 to 41% of energy from total fat and 7 to 14% from
saturated fat between extreme quintiles). These findings are consistent
with those from a similar cohort in women, the NHS, and from an
analysis of adenomas of the distal colorectum in the same cohort of
be less readily digested or absorbed in the small intestine, perhaps
because
men. In all three analyses, the specific food item most strongly
associated with increased risk of colon cancer or adenoma was beef,
pork, or lamb as a main dish. Although an association between animal
association was attributable to consumption of red meat. Furthermore,
in an analysis of the NHS data with red meat and animal fat in the
Biased recall was not likely to explain our findings because the
dietary data were collected before the diagnosis of colon cancer. We
controlled for history of colonoscopy or sigmoidoscopy prior to 1986,
and high red meat consumers tended to have slightly fewer endo
or due to its physical
some fatty acids (e.g., palmitic acid) that appear to be strong
mitogens of adenoma cells in culture.
Alternatively, it has been hypothesized that a high consumption of
or saturated fat and colon cancer incidence existed in the NHS, this
same model, red meat remained significantly predictive of colon
cancer, whereas the association with animal fat was eliminated (un
published data). Overall, the results from these three analyses provide
evidence for an association between red meat intake and colorectal
neoplasia but do not support the hypothesis that fat consumption per
se increases risk of colorectal tumors.
of its high stearic acid content
imbediment in muscle tissue, and thus more of it may reach the
large bowel. Moreover, the specific fatty acid profile of red meat
could be particularly harmful. For example, red meat is high in
protein rather than fat increases the risk of cancer (61). However, the
results from the NHS cohort and this cohort actually suggest an
inverse association between non-red meat sources of protein and
colon tumors. Similarly, among the many published reports from
dietary epidemiological studies of colon cancer and adenomas, we are
aware of none which have reported a significant positive association
with intake of non-red meat protein; on the contrary, most other
prospective studies have similarly reported either significant or non
significant inverse associations with high protein foods (poultry, fish,
and dairy) or with total protein (30, 32, 33, 36, 37). An inverse
2394
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
MEAT, FAT, FIBER, AND COLON CANCER
association between non-red meat protein and risk of colorectal ade
noma has also been observed in most studies (42, 62—65). Some
case-control
studies
of colon cancer
have indicated
a positive
associ
ation with total protein; however, because these studies generally have
found a positive association with total energy intake and colon cancer,
energy from protein as a percentage of total energy is often actually
lower among cases. Moreover, a clearer inverse association with
protein may have emerged if non-red meat protein sources were
analyzed separately from red meat. A possible explanation for a
protective effect of protein is that low intakes of methionine may
contribute to DNA methylation abnormalities, which appear to be
important in the initiation and progression of colon cancer (66).
cancers and adenomas, could be due to limitations of ecological
studies. National per capita levels of protein consumption are corre
lated with various factors that could explain the higher risk of colon
cancer in affluent countries (e.g., red meat, fat, physical inactivity,
obesity, low fiber, and long-term smoking). Yet within high-risk
populations, data from some epidemiological investigations (30, 32,
33, 36, 37, 42, 62—65)including the current study suggest ample
protein intake during adulthood may actually be beneficial for the risk
of colon cancer, although the effects of high intakes of total energy or
protein during developmental years could be quite different.
Besides macronutrients, other factors in red meat may account for
its association with colon cancer. Babbs (67) hypothesizes that high
consumption of red meat may increase concentrations of fecal iron,
which could influence risk of colon cancer via the generation of
hydroxyl radicals. Dietary iron enhances lipid peroxidation in the
mouse colon (68) and augments dimethyihydrazine-induced
colorec
tal tumors in mice (69) and rats (70). Alternatively, some evidence
suggests that carcinogens formed when meat is cooked may be critical
(71). Human data are sparse, but in one case-control study, the risk of
colorectal cancer was markedly elevated among frequent meat eaters
who preferred a heavily browned surface but was not increased among
those who consumed meat fried with a medium or lightly browned
surface (28). Thermolyzed protein promotes precursor lesions and
cancers of the rat colon, an influence that is dose-dependent and
proportional to the cooking time (72). Others speculate that diets high
in meat increase the risk of colon cancer by raising the concentration
of endogenous nitrosamines (73) or tryptophan metabolites (74). For
this analysis, we did not have data on cooking practices.
Total energy intake was not directly related to colon cancer risk,
as had been suggested by numerous case-control studies (3). Our
finding was consistent with other prospective studies of colon
cancer and adenoma, which also did not show an association with
total energy. This difference observed between prospective and
some case-control studies may be due to a general overreporting of
past food intake by cases relative to controls when diet is assessed
after the diagnosis of cancer.
When we examined the risk of colon cancer in relation to the
consumption of red meat separately among smokers and nonsmok
ers, we found markedly stronger relative risks among nonsmokers.
The most likely explanation for this finding is that the smoking
related colon cancers, estimated to be 37.5% of colon cancers
among smokers, attenuated the relative risks associated with the
intake of red meat among smokers. An association between smok
ing at young ages and risk of colorectal cancer needs to be taken
into account in future studies.
with the earlier
report among
female
nurses,
sure of fiber intake.
Despite a relatively wide acceptance of the fiber-colon cancer
hypothesis, evidence from epidemiological studies is weak. A meta
analysis
The positive association between protein intake and colon cancer
incidence observed in ecological studies, in contrast to the inverse
association observed in case-control and prospective studies of colon
Consistent
from the substudy, the overall median intake of dietary fiber was 21
g daily, with medians of 13 g for the low quintile and 34 g for the high
quintile. We were thus able to examine the effects of fiber at recom
mended intakes (25 to 35 g daily; Ref. 75), which are considerably
higher than the mean dietary fiber intake in the U.S. adult population
(13.3 g per day; Ref. 76). The fact that a strong inverse association
between fiber intake and symptomatic diverticular disease was found
in this cohort4 indicates that we had a physiologically relevant mea
we did not
of case-control
case-control
of colon cancer
demonstrated
a com
studies which examined
sources
of fiber separately,
grain
fiber or cereal intake was either unrelated or positively associated with
colon cancer risk, whereas intake of fruits or vegetables was protec
tive (3). Possibly, some specific component or type of fiber rather than
total dietary fiber may be protective, or perhaps the influence of fiber
occurs during earlier stages of carcinogenesis. Several studies of
adenomatous precursors (60—63), including data from this cohort, do
support a protective effect of fiber.
Alternatively, the lack of an association with cereal fiber intake and
inverse associations between vegetable intake and malignancies at
other sites where a direct influence of fiber is unlikely suggest that
chemopreventative factors in plant foods other than fiber may be the
active agents. We did not observe a statistically significant inverse
association between intake of any single fruit or vegetable item and
the risk of colon cancer. The absence of strong associations between
fruits and vegetables
and colon cancer
in this cohort
and in the NHS
contrasts with findings in numerous case-control studies. One possible
explanation is that the influence of the protective agent(s) occurs at
deficient or very low intakes and that consumption of fruits and
vegetables in these self-selected cohorts is considerably higher than
that in general population studies. A recent report from a cohort study
of women in Iowa also did not show a clear inverse association with
fruit and vegetable intake (78). Of note, garlic was the specific
vegetable item with the strongest inverse association with risk of
cancer of the distal colon, a finding remarkably similar to that ob
served in the Iowa women (78). Garlic and other allium vegetables
including onions and chives may have a anticarcinogenic effect,
possibly due to an induction of enzymatic detoxification systems,
antibacterial activity, or a reduction in tumor proliferation (79). As
very little study has been conducted regarding allium compounds and
cancer in humans, this finding requires further investigation.
In summary, these findings provide further evidence for the hy
pothesis that consumption of red meat increases the risk of colon
cancer, the second leading cause of death from malignancies in the
United States (80). Major sources of protein and fat other than red
meat do not appear to have this deleterious effect. These data provide
direct support for existing dietary recommendations to substitute fish
and poultry for red meat (56, 57).
4 w. H. Aldoori,
observe an important effect of fiber. The absence of an association
was not due to a limited range in fiber intake; based on diet records
studies
bined odds ratio of 0.58 between highest and lowest quintiles based on
fiber intake but a stronger odds ratio of 0.48 based on vegetable
consumption (77). These estimates, however, may be biased because
of the exclusion of several studies that did not support the hypothesis.
Furthermore, as suggested by our study, some confounding by red
meat intake and physical activity level may have occurred. In the
E. Giovannucci,
E. B. Rimm, A. L. Wing, D. V. Trichopoulos,
and
w. C.Willett.A prospectivestudyofdietandtheriskofsymptomaticdiverticulardisease
in men, submitted for publication.
2395
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
MEAT, FAT, FIBER, AND COLON CANCER
ACKNOWLEDGMENTS
Treatment, pp. 158—174.Amsterdam: Exerpta Medica, mt. Congress Series No. 484,
1980.
We are indebted to Mira Koyfman, Mildred Wolff, Elizabeth Frost-Hawes,
KerryPillsworth,CindyDyer,Jan Vomacka,and Jill Arnoldfor experthelp.
31. Gerhardsson, M., Floderus, B., and Norell, S. E. Physical activity and colon cancer
risk. Int. J. Epidemiol., 17: 743—746,1988.
32. Stemmennann,
G. N., Nomura, A. M., and Heilbrun, L. K. Dietary fat and the risk of
colorectal cancer. Cancer Res., 44: 4633-4637, 1984.
33. Hirayama, T. A large-scale study on cancer risks by diet—with special reference to
REFERENCES
the risk reducing effects of green-yellow vegetable consumption. in: Y. Hayashi, M.
Magao, T. Sugimura, et aL (eds.), Diet, Nutrition, and Cancer, pp 41—53.Tokyo:
1. Cannon-Albright, L A., Skolnick. M. H., Bishop, D. T., Lee, R. G., and Burt, R. W.
Japan Scientific Societies Press, 1986.
Common inheritance of susceptibility to colonic adenomatous polyps and associated
34. Garland, C., Shekelle, R. E., Barrett-Connor, E., Criqui, M. H., Rossof, A. H., and
Paul, 0. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year
colorectal cancers. N. EngI. J. Med., 319: 533—537,1988.
2. Haenszel, W., and Kurihara, M. Studies of Japanese migrants. I. Mortality from
cancer and other diseases among Japanese in the United States. J. Natl. Cancer Inst.,
40:43—68,
1968.
3. Willett, W. The search for the causes of breast and colon cancer. Nature (Lond.), 339:
prospective study in men. Lancet, 1: 307—309,1985.
35. Phillips, R. L., and Snowdon, D. A. Association of meat and coffee use with cancers
of the large bowel, breast, and prostate among Seventh-Day Adventists: preliminary
results. Cancer Res., 43 (Suppl.): 2403—2408,1983.
389—394,1989.
4. Doll, R., and Peto, R. The causes of cancer: quantitative estimates of avoidable risks
of cancer in the United States today. J. Natl. Cancer Inst., 66: 1191—1308,1981.
5. Boyle, P., Zaridze, D. G., and Smans, M. Descriptive epidemiology of colorectal
cancer. Int. J. Cancer, 36: 9—18,1985.
6. Armstrong, B., and Doll, R. Environmental factors and cancer incidence and mortality
in different countries, with special reference to dietary practices. Int. J. Cancer, 15:
617-631, 1975.
7. Rose, D. P., Boyer, A. P., and Wynder, E. L International comparisons of mortality
rates for cancer of the breast, ovary, prostrate, and colon, and per capita food
consumption. Cancer (Phila.), 58: 2363—2371, 1986.
8. Macquart-Moulin, G., Riboli, E., Cornee, J., Charnay, B., Berthezene, P., and Day, N.
Case-control study on colorectal cancer and diet in Marseilles. Int. J. Cancer, 38:
183-191, 1986.
9. Berta, J. L., Coste, T., Rautureau, J., Guilloud-Bataille, M., and Pequignot, G. Diet
and rectocolonic cancers. Results of a case-control study. Gastroenterol. Clin. Biol.,
9: 348—353,1985.
10. Tuyns, A. J., Haelterman, M., and Kaaks, R. Colorectal cancer and the intake of
nutrients: oligosaccharides are a risk factor, fats are not. A case-control study in
Belgium. Nutr. Cancer, 10: 181—196,
1987.
11. Benito, E., Stiggelbout, A., Bosch, F. X., Obrador, A., Kaldor, J., Mulct, M., and
Munoz, N. Nutritional factors in colorectal cancer risk: a case-control study in
Majorca. tnt. J. Cancer, 49: 161—167,1991.
12. Meyer, F., and White, E. Alcohol and nutrients in relation to colon cancer in
middle-aged adults. Am. J. Epidemiol., 138: 225—236,1993.
13. Jam, M., Cook, G. M., Davis, F. G., Grace, M. G., Howe, G. R., and Miller, A. B. A
36. Willett, W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A., and Speizer, F. E.
Relation of meat, fat, and fiber intake to the risk ofcolon cancer in a prospective study
among women. N. Engl. J. Med., 323: 1664—1672, 1990.
37. Goldbohm, R. A., van den Brandt, P. A., vant't Veer, P., Brains, H. A. M., Dorant,
E., Stunnans, F., and Hermus, R. J. J. A prospective cohort study on the relation
between meat consumption and the risk of colon cancer. Cancer Rca., 54: 718—723,
1994.
38. Burkitt, D. P. Epidemiology of cancer of the colon and rectum. Cancer (Phila.), 28:
3—13,1971.
39. Modan, B., Barell, V., Lubin, F., Modan, M., and Greenberg,
as an etiology factor in cancer of the colon. J. Natl. Cancer
40. Dales, L C., Friedman, G. D., Ury, H. K., Grossman, S.,
case-control study of relationships of diet and other traits
American blacks. Am. J. Epidemiol., 109: 132—144,
1979.
41. Heilbrun, L K, Nomura, A., Hankin, J. H., and Stemmermaim, G. N. Diet and
colorectal cancer with special reference to fiber intake. mt. J. Cancer, 44: 1—6,
1989.
42. Giovannucci, E., Stampfer, M. J., Colditz, G., Rimm, E. B., and Willett, W. C.
Relationship of diet to risk of colorectal adenoma in men. J. Nail. Cancer Inst., 84:
91—98,1992.
43. Rimm, E. B., Giovannucci, E., Willett, W. C., Colditz, G. A., Ascherio, A., Rosner,
B., and Stampfer, M. J. Prospective study of alcohol consumption and risk of
coronary disease in men. Lancet, 338: 464—468,1991.
44. Rimm, E. B., Stampfer, M. J., Colditz, G. A., Giovannucci, E., and Willett, W. C.
Effectiveness of various mailing strategies among nonrespondents in a prospective
cohort study. Am. J. Epidemiol., 131: 1068—1071,1990.
case-control study of diet and cob-rectal cancer. Int. J. Cancer, 26: 757—768,
1980.
14. Potter, J. D., and McMichael, A. J. Diet and cancer of the colon and rectum: a
case-controlstudy.J. Nat].CancerInst.,76:557—569,
1986.
15. Lyon, J. L, Mahoney, A. W., West, D. W., Gardner, K. R., Smith, A. W., Sorenson,
A. W., and Stanish, W. Energy intake: its relationship to colon cancer risk. J. Nail.
Cancer Inst., 78: 853—861,1987.
16. Graham, S., Marshall, J., Haughey, B., Mittleman, M., Swanson, M., Zielezny, M.,
Byes, T., Wilkinson, G., and West, D. Dietary epidemiology of cancer of the colon
in Western New York. Am. J. Epidemiol., 128: 490—503, 1988.
17. Bristol, J. B., Emmett, P. M., Heaton, K. W., and Williamson, R. C. Sugar, fat, and
the risk of colorectal cancer. Br. Med. J., 291: 1467—1470,1985.
18. Kune, G. A., and Kune, S. The nutritional causes ofcolorectal cancer: an introduction
to the Melbourne study. Nutr. Cancer, 9: 1—4,1987.
19. West, D. W., Slattery, M. L., Robison, L. M., Schuman, K. L., Ford, M. H., Mahoney,
A. W., Lyon, J. L., and Sorensen, A. W. Dietary intake and colon cancer: sex and
anatomic site-specific associations. Am. J. Epidemiol., 130: 883—894, 1989.
20. Whittemore, A. F., Wu-Williams, A. H., Lee, M., et aL Diet, physical activity and
colorectal cancer among Chinese in North America and China. J. NatI. Cancer Inst.,
82: 915—926,1990.
21 . Peters, R. K., Pike, M. C., Garabrandt, D., and Mack, T. M. Diet and colon cancer in
Los Angeles County, Califomia. Cancer Causes Control, 3: 457—473, 1992.
22. Manousos, 0., Day, N. E., Trichopoulos, D., Gerovassilis, F., Tzonou, A., and
Polychronopoulou, A. Diet and colorectal cancer: a case-control study in Greece. Int.
J. Cancer, 32: 1—5,1983.
23. La Vecchia, C., Negri, E., DeCarli, A., D'Avanzo, B., Gailotti, L, Gentile, A., and
Franceschi, S. A case-control study of diet and colorectal cancer in Northern Italy. tat.
J. Cancer, 41: 492—498,1988.
24. Miller, A. B., Howe, G. R., Jam, M., Craib, K. J. P., and Harrison, L Food items and
food groups as risk factors in a case-control study of diet and colorectal cancer. Int.
J.Cancer,32: 155—161,
1983.
25. Young, T. B., and Wolf, T. B. Case-control study of proximal and distal colon cancer
and diet in Wisconsin. Int. J. Cancer, 42: 167—175,1988.
26. Benito, E., Obrador, A., Stiggelbout, A., Bosch, F. X., Mulct, M., Munoz, N., and
Kaldor, J. A population-based case-control study of colorectal cancer in Majorca. mt.
J. Cancer, 45: 69—76,1990.
27. Lee, H. P., Gourley, L., Duffy, S. W., Esteve, J., Lee, J., and Day, N. E. Colorectal
45. Willett, W. C., Sampson, L., Stampfer, M. J., Rosner, B., Bain, C., Witschi, J.,
Hennekens, C. H., and Speizer, F. E. Reproducibility and validity of a semiquanti
tative food frequency questionnaire. Am. J. Epidemiol., 122: 51—65,1985.
46. Willeu, W. C., Sampson, L, Browne, M. L, Stampfer, M. J., Rosner, B., Hennekens,
C. H., and Speizer, F. E. The use of a self-administered questionnaire to assess diet
four years in the past. Am. J. Epidemiol., 127: 188—199,1988.
47. U.S. Dept. of Agriculture. Agricultural Handbook No. 8 Series. Composition of
foods—raw,processed, and prepared. Washington, DC: U.S. Government Printing
Office, 1963-1988.
48. Paul, A. A., and Southgate, D. A. McCance and Widdowson's The Composition of
Foods, Ed. 4, revised. London: Her Majesty's Stationery Office, 1979.
49. Southgate, D. A., Bailey, B., Collinson, E., and Walker, A. F. A guide to calculating
intakes of dietary fiber. J. Hum. Nutr., 30: 303—313,1976.
50. Willett, W. C., and Stampfer, M. J. Total energy intake: implications for epidemio
logic analyses. Am. J. Epidemiol., 124: 17—27,
1986.
51. Rimm, E B., Giovannucci, E. L, Stampfer, M. J., Colditz, G. A., Litin, L B., and
Willeti, W. C. Reproducibility and validity of an expanded self-administered semi
quantitative food frequency questionnaire
Epidemiol., 135: 1114—1126, 1992.
among male health professionals. Am. I.
52. Stampfer, M. J., Willett, W. C., Speizer, F. E., et al. Test of the National Death Index.
Am. J. Epidemiol., 119: 837—839, 1984.
53. Rothman, K. J. Modern Epidemiology. Boston: Little, Brown and Company, 1986.
54. Miettinen, 0. Estimability and estimation in case-referent studies. Am. J. Epidemiol.,
103: 226—235,1976.
55. Cox, D. R., and Oakes, D. Analysis of Survival Data. London: Chapman & Hall,
1984.
56. Department
of Health and Human Services. Report of the Surgeon General on
nutrition and health. Washington, DC: National Academy Press, 1989.
57. National Research Council, Committee on Diet and Health. Diet and health: impli
cations for reducing chronic disease risk. Washington, DC: National Academy Press,
1989.
58. Giovannucci, E., Rimm, E. B., Stampfer, M. J., Colditz, G. A., Ascherio, A., Kearney,
J., and Willett, W. C. A prospective study of cigarette smoking and risk of colorectal
adenoma and colorectal cancer in U. S. men. J. Nail. Cancer Inst., 86: 183—191,
1994.
cancer and diet in an Asian population: a case-control study among Singapore
Chinese. mt. J. Cancer, 43: 1007—1016,
1989.
28. Gerhardsson
R. A. Low fiber intake
Inst., 55: 15—18,1975.
and Williams, S. R. A
to colorectal cancer in
de Verdier, M., Hagman, U., Peters, R. K., and Steineck, G. Meat,
59. Giovannucci, E., Colditz, G. A., Stampfer, M. J., Hunter, D., Rosner, B. A., Willett,
W. C., and Speizer, F. E. A prospective study of cigarette smoking and risk of
colorectal adenoma and colorectal cancer in U. S. women. J. Nail. Cancer Inst., 86:
cooking methods and colorectal cancer: a case-referent study in Stockholm. mt. J.
Cancer, 49: 520—525, 1991.
29. Willett, W., and Stampfer, M. J. Total energy intake: implications for epidemiologic
analyses. Am. J. Epidemiol., 124: 17—27,1986.
30. Bjelke, E. Epidemiology of colorectal cancer, with emphasis on diet. in: W. Davis, K.
R. Harrup, and G. Stathopoulos (eds.), Human Cancer. Its Characterization and
192—199,
1994.
60. Friedman, E., Isaksson, P., Rafter, J., Marian, B., Winawer, S., and Newmark, H.
Fecal diglycerides as selective endogenous mitogens for premalignant and malignant
human colonic epithelial cells. Cancer Res., 49: 544—554, 1989.
61. Youngman, L. D., and Campbell, T. C. The sustained development of preneoplastic
lesions depends on high protein intake. Nutr. Cancer, 18: 131—142,1992.
2396
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
MEAT, FAT, FIBER, AND COLON CANCER
62. Neugut, A. I., Garbowski, 0. C., Lee, W. C., Murray, T., Nieves, J. W., Forde, K. A.,
Treat, M. R., Waye, J. D., and Fenoglio-Preiser, C. Dietary risk factors for the
incidence and recurrence of colorectal adenomatous polyps. A case-control study.
Ann. Intern. Med., 11: 91—95,1993.
63. Kato, I., Tominaga, S., Matsuura, A., Yoshi, Y., Shirai, M., and Kobayashi, S. A
comparative case-control study ofcolorectal cancer and adenoma. Jpn. J. Cancer Res.,
81:1101—1108,
1990.
64. Little, J., Logan, R. F. A., Hawtin, P. G., Hardcastle,
J. D., and Turner, I. D.
Colorectal adenomas and diet: a case-control study of subjects participating in the
Nottingham faecal occult blood screening programme. Br. J. Cancer, 67: 177—184,
1993.
65. SandIer,R. S., Lyles,C. M., Peipins,L A., McAuliffe,C. A., Woosley,J. T., and
Kupper, L. L Diet and the risk of colorectal adenomas: macronutrients, cholesterol
and fiber. J. NatL Cancer Inst., 85: 875—884, 1993.
66. Giovannucci, E., Stampfer, M. J., Colditz, 0. A., Rimm, E. B., Trichopoulos, D.,
Rosner, B. A., Speizer, F. E., and Willett, W. C. Folate, methionine, and alcohol
intake and risk of colorectal adenoma. J. Nail. Cancer Inst., 85: 875—884,1993.
67. Babbs,C. F. Freeradicalsandtheetiologyof coloncancer.FreeRad.Biol.Med.,8:
191—200,
1990.
68. Younes, M., Trepkau, H. D., and Sieges, C. P. Enhancement of dietary iron
peroxidation in mouse colon. Rca. Commun. Chem. Pathol. Pharmacol., 70: 349—
354, 1990.
69. Sieges, C. P., Bumann, D., Baretton, G., and Younes, M. Dietary iron enhances the
tumor rate in dimethyihydrazine-induced colon carcinogenesis in mice. Cancer LeU,
41:251—256,
1988.
70. Nelson, R. L, Yoo, S. J., Tanure, J. C., Andrianpoulos, G., and Misumi, A. The effect
of iron on experimental colorectal carcinogenesis. Anticancer Res., 9: 1477—1482,
1989.
71. Ames, B. N. Dietary carcinogens and anticarcinogens. Oxygen radicals and degen
erative diseases. Science (Washington DC), 221: 1256—1264, 1983.
72. Zhang, X. M., Stamp, D., Minkin, S., Medline, A., Corpet, D. E., Bruce, W. R., and
Archer, M. C. Promotion of aberrant crypt foci and cancer in rat colon by thermolyzed
protein. J. Nail. Cancer Inst., 84: 1026—1030, 1992.
73. Suzuki, K., and Mitsuoka, T. Increase in faecal nitrosamines in Japanese individuals
given a Western diet. Nature (Lond.), 294: 453—456, 1981.
74. Hill, M. J., and Drasar, B. S. Bacteria and the aetiology of human cancer. Br. J.
Cancer, 28: 94, 1973.
75. Diet, Nutrition and Cancer Prevention: A Guide to Food Choices. NIH Publ. No.
(NCI) 85—2711,1984.
76. Lanza, E., Jones, D. Y., Block, G., and Kessler, L Dietary fiber intake in the U.S.
population. Am. J. Clin. Nuts., 46: 790—797,1987.
77. Trock, B., Lanza, E., and Greenwald, P. Dietary fiber, vegetables, and colon cancer:
criticalreviewandmeta-analyses
oftheepidemiologic
evidence.J. Natl.CancerInst.,
82: 650—661, 1990.
78. Steinmetz, K. A., Kushi, L. H., Bostick, R. M., Folsom, A. R., and Potter, J. D.
Vegetables, fruit, and colon cancer in the Iowa Women's Study. Am. J. Epidemiol.,
139: 1—15,1994.
79. Steinmetz, K. A., and Potter, J. D. Vegetables, fruit, and cancer. II. Mechanisms.
Cancer Causes Control, 2:427-442,1991.
80. Silverberg, E., Boring, C., and Squires, T. S. Cancer statistics. CA Cancer J. Clin., 40:
9—26,1990.
2397
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.
Intake of Fat, Meat, and Fiber in Relation to Risk of Colon
Cancer in Men
Edward Giovannucci, Eric B. Rimm, Meir J. Stampfer, et al.
Cancer Res 1994;54:2390-2397.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/54/9/2390
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.