Hindawi Publishing Corporation

Journal of Oncology
Volume 2013, Article ID 703854, 14 pages
http://dx.doi.org/10.1155/2013/703854

Review Article
Subsite-Specific Dietary Risk Factors for Colorectal Cancer:
A Review of Cohort Studies
Anette Hjartker,1 Bjarte Aagnes,2 Trude Eid Robsahm,2 Hilde Langseth,2
Freddie Bray,3 and Inger Kristin Larsen4
1

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046 Blindern, 0317 Oslo, Norway
Department of Etiological Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, 0304 Oslo, Norway
3
Section of Cancer Information, International Agency for Research on Cancer, 69372 Lyon, France
4
Department of Registration, Cancer Registry of Norway, Institute of Population-Based Cancer Research, 0304 Oslo, Norway
2

Correspondence should be addressed to Anette Hjartaker; anette.hjartaker@medisin.uio.no

Received 11 October 2012; Accepted 30 November 2012
Academic Editor: Anne-Kathrin Illner
Copyright 2013 Anette Hjartaker et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Objective. A shift in the total incidence from left- to right-sided colon cancer has been reported and raises the question as to whether
lifestyle risk factors are responsible for the changing subsite distribution of colon cancer. The present study provides a review of the
subsite-specific risk estimates for the dietary components presently regarded as convincing or probable risk factors for colorectal
cancer: red meat, processed meat, fiber, garlic, milk, calcium, and alcohol. Methods. Studies were identified by searching PubMed
through October 8, 2012 and by reviewing reference lists. Thirty-two prospective cohort studies are included, and the estimates are
compared by sex for each risk factor. Results. For alcohol, there seems to be a stronger association with rectal cancer than with colon
cancer, and for meat a somewhat stronger association with distal colon and rectal cancer, relative to proximal colon cancer. For fiber,
milk, and calcium, there were only minor differences in relative risk across subsites. No statement could be given regarding garlic.
Overall, many of the subsite-specific risk estimates were nonsignificant, irrespective of exposure. Conclusion. For some dietary
components the associations with risk of cancer of the rectum and distal colon appear stronger than for proximal colon, but not
for all.

1. Introduction
Global estimates for 2008 indicate that colorectal cancer is
the third most common cancer in the world [1]. Reports in
several countries have described diverging incidence rates in
colorectal cancer by subsite, including, in relative terms, an
increasing proportion of proximal tumors [215], and thus
a shift in absolute incidence from left- to right-sided colon
cancers.
The reasons for this trend are not well understood; the
subsites differ in physical function, artery supply, histology,
and innervation, and they also derive from different segments
in the primitive intestinal tract in the embryo [16]. The
proximal colon originates from the midgut, whereas the distal
colon and the rectum derivate originate from the hindgut.

Comparisons have also shown that proximal colon tumors

tend to have different molecular characteristics, with a higher
proportion of microsatellite instability, and are more likely to
have CpG island methylator phenotype and Ki-ras mutations
than distal colon and rectal tumors [17].
It has been estimated that 45 percent of all colorectal
cancer cases can be prevented in high-risk populations
through modifications of diet, physical activity habits, and
weight control [18]. According to the recent report from
the World Cancer Research Fund/American Institute for
Cancer Research (WCRF/AICR), there is convincing evidence that dietary fiber protects against colorectal cancer
and that red and processed meat and alcohol (particularly
in men) increase the risk of the disease [19]. Further, it
is stated that garlic, milk, and calcium probably protect

Journal of Oncology
Table 1: Search results as of October 8, 2012.

1
2
3
4
5
6
7
8
9
10
11
12
13
14

Queries
Search colorectal neoplasms
Search risk factors
Search diet
Search nutrition
Search alcohol
Search cohort study
Search 3 OR 4 OR 5
Search 2 AND 7
Search 1 AND 8
Search 6 AND 9
Search case control study
Search review
Search 10 NOT 11 NOT 12
Search 13 Limits: Human, English

Result
148374
745969
332911
259739
718622
1253216
1215492
81363
2099
627
622385
2082039
356
341

against colorectal cancer. No distinction is, however, made for

the different subsites of the colorectum [19]. Also, although
meta- [2023] and pooled analyses [2426] have provided
quantitative synthesis for several of the dietary risk factors,
little emphasis has been placed on subsite risks.
Based on the biological differences in the colorectal
segments and the reported differences in incidence, we may
suggest differences across the segments in their association
to lifestyle factors, such as diet. The aim of the present paper
is to give an updated overview summarizing the etiological
differences between the colorectal subsites with regard to the
dietary factors considered to be convincing or probable risk
factors for colorectal cancer.

2. Material and Methods

The specific risk factors studied were red meat, processed
meat, fiber, garlic, milk, calcium, and alcohol, selected given
an a priori assessment of their importance in colorectal
cancer etiology following the WCRF/AICR report in 2011
[19], and for which their modification could lead to a
reduction in rates of colorectal cancer. The outcome was the
risk of primary colorectal cancer according to subsite.
A search for cohort studies published as original articles was conducted via a search of PubMed (http://www
.ncbi.nlm.nih.gov/), using a search strategy that combined
the term colorectal neoplasms with the terms risk factors
and cohort study with either the term diet, nutrition,
or alcohol. The search was restricted to studies published
or available online as of October 8, 2012, in the English
language. A detailed description of the search strategy and
the resulting papers retrieved is given in Table 1, and the
procedure is described in Figure 1. A total of 341 articles were
identified and reviewed according to title and abstract. The
initial evaluation yielded 108 articles in the study database
and underwent a second evaluation based on full-text review.
A similar PubMed search for case-control studies nested
within a cohort identified 46 articles, of which one underwent
full-text review. In addition, further 62 articles were identified

by scanning the reference lists of retrieved articles, reviews,

meta-, and pooled analyses and underwent full-text review
(Figure 1).
Studies were included if they provided risk estimates (and
corresponding confidence intervals) for both proximal and
distal colon cancer. Proximal colon (right sided) includes
ceacum, ascending and transverse colon, while distal colon
(left-sided) includes descending colon, sigmoid flexure, and
sigmoideum. Some studies have not followed the abovementioned classification [2729], and this is specified in
Table 2. Further, to be included, the cohorts had to be
either population based, registry based, or obtained from
censuses. Studies on specific subpopulations (e.g., hospitalbased cohorts) were not included nor were studies examining
second cancers, metastasis, survival, or mortality. Following
the full-text evaluation, 139 articles were excluded for the
reasons indicated in Figure 1, and 32 articles were included
in the review. Of these, seven gave data on (red) meat [30
36], five on processed meat [3135], eight on fiber [3744],
one on garlic [37], three on milk [4547], seven on calcium
[28, 45, 4751], and ten on alcohol [27, 29, 36, 5258].
The number adds up to more than 32 as several papers
give data for more than one risk factor. If several papers on
the same risk factor were published for a given cohort, all data
was retrieved from the most recent paper. The relative risk
(RR), hazard rate ratio (HRR), hazard ratio (HR), incidence
rate ratio (IRR) or odds ratio (OR), and corresponding
95% confidence intervals (95% CI) for each risk factor are
presented (as RR) in Figures 28, sorted in ascending order
of magnitude by sex. For one study the risk estimates were
tabulated according to the lowest versus highest exposure
category in the original paper [28] and are presented as the
inverse of the value in the corresponding figure (Figure 7).
Meta-analyses were not performed as a consequence of
the heterogeneity in factors such as exposure measurement,
the categorization of risk factor levels, and the confounders
adjusted for in the studies [59].

3. Results
Overall, data from 21 cohorts with information on one or
more of the risk factors were included in this review. Table 2
gives a detailed description of the studies, with information
on cohort size, number of cases, sex, age distribution, followup time, and factors adjusted for in the risk analyses. The
European Prospective Investigation into Cancer and Nutrition (EPIC) study consists of subcohorts from 10 European
countries. The other cohorts were from the USA (10 cohorts),
Sweden (2), Denmark (2), Japan (3), Korea (1), UK (1), and
the Netherlands (1). The subsite-specific results (Figures 2
8) are described according to the individual risk factors, as
presented in the following.
3.1. Red Meat. Seven cohort studies were included in the
review, of which five reported on red meat [3033, 35], one on
beef and pork [34], and one on meat (not further specified)
[36]. The five studies on red meat reported an increased risk of
colorectal cancer with increasing intake [3033, 35] (Table 2),

Journal of Oncology

341 publications were identified from the literature search

Limited to prospective cohort studies on humans, in English,
published before October 8, 2012

46 publications
identified from
additional search

62 publications
included from
other sources

45 publications
excluded after
title and
abstract review

233 publications
excluded after title and
abstract review

1 publication

108 publications

171 publications full-text reviewed

Number of
publications:
(139 total)
(76)
(26)
(2)
(5)
(6)

Reasons for exclusion after full-text review

no analyses/risk estimates by colonic subsites
not a relevant risk factor
data on mortality or survival only
outcome adenomas
updated data available
Not an appropriate design:

(1)
(5)
(2)
(16)

reviews
meta-analysis or pooled analysis
randomised trials
case-control studies

32 publications included in the review

Figure 1: Flow diagram of the study selection.

although most of the risk estimates were not statistically different from unity. In Figure 2, there appears to be somewhat
more consistency with the observation of an increased risk
of cancers of the rectum and distal colon than there is for
proximal colon cancer. This picture remains when restricting
the evaluation to studies with adequate statistical power. In a
Swedish study, women consuming 94 or more grams of red
meat per day had an increased risk of distal colon cancer
of 2.22 (95% CI 1.343.68) compared to women consuming
less than 50 grams/day, and there was a significant trend
of increasing risk with increasing consumption (trend <
0.001) [32]. A long-term high intake of red meat yielded

an increased risk of rectal cancer of 43% (95% CI 1.00

2.05) relative to low intake in a US study [31], whereas in
another US study there was a significant trend of increased
risk of both proximal colon, distal colon and rectal cancer
with increasing consumption of red meat (including both
processed and nonprocessed red meat) (for all trend = 0.02)
[35].
Neither beef consumption nor pork consumption was
significantly associated with risk of cancer of any colorectal
subsite in a Japanese study [34], while the frequency of meat
consumption (not further specified) was positively associated
with proximal and distal colon cancer in South Korean men,

Cases

Garlic

Fiber/
whole
grain

61433

88757

Larsson et al., [39]

Fuchs et al., [38]

41837

41837

489611

Schatzkin et al.,
[41]

Steinmetz et al.,
[37]
Steinmetz et al.,
[37]

85903 M
105108 F

158800

Nomura et al., [40]

Kabat et al., [42]

Egeberg et al., [43]

142250 M
335062 F
26630 M
29189 F

478040

Norat et al., [33]

Murphy et al., [44]

733 CRC, 234 PC, 155 DC, 230 RC

61433

F
F

212 CC, 86 PC, 120 DC

787 CRC, 281 PC, 255 DC, 143 RC

212 CC, 86 PC, 120 DC

805 CRC, 249 PC, 170 DC, 252 RC

2974 CRC, 1139 PC, 914 DC, 858 RC

M: 1138 CRC, 382 PC, 327 DC, 276 RC

F: 972 CRC, 356 PC, 234 DC, 179 RC

M: 244 CC, 89 PC, 140 DC, 169 RC

F: 217 CC, 84 PC, 118 DC, 114 RC
1476 CRC, 798 PC, 351 DC, 303 RC

5569

5569

3459

4076

5071

4575

5079

5064

2570

3570

4075

5074

4064

5071

4075

3570

4075

5074

4064

B
B

5071

3080

Age

Sex

4517 CRC, 1298 PC, 1266 DC, 1648 RC

1329 CRC, 351 PC, 391 DC, 474 RC

1667 CRC, 667 PC, 408 DC, 470 RC

148610

474 CRC, 142 PC, 100 DC, 198 RC

41835

Sato et al., [34]

2719 CRC, 1150 PC, 787 DC, 724 RC

300948

1329 CRC, 351 PC, 391 DC, 474 RC

251 CRC, 69 PC, 89 DC, 46 RC

478040

Norat et al., [33]

733 CRC, 234 PC, 155 DC, 230 RC

47949

61433

Larsson et al., [32]

1667 CRC, 667 PC, 408 DC, 470 RC

Giovannucci et al.,
[30]
Cross et al., [35]

148610

869725 M M: 3051 CRC, 536 PC, 751 DC, 1535 RC

395501 F
F: 1093 CRC, 236 PC, 225 DC, 451 RC
300948
2719 CRC, 1150 PC, 787 DC, 724 RC
396/368 CRC, 123/115 PC, 85/75 DC,
41835
159/155 RC$

Cohort

Chao et al., [31]

Sato et al., [34]

Cross et al., [35]

Shin et al., [36]

Reference

Processed Chao et al., [31]

meat
Larsson et al., [32]

Red
meat

Exposure

16

14.8

7.3

7.8

10.6

11

4.8

13.9

8-9

11

7.2

4.8

13.9

8-9

11

7.2

The Miyagi Cohort Study, Japan

NIH-AARP Diet and Health Study, U.S.

Korean National Health System, Korea

MCS

NIH-AARP

KNHS

Abbreviation

1, 7

1, 7

The Iowa Womens Health Study, U.S.

The Iowa Womens Health Study, U.S.

IWHS

IWHS

The Cancer Prevention Study II Nutrition

CPS-II
Cohort, U.S.
The Swedish Mammography Cohort,
1, 3, 6, 7, 8, 12
SMC
Sweden
1, 2, 3, 4, 5, 6, 7, The European Prospective Investigation
EPIC
8, 14
into Cancer and Nutrition, Europe
1, 3, 4, 5, 8, 9, 10, The Health Professionals Follow-up Study,
HPFS
11, 14
U.S.
2, 3, 5, 6, 7, 12 NIH-AARP Diet and Health Study, U.S.
NIH-AARP
1, 2, 3, 4, 5, 6, 7,
The Miyagi Cohort Study, Japan
MCS
8, 11, 12
1, 2, 3, 4, 5, 6, 7, The Cancer Prevention Study II Nutrition
CPS-II
8, 10, 12, 13
Cohort, U.S.
The Swedish Mammography Cohort,
1, 3, 6, 7, 8, 12
SMC
Sweden
1, 2, 3, 4, 5, 6, The European Prospective Investigation
EPIC
7, 8, 14
into Cancer and Nutrition, Europe
1, 2, 3, 4, 5, 6, 7, The European Prospective Investigation
EPIC
8, 12, 13, 14
into Cancer and Nutrition, Europe
DDCHPC
1, 3, 4, 6, 8, 12, 13 The Danish Diet, Cancer and Health
Prospective Cohort study, Denmark
1, 3, 4, 5, 6, 7, 11,
The Womens Health Initiative, U.S.
WHI
12, 13, 14
MEC
1, 3, 4, 5, 6, 8, 9, The Multiethnic Cohort Study, Hawaii and
10, 11, 13, 14 Los Angeles, U.S.
2, 3, 4, 5, 6, 7, 8,
NIH-AARP Diet and Health Study, U.S.
NIH-AARP
11, 12, 13, 14
The Swedish Mammography Cohort,
1, 3, 6, 7, 12
SMC
Sweden
1, 3, 4, 5, 6, 7,
The Nurses Health Study, U.S.
NHS
8, 9, 10, 11

2, 3, 5, 6, 7, 12
1, 2, 3, 4, 5, 6, 7,
8, 11, 12
1, 2, 3, 4, 5, 6, 7,
8, 10, 12, 13

Follow-up,
Adjustments Study Cohort, Country or Continent
yr

Table 2: Characteristics of cohort studies included in the review on subsite specific dietary risk factors for colorectal cancer.

4
Journal of Oncology

60866

61463

87998 F
47344 M

Calcium McCullough et al.,

[45]

Terry et al., [48]

Wu et al., [49]

478732

29132

47931

106203

11644

Pedersen et al., [54]

Giovannucci et al.,
[53]

Klatsky et al., [27]

Wu et al., [52]

B
B

M: 58 CRC
F: 68 CRC

203 CC, 69 PC, 52 TDC, 77 SC, 66 RC

205 CC, 69 PC, 89 DC, 46 RC

613 CRC, 159 PC, 202 DC, 202 RC

1833 CRC, 476 PC, 528 DC, 649 RC

4075

2395

4.5

14.7

6.2

11

3570

13.3

5569

12

1922

4064

2684

3080

5569

41836
1255 CRC, 633 PC, 594 DCR
F
869725 M M: 3051 CRC, 536 PC, 751 DC, 1535 RC
B
395501 F
F: 1093 CRC, 236 PC, 225 DC, 451 RC
M: 241 CRC, 78 PC, 65 DC, 81 RC
153000
B
F: 217 CRC, 76 PC, 54 DC, 69 RC
M: 881 CRC, 240 PC, 293 DC, 232 RC
4118
B
F: 622 CRC, 254 PC, 189 DC, 108 RC
21199
307 CRC, 78 PC, 78 DC, 131 RC
M

Ferrari et al., [56]

Bongaerts et al.,
[57]
Akhter et al., [55]

Park et al., [58]

Shin et al., [36]

4668

277 CRC, 43 PC, 33 TDC, 113 SC, 88 RC M

421 CRC, 124 PC, 103 DC, 119 RC

482 CRC, 172 PC, 112 DC, 74 RC

449 CRC, 124 PC, 131 DC, 173 RC

464 CRC, 129 PC, 183 DC, 146 RC

Age

Japan Hawaii Cancer Study, Japan

Korean National Health System, Korea

1, 3, 4, 5, 6, 7, 12,
UK Dietary Cohort Consortium, UK
14
The Netherlands Cohort study, The
1, 2, 3, 4, 6, 7, 11
Netherlands
1, 3, 4, 5, 6, 11, 12 The Miyagi Cohort study, Japan
The European Prospective Investigation
1, 2, 3, 4, 5, 7, 12
into Cancer and Nutrition, Europe
The Copenhagen Centre for Prospective
1, 2, 5, 14
Population Studies, Denmark
1, 3, 4, 5, 6, 7, 9, The Health Professionals Follow-up Study,
10, 11, 14
U.S.
Northern California Kaiser Permanente
1, 2, 5, 6, 12, 14
Study, U.S.
Retirement Community of Los Angeles,
1
U.S.

1, 3, 4, 5, 6, 7, 13 The Iowa Womens Health study, U.S.

RCLA

NCKPS

HPFS

CCPPS

EPIC

MCS

NLCS

UKDCC

IWHS
KNHS

JHCS

Follow-up,
Adjustments Study Cohort, Country or Continent
Abbreviation
yr
1, 3, 4, 5, 6, 7, 8,
M 4579
6.7
The Cohort of Swedish Men, Sweden
COSM
10, 11, 12, 14
The Swedish Mammography Cohort,
F 4076
14.8
1, 3, 6, 7, 12
SMC
Sweden
1, 3, 4, 5, 6, 7, 11, The Cancer Prevention Study II Nutrition
M 5074
4-5
CPS-II
12
Cohort, U.S.
1, 3, 4, 5, 6, 7, 8, The Japan Public Health Center-based
M 4574
7.8
JPHC
14
Prospective Study, Japan
1, 3, 4, 5, 6, 7, 8,
M 4579
6.7
The Cohort of Swedish Men, Sweden
COSM
10, 11, 12, 14
61.9
The Breast Cancer Detection
F
8.5
1, 7
BCDDP
(mean)
Demonstration Project, U.S.
1, 3, 4, 5, 6, 7, 11, The Cancer Prevention Study II Nutrition
M 5074
4-5
CPS-II
12
Cohort, U.S.
The Swedish Mammography Cohort,
F 3975
11.3
1, 3, 6, 7, 8, 12
SMC
Sweden
3055 F
16
1, 3, 4, 5, 6, 8, 10, The Nurses Health Study, U.S. and The
NHS &
B
4075 M
10
11, 13, 14
Health Professionals Follow-up Study, U.S.
HPFS

Sex

M: male, F: female, B: both sexes, CRC: colorectal cancer, PC: proximal colon cancer, DC: distal colon cancer, RC: rectal cancer, DCR: distal colorectal cancer, TDC: transverse and descending colon cancer, SC:
sigmoid colon cancer. The numbers come, all or partly, from tables, and may thus not include all cases in the cohort. Subcohort. The risk estimates are adjusted for: 1: age, 2: sex, 3: BMI, 4: physical activity, 5:
smoking, 6: dietary items, 7: energy intake, 8: alcohol intake, 9: history of polyps, 10: NSAIDS/aspirin, 11: family history of CRC, 12: education, 13: hormone replacement therapy or oral contraceptive use, 14: others.
$
The numbers vary according to the exposure analyzed.

Alcohol

45354

Flood et al., [50]

8006

1025 CC, 426 PC, 411 DC

45306

Larsson et al., [47]

Stemmermann et
al., [28]
Razzak et al., [29]

572 CRC, 164 PC, 121 DC, 191 RC

35194

Ishihara et al., [51]

421 CRC, 124 PC, 103 DC, 119 RC

60866

798 CRC, 246 PC, 170 DC, 249 RC

449 CRC, 124 PC, 131 DC, 173 RC

McCullough et al.,
[45]

45306

Larsson et al., [47]

Cases

60708

Cohort

Reference

Larsson et al., [46]

Milk

Exposure

Table 2: Continued.

Journal of Oncology
5

Journal of Oncology

Cohort
Referenc e
Proximal
MCS
Sato, 2006 [34]
CPS-II
Chao, 2005 [31]
MCS
Sato, 2006 [34]
NIP-AARP
Cross, 2010 [35]
EPIC
Norat, 2005 [33]
SMC
Larsson, 2005 [32]
KNHS
Shin, 2011 [36]
HPFS
Giovannucci, 1994 [30]
KNHS
Shin, 2011 [36]
Distal
EPIC
Norat, 2005 [33]
CPS-II
Chao, 2005 [31]
NIP-AARP
Cross, 2010 [35]
MCS
Sato, 2006 [34]
MCS
Sato, 2006 [34]
KNHS
Shin, 2011 [36]
SMC
Larsson, 2005 [32]
KNHS
Shin, 2011 [36]
HPFS
Giovannucci, 1994 [30]
Rectal
MCS
Sato, 2006 [34]
MCS
Sato, 2006 [34]
EPIC
Norat, 2005 [33]
NIP-AARP
Cross, 2010 [35]
CPS-II
Chao, 2005 [31]
SMC
Larsson, 2005 [32]
KNHS
Shin, 2011 [36]
KNHS
Shin, 2011 [36]
HPFS
Giovannucci, 1994 [30]

Age

Exposure

RR (95% CI)

4064
5074
4064
5071
3570
4075
3080
4075
3080

1-2 times/week versus almost never (beef)

Longtime high versus low (red meat)
3-4 times/week versus almost never (pork (without ham and sausage))
Quin. median 61.6 versus 9.5 g/1000 kcal (non-/processed red meat)
80 versus <10 g/day (red meat)
94 versus <50 g/day (red meat)
4 times versus 1 time/week (meat unspecified)
Quin. median 129.5 versus 18.5 g/d (red meat)
4 times versus 1 time/week (meat unspecified)

0.97 (0.55, 1.70)

1.02 (0.77, 1.36)
1.05 (0.50, 2.22)
1.15 (0.94, 1.41)
1.18 (0.73, 1.91)
1.03 (0.67, 1.60)
1.70 (1.10, 2.70)
0.87 (0.43, 1.76)
1.40 (1.00, 1.90)

3570
5074
5071
4064
4064
3080
4075
3080
4075

80 versus <10 g/day ((red meat)

Longtime high versus low (red meat)
Quin. median 61.6 versus 9.5 g/1000 kcal (non-/processed red meat)
1-2 times/week versus almost never (beef)
(
3-4 times/week versus almost never (pork (without ham and sausage))
4 times versus 1 time/week (meat unspecified)
94 versus <50 g/day ((red meat)
4 times versus <1 time/week (meat unspecified)
meat)
Quin. median 129.5 versus 18.5 g/day (red
(

1.24 (0.80, 1.94)

1.29 (0.88, 1.89)
1.29 (1.00, 1.66)
1.06 (0.46, 2.43)
1.90 (0.63, 5.74)
1.30 (0.70, 2.10)
2.22 (1.34, 3.68)
1.30 (1.00, 1.70)
1.78 (0.97, 3.25)

4064
4064
3570
5071
5074
4075
3080
3080
4075

3-4 times/week versus almost never (pork (without ham and sausage))
1-2 times/week versus almost never (beef)
(
80 versus <10 g/day ((red meat)
Quin. median 61.6 versus 9.5 g/1000 kcal (non-/processed red meat)
Longtime high versus low (red meat)
94 versus <50 g/day ((red meat)
4 times versus 1 time/week (meat unspecified)
4 times versus 1 time/week (meat unspecified)
Quin. median 129.5 versus 18.5 g/day (red
(
meat)

0.74 (0.39, 1.42)

1.01 (0.62, 1.67)
1.13 (0.74, 1.71)
1.35 (1.03, 1.76)
1.43 (1.00, 2.05)
1.28 (0.83, 1.98)
1.40 (1.00, 1.90)
1.10 (0.90, 1.30)
1.22 (0.36, 4.14)

0.125

0.25

0.5

Figure 2: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of red meat. (The results are stratified
on sex. Open circles: both gender combined. Closed black circles: females. Closed grey circles: men. All estimates are sorted from the lowest
to the highest by subsite and sex.)

Cohort
Proximal
MCS
NIP-AARP
CPS-II
EPIC
SMC
Distal
MCS
NIP-AARP
EPIC
CPS-II
SMC
Rectal
MCS
CPS-II
NIP-AARP
EPIC
SMC

Reference

Age

Exposure

RR (95% CI)

Sato, 2006 [34]

Cross, 2010 [35]
Chao, 2005 [31]
Norat, 2005 [33]
Larsson, 2005 [32]

4064
5071
5074
3570
4075

3-4 times/week versus almost never (ham and sausage)

Quin. median 22.3 versus 1.6 g/1000 kcal (processed meat)
Longtime high versus low (processed meat)
80 versus <10 g/day (processed meat)
32 versus <12 g/day (processed meat)

0.69 (0.32, 1.51)

1.09 (0.89, 1.33)
1.14 (0.87, 1.50)
1.19 (0.70, 2.01)
1.02 (0.69, 1.52)

Sato, 2006 [34]

Cross, 2010 [35]
Norat, 2005 [33]
Chao, 2005 [31]
Larsson, 2005 [32]

4064
5071
3570
5074
4075

3-4 times/week versus almost never (ham and sausage)

Quin. median 22.3 versus 1.6 g/1000 kcal (processed meat)
80 versus <10 g/day (processed meat)
Longtime high versus low (processed meat)
32 versus <12 g/day (processed meat)

0.65 (0.28, 1.55)

1.10 (0.86, 1.41)
1.48 (0.87, 2.53)
1.50 (1.04, 2.17)
1.39 (0.86, 2.24)

Sato, 2006 [34]

Chao, 2005 [31]
Cross, 2010 [35]
Norat, 2005 [33]
Larsson, 2005 [32]

4064
5074
5071
3570
4075

3-4 times/week versus almost never (ham and sausage)

Longtime high versus low (processed meat)
Quin. median 22.3 versus 1.6 g/1000 kcal (processed meat)
80 versus <10 g/day (processed meat)
32 versus <12 g/day (processed meat)

1.10 (0.60, 2.03)

1.20 (0.87, 1.68)
1.30 (1.00, 1.68)
1.62 (1.04, 2.50)
0.90 (0.60, 1.34)

0.125 0.25

0.5

Figure 3: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of processed meat. (The results are
stratified on sex. Open circles: both gender combined. Closed black circles: females. All estimates are sorted from the lowest to the highest
by subsite and sex.)

and with proximal colon and rectal cancer in South Korean

women [36].
3.2. Processed Meat. Four studies have reported on processed meat [3133, 35] and one has reported on ham and
sausages [34] (Table 2). In the EPIC study, consumption of
80 grams or more of processed meat per day conferred

a 62% (95% CI 1.042.50) increased risk of rectal cancer

compared to an intake of less than 10 grams per day
[33], and in a US study a high long-term intake of processed meat was associated with a 50% (95% CI 1.04
2.17) increased risk of distal colon cancer [31] (Figure 3).
In a more recent American study, consuming 22.3 grams
or more of processed meat per 1000 kcal increased the risk

Journal of Oncology
Cohort
Proximal
EPIC
EPIC
NIH-AARP
SMC
NHS
IWHS
WHI
MEC
DDCHPC
MEC
Distal
EPIC
NIH-AARP
EPIC
SMC
IWHS
MEC
WHI
NHS
MEC
DDCHPC
Rectal
EPIC
EPIC
NIH-AARP
NHS
MEC
WHI
DDCHPC
SMC
MEC
DDCHPC

Reference

7
Age

Exposure

RR (95% CI)

Murphy, 2012 [44]

Murphy, 2012 [44]
Schatzkin, 2007 [41]
Larsson, 2005 [39]
Fuchs, 1999 [38]
Steinmetz, 1994 [37]
Kabat, 2008 [42]
Nomura, 2007 [40]
Egeberg, 2010 [43]
Nomura, 2007 [40]

2570
2570
5071
4076
3459
5569
5079
4575
5064
4575

Per 10 g/day increase (fiber)

28.5 versus <16.4 g/day (fiber)
Quin. median 15.9 versus 6.6 g/1000 kcal/day (fiber)
4.5 versus <1.5 serv/day (whole grain)
Quin. median 24.9 versus 9.8 g/day (fiber)
24.7 versus <14.5 g/day (fiber)
Quin. 21.2 versus <9.9 g/day (fiber)
Quin. median 18.6 versus 7.5 g/1000 kcal/day (fiber)
Per every 50 g increment/day (whole grain)
Quin. median 16.5 versus 6.1 g/1000 kcal/day (fiber)

0.83 (0.75, 0.92)

0.92 (0.71, 1.20)
0.93 (0.72, 1.18)
0.69 (0.40, 1.20)
1.00 (0.61, 1.61)
1.03 (0.48, 2.22)
1.20 (0.73, 1.95)
1.31 (0.86, 1.97)
0.78 (0.66, 0.92)
0.81 (0.54, 1.23)

Murphy, 2012 [44]

Schatzkin, 2007 [41]
Murphy, 2012 [44]
Larsson, 2005 [39]
Steinmetz, 1994 [37]
Nomura, 2007 [40]
Kabat, 2008 [42]
Fuchs, 1999 [38]
Nomura, 2007 [40]
Egeberg, 2010 [43]

2570
5071
2570
4076
5569
4575
5079
3459
4575
5064

28.5 versus <16.4 g/day (fiber)

Quin. median 15.9 versus 6.6 g/1000 kcal/day (fiber)
Per 10 g/day increase (fiber)
4.5 versus <1.5 serv/day (whole grain)
>24.7 versus <14.5 g/day (fiber)
Quin. median 18.6 versus 7.5 g/1000 kcal/day (fiber)
Quin. 21.2 versus <9.9 g/day (fiber)
Quin. median 24.9 versus 9.8 g/day (fiber)
Quin. median 16.5 versus 6.1 g/1000 kcal/day (fiber)
Per every 50 g increment/day (whole grain)

0.70 (0.53, 0.92)

0.97 (0.73, 1.28)
0.98 (0.88, 1.08)
0.54 (0.27, 1.08)
0.66 (0.34, 1.29)
0.69 (0.41, 1.17)
0.97 (0.46, 2.05)
1.08 (0.67, 1.72)
0.56 (0.35, 0.90)
0.90 (0.79, 1.02)

Murphy, 2012 [44]

Murphy, 2012 [44]
Schatzkin, 2007 [41]
Fuchs, 1999 [38]
Nomura, 2007 [40]
Kabat, 2008 [42]
Egeberg, 2010 [43]
Larsson, 2005 [39]
Nomura, 2007 [40]
Egeberg, 2010 [43]

2570
2570
5071
3459
4575
5079
5064
4076
4575
5064

Per 10 g/day increase (fiber)

28.5 versus <16.4 g/day (fiber)
Quin. median 15.9 versus 6.6 g/1000 kcal/day (fiber)
Quin. median 24.9 versus 9.8 g/day (fiber)
Quin. median 18.6 versus 7.5 g/1000 kcal/day (fiber)
Quin. 21.2 versus <9.9 g/day (fiber)
Per every 50 g increment/day (whole grain)
4.5 versus <1.5 serv/day (whole grain)
Quin. median 16.5 versus 6.1 g/1000 kcal/day (fiber)
Per every 50 g increment/day (whole grain)

0.87 (0.79, 0.96)

0.90 (0.72, 1.14)
1.13 (0.84, 1.51)
0.63 (0.37, 1.08)
0.82 (0.48, 1.43)
0.88 (0.39, 2.01)
1.02 (0.88, 1.19)
1.11 (0.67, 1.83)
0.52 (0.32, 0.84)
0.90 (0.80, 1.01)

0.125

0.25

0.5

Figure 4: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of fiber and whole grain. (The results are
stratified on sex. Open circles: both gender combined. Closed black circles: females. Closed grey circles: men. All estimates are sorted from
the lowest to the highest by subsite and sex.)

Cohort

Age

Exposure

RR (95% Cl)

Steinmetz, 1994 [37]

5569

1 versus 0
serv/day

1.00 (0.56, 1.79)

Steinmetz, 1994 [37]

5569

1 versus 0
serv/day

0.52 (0.30, 0.93)

Reference

Proximal
IWHS
Distal
IWHS

0.125

0.25

0.5

Figure 5: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of garlic. (Closed black circles: females.)

of rectal cancer with 30% (95% CI 1.001.68) compared to

consuming 1.6 gram or less per 1000 kcal [35]. No significant
associations were seen in Swedish [32] and Japanese studies
[34].
3.3. Fiber. Eight cohort studies were included in the review;
six have provided estimates for the risk of the colonic subsites
in relation to fiber consumption [37, 4042, 44] and two
have provided estimates for the whole grain consumption
[39, 43] (Table 2). As for fiber, most of the risk estimates were
not statistically different from unity [37, 41, 42] (Figure 4).
The EPIC study reported an inverse association between
fiber intake and colorectal cancer with no strong evidence of
different associations across the subsites: when fiber intake
was analyzed as a categorical variable, a significant inverse

association was seen for distal colon cancer only (trend =

0.02), whereas when fiber intake was analyzed as a continuous
variable and corrected for measurement errors, significant
inverse associations were seen for proximal colon (HR per
10 gram/day increase 0.83, 95% CI 0.750.92) and rectum
cancer (HR per 10 gram day/increase 0.87, 95% CI 0.790.96),
but not for distal colon cancer [44]. The Multiethnic Cohort
observed a reduced risk for distal colon and rectal cancer
among those in the highest compared to the lowest fiber
intake group, but the reduction was only significant in men
(RR 0.56, 95% CI 0.350.90 and RR 0.52, 95% CI 0.320.84,
resp.) [40].
Two Scandinavian papers have reported on associations between whole grain consumption and cancer risk of
colorectal subsites [39, 43]. In a Danish study, which is also

8
Cohort
Proximal
SMC
SMC
CPS-II
COSM
Distal
SMC
SMC
COSM
CPS-II
Rectal
SMC
SMC
COSM
CPS-II

Journal of Oncology
Reference

Age

Exposure

RR (95% CI)

Larsson, 2005 [46]

Larsson, 2005 [46]
McCullough, 2003 [45]
Larsson, 2006 [47]

4076
4076
5074
4579

1 serv/day versus never or seldom (full-fat cultured milk)

1 serv/day versus never or seldom (whole milk)
1.1 serv/day versus none (total milk)
1.5 glasses/day versus <2 glasses/week (total milk)

0.80 (0.56, 1.15)

1.58 (1.15, 2.16)
0.68 (0.42, 1.09)
0.76 (0.45, 1.30)

Larsson, 2005 [46]

Larsson, 2005 [46]
Larsson, 2006 [47]
McCullough, 2003 [45]

4076
4076
4579
5074

1 serv/day versus never or seldom (full-fat cultured milk)

1 serv/day versus never or seldom (whole milk)
1.5 glasses/day versus <2 glasses/week (total milk)
1.1 serv/day versus none (total milk)

0.71 (0.44, 1.13)

0.72 (0.47, 1.10)
0.53 (0.33, 0.87)
0.92 (0.54, 1.58)

Larsson, 2005 [46]

Larsson, 2005 [46]
Larsson, 2006 [47]
McCullough, 2003 [45]

4076
4076
4579
5074

1 serv/day versus never or seldom (full-fat cultured milk)

1 serv/day versus never or seldom (whole milk)
1.5 glasses/day versus <2 glasses/week (total milk)
1.1 serv/day versus none (total milk)

0.91 (0.62, 1.31)

0.99 (0.72, 1.37)
0.69 (0.45, 1.06)
0.89 (0.54, 1.47)

0.125 0.25 0.5

Figure 6: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of milk. (The results are stratified on
sex. Closed black circles: females. Closed grey circles: men. All estimates are sorted from the the lowest to the highest by subsite and sex.)
Cohort
Reference
Age
Proximal
NHS and HPFS
Wu, 2002 [49] 3055 (F), 4075 (M)
BCDDP
Flood, 2005 [50]
61.9 (mean)
BCDDP
Flood, 2005 [50]
61.9 (mean)
SMC
Terry, 2002 [48]
3975
NHS
Wu, 2002 [49]
3055
5074
CPS-II
McCullough, 2003 [45]
4579
COSM
Larsson, 2006 [47]
45 74
JPHC
Ishihara, 2008 [51]
50 74
CPS-II
McCullough, 2003 [45]
40 75
HPFS
Wu, 2002 [49]
4668
JHCS
Stemmermann, 1990 [28]
Distal
NHS and HPFS
Wu, 2002 [49] 30 55 (F), 4075 (M)
SMC
Terry, 2002 [48]
3975
BCDDP
Flood, 2005 [50]
61.9 (mean)
BCDDP
Flood, 2005 [50]
61.9 (mean)
NHS
Wu, 2002 [49]
30 55
HPFS
Wu, 2002 [49]
4075
JPHC
Ishihara, 2008 [51]
4574
COSM
Larsson, 2006 [47]
45 79
CPS-II
McCullough, 2003 [45]
5074
CPS-II
McCullough, 2003 [45]
5074
JHCS
Stemmermann, 1990 [28]
4668
Rectal
SMC
Terry, 2002 [48]
3975
61.9 (mean)
BCDDP
Flood, 2005 [50]
61.9 (mean)
BCDDP
Flood, 2005 [50]
COSM
Larsson, 2006 [47]
45 79
CPS-II
McCullough, 2003 [45]
5074
4574
JPHC
Ishihara, 2008 [51]
5074
CPS-II
McCullough, 2003 [45]

RR (95% CI)

Exposure
>1250 versus 500 mg/day (total calcium)
>830 versus <412 mg/day (dietary calcium)
>1270 versus <472 mg/day (total calcium)
Quart. median 914 versus 486 mg/day (dietary calcium)
>1250 versus 500 mg/day (total calcium)
>1255 versus <561 mg/day (total calcium)
1445 versus <956 mg/day (total calcium)
661 versus <337 mg/day (dietary calcium)
988 versus <504 mg/day (dietary calcium)
>1250 versus 500 mg/day (total calcium)
Low versus high (dietary calcium)

1.14 (0.72, 1.81)

0.60 (0.38, 0.97)
0.68 (0.42, 1.08)
0.87 (0.55, 1.39)
1.28 (0.75, 2.16)
0.57 (0.28, 1.13)
0.58 (0.33, 1.00)
0.78 (0.42, 1.44)
0.81 (0.45, 1.47)
0.92 (0.45, 1.87)
1.00 (0.45, 1.67)

>1250 versus 500 mg/day (total calcium)

Quart. median 914 versus 486 mg/day (dietary calcium)
>830 versus <412 mg/day (dietary calcium)
>1270 versus <472 mg/day (total calcium)
>1250 versus 500 mg/day (total calcium)
>1250 versus 500 mg/day (total calcium)
661 versus <337 mg/day (dietary calcium)
1445 versus <956 mg/day (total calcium)
>988 versus <504 mg/day (dietary calcium)
>1255 versus <561 mg/day (total calcium)
Low versus high (dietary calcium)

0.65 (0.43, 0.98)

0.45 (0.26, 0.79)
0.66 (0.37, 1.16)
0.71 (0.40, 1.26)
0.73 (0.41, 1.27)
0.58 (0.32, 1.05)
0.60 (0.35, 1.01)
0.83 (0.49, 1.40)
0.91 (0.41, 2.00)
1.00 (0.47, 2.13)
1.67 (0.77, 5.00)

Quart. median 914 versus 486 mg/day (dietary calcium)

>830 versus <412 mg/day (dietary calcium)
>1270 versus <472 mg/day (total calcium)
1445 versus <956 mg/day (total calcium)
>988 versus <504 mg/day (dietary calcium)
661 versus <337 mg/day (dietary calcium)
>1255 versus <561 mg/day (total calcium)

0.70 (0.45, 1.09)

0.87 (0.43, 1.77)
0.93 (0.43, 2.01)
0.61 (0.38, 0.98)
0.79 (0.45, 1.40)
0.88 (0.48, 1.61)
1.01 (0.53, 1.93)
0.125 0.25

0.5

Figure 7: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of calcium. (The results are stratified on
sex. Open circles: both gender combined. Closed black circles: females. Closed grey circles: men. All estimates are sorted from the lowest to
the highest by subsite and sex, except Stemmermann et al. [28].)

included in the EPIC study, total consumption of whole grain

products was associated with a significantly lower risk of
proximal colon cancer and a borderline significantly lower
risk of distal colon cancer and rectal cancer in men (IRR
per each increment in intake of 50 gram per day 0.78, 95%
CI 0.660.92 for proximal colon, 0.90, 95% CI 0.791.02 for
distal colon, and 0.90, 95% CI 0.801.01 for rectum) but not

in women (data not given) [43]. No significant associations

between whole grain consumption and cancer of any of the
colorectal subsites were seen in the Swedish Mammography
Cohort [39] (Figure 4).
The width of the confidence intervals for the risk estimates on fiber and whole grain varies markedly between the
included studies. However, whether all studies are included

Journal of Oncology
Cohort
Proximal
EPIC
CCPPS
UKDCC
NLCS
NCKPS
KNHS
UKDCC
RCLA
IWHS
NLCS
NLCS
KNHS
MCS
UKDCC
HPFS
RCLA
Distal
CCPPS
NLCS
NCKPS
EPIC
UKDCC
KNHS
IWHS
NLCS
RCLA
UKDCC
KNHS
NLCS
UKDCC
HPFS
RCLA
MCS
Rectal
UKDCC
NLCS
EPIC
CCPPS
NCKPS
NLCS
UKDCC
KNHS
UKDCC
KNHS
MCS
NLCS

Reference

9
Age

Exposure

RR (95% CI)

Ferrari, 2007 [56]

Pedersen, 2003 [54]
Park, 2010 [58]
Bongaerts, 2008 [57]
Klatsky, 1988 [27]
Shin, 2011 [36]
Park, 2010 [58]
Wu, 1987 [52]
Razzak, 2011 [29]
Bongaerts, 2008 [57]
Bongaerts, 2008 [57]
Shin, 2011 [36]
Akhter, 2007 [55]
Park, 2010 [58]
Giovannucci, 1995 [53]
Wu, 1987 [52]

3570
2395
2684
5569
Missing
3080
2684
Missing
5569
5569
5569
3080
4064
2684
4075
Missing

>60 versus 0.14.9 g/day

>41 drinks/week versus nondrinkers
30 g/d versus >0<5 g/d
30 g/day versus abstainers
3 drinks/day versus never
Almost everyday versus none
30 g/d versus >0<5 g/d
31 mL/day versus nondaily
>11 versus 1.8 g/day
30 g/day versus abstainers
30 g/day versus abstainers
Almost everyday versus none
45.6 g/day versus never
30 g/d versus >0<5 g/d
>2.0 versus <0.26 drinks/day
31 mL/day versus nondaily

0.92 (0.51, 1.66)

1.00 (0.40, 2.40)
1.25 (0.63, 2.47)
1.29 (0.85, 1.96)
1.81 (0.59, 5.57)
0.40 (0.10, 2.60)
0.50 (0.11, 2.37)
1.00 (0.40, 2.80)
1.08 (0.82, 1.44)
2.28 (1.12, 4.62)
1.19 (0.69, 2.06)
1.20 (0.90, 1.70)
1.40 (0.72, 2.75)
1.78 (0.71, 4.46)
2.23 (1.04, 4.78)
2.84 (1.20, 6.50)

Pedersen, 2003 [54]

Bongaerts, 2008 [57]
Klatsky, 1988 [27]
Ferrari, 2007 [56]
Park, 2010 [58]
Shin, 2011 [36]
Razzak, 2011 [29]
Bongaerts, 2008 [57]
Wu, 1987 [52]
Park, 2010 [58]
Shin, 2011 [36]
Bongaerts, 2008 [57]
Park, 2010 [58]
Giovannucci, 1995 [53]
Wu, 1987 [52]
Akhter, 2007 [55]

2395
5569
Missing
3570
2684
3080
5569
5569
Missing
2684
3080
5569
2684
4075
Missing
4064

>41 drinks/week versus nondrinkers

30 g/day versus abstainers
3 drinks/day versus never
>60 versus 0.14.9 g/day
30 g/d versus >0<5 g/d
Almost everyday versus none
>11 versus 1.8 g/day
30 g/day versus abstainers
31 mL/day versus nondaily
30 g/d versus >0<5 g/d
Almost everyday versus none
30 g/day versus abstainers
30 g/d versus >0<5 g/d
>2.0 versus <0.26 drinks/day
31 mL/day versus nondaily
45.6 g/day versus never

1.00 (0.40, 2.30)

1.41 (0.94, 2.11)
1.52 (0.40, 5.71)
1.68 (1.08, 2.62)
2.36 (1.13, 4.91)
0.40 (0.10, 3.00)
0.98 (0.73, 1.33)
1.32 (0.52, 3.37)
1.66 (0.80, 3.60)
3.76 (0.92, 15.37)
1.20 (0.90, 1.50)
1.46 (0.89, 2.41)
1.64 (0.64, 4.16)
2.01 (0.93, 4.34)
2.21 (0.80, 6.00)
4.17 (1.63, 10.66)

Park, 2010 [58]

Bongaerts, 2008 [57]
Ferrari, 2007 [56]
Pedersen, 2003 [54]
Klatsky, 1988 [27]
Bongaerts, 2008 [57]
Park, 2010 [58]
Shin, 2011 [36]
Park, 2010 [58]
Shin, 2011 [36]
Akhter, 2007 [55]
Bongaerts, 2008 [57]

2684
5569
3570
2395
Missing
5569
2684
3080
2684
3080
4064
5569

30 g/d versus >0<5 g/d

30 g/d versus abstainers
>60 versus 0.14.9 g/day
>41 drinks/week versus nondrinkers
3 drinks/day versus never
30 g/d versus abstainers
30 g/d versus >0<5 g/d
Almost everyday versus none
30 g/d versus >0<5 g/d
Almost everyday versus none
45.6 g/d versus never
30 g/d versus abstainers

1.01 (0.48, 2.11)

1.69 (1.08, 2.64)
1.93 (1.35, 2.78)
2.20 (1.00, 4.60)
3.17 (1.05, 9.57)
0.72 (0.16, 3.10)
1.53 (0.40, 5.91)
2.80 (1.70, 4.70)
1.06 (0.39, 2.92)
1.10 (0.90, 1.30)
1.84 (1.05, 3.21)
2.08 (1.20, 3.59)
0.125

0.25

0.5

Figure 8: Estimates of relative risk with 95% CI for the highest versus the lowest exposure categories of alcohol. (The results are stratified on
sex. Open circles: both gender combined. Closed black circles: females. Closed grey circles: men. All estimates are sorted from the lowest to
the highest by subsite and sex.)

or those with the lowest power are excluded, there are rather
minimal differences in relative risk across the subsites.
3.4. Garlic. Only one study on garlic is included in the review.
The Iowa Womens Health Study reported that having at least
one serving per week of garlic was associated with a 48%
reduced risk of distal colon cancer compared to zero servings
of garlic (RR 0.52, 95% CI 0.300.93) [37] (Table 2, Figure 5).
3.5. Milk. Three cohort studies were included in the review
[4547]. Two cohort studies have examined the relation
between total consumption of milk and the risk of cancer in
colorectal subsites [45, 47] (Table 2, Figure 6). No significant
associations were seen for any of the colorectal subsites in
a US study that combined both sexes (estimates not given
for women) [45]. In a study of Swedish men, a significantly

reduced risk for distal colon cancer was seen for those
consuming 1.5 glasses or more of milk per day compared to
those consuming less than two glasses per week (RR 0.53, 95%
CI 0.330.87) [47].
In another Swedish study restricted to high fat dairy
food and conducted among women only, a significant inverse
trend was observed between consumption of full-fat cultured
milk and risk of distal colon cancer (trend = 0.03), whereas
a significant increased risk of proximal colon cancer was
observed among women who consumed whole milk (1 or
more servings per day compared to never/seldom consumers
RR 1.58, 95% CI 1.152.16) [46].
3.6. Calcium. Seven papers from eight cohorts were included
in the review [28, 45, 4751] (Table 2, Figure 7). In the
analyses from the Nurses Health Study and the Health

10
Professionals Follow-Up Study that studied colon cancer
only, non-significant inverse associations were seen between
total calcium and distal colon cancer for both men and
women, and a pooled analysis of the two cohorts gave a
significant inverse trend for distal colon cancer (trend =
0.01) [49]. Likewise, a significant inverse trend was reported
between total calcium and distal colon cancer in the Swedish
Mammography Cohort (trend = 0.02) [48], while in
a US female cohort, a significant inverse trend was seen
between dietary calcium intake and proximal colon cancer
(trend = 0.01) [50]. No association was seen for total
calcium. In a US study examining both sexes, total calcium
intake was significantly inversely associated with proximal
colon cancer among men (trend = 0.04), but not dietary
calcium, and there were no significant associations seen for
women (estimates not given) [45]. In a study of Swedish men,
a significant inverse relation was found between total calcium
and rectal cancer (trend = 0.02), whereas nonsignificant
inverse associations were seen for cancer of the colon [47]. No
significant associations between dietary calcium and cancer
of any colorectal subsite were reported in a Japanese study
either for men or for women (estimates not given for women)
[51]. An earlier study of Hawaiian-Japanese men reported a
significant inverse association between dietary calcium and
sigmoid colon cancer (trend = 0.02) [28]. In addition to
the eight cohorts included in this paper, an additional cohort
study among American women states that their data provided
little support for a protective effect of total calcium at either
tumor subsite, but does not present risk estimates [60].
3.7. Alcohol. Ten articles [27, 29, 36, 5258] were included
in the review (Table 2). Three analyses for both sexes combined consistently showed a higher risk of rectal cancer
with increasing alcohol consumption and no significant
associations for any of the colon subsites [27, 54, 57]. In
the EPIC study [56] an increased risk was reported both for
rectal and distal colon cancer, whereas in the UK dietary
cohort consortium (part of which is included in the EPIC
study) [58] a significantly increased risk was found for distal
colon cancer only (Figure 8). Several sex-specific analyses
have been done. Among men, two older studies with limited
statistical power reported that alcohol consumption was
positively related to proximal colon cancer only [52, 53],
whereas four more recent studies reported non-significant
associations with proximal colon cancer [36, 55, 57, 58]. A
study among Japanese men reported increased risk for distal
colon cancer, but the confidence interval for the risk estimate
was very wide (consumption of 45.6 grams alcohol or more
per day compared to never drinkers HR 4.17, 95% CI 1.63
10.66) [55]. In terms of consumption of alcohol and rectum
cancer among men, two of four studies have reported a
positive association [55, 57].
For women, fewer significant associations have been
reported. In the Iowa Womens Health Study, alcohol was
not significantly associated with either proximal colon or
distal colorectal cancer, nor did further separation into
distal colon and rectal cancer reveal any significant associations (estimates not given) [29]. Furthermore, no significant
associations were seen in an earlier study of American women

Journal of Oncology
[52] or in the UK dietary cohort consortium [58]. In The
Netherlands Cohort Study, however, women consuming 30
grams or more of alcohol per day had HRR of proximal colon
cancer of 2.28 (95% CI 1.124.62) compared to abstainers,
whereas analyses for the other subsites were not sufficiently
robust to draw any conclusions [57]. In a Korean study,
women who frequently consumed alcohol or who consumed
greater amounts of alcohol had a higher risk of rectal cancer
[36].

4. Discussion
This review provides an overall and updated synthesis of
the results from cohort studies examining the association
between dietary factors that are convincingly or probably
related to the risk of colorectal cancer and subsite-specific
colorectal cancer. Our study indicates that consumption of
alcohol is more strongly related to the risk of rectal cancer
than to colon cancer, also that meat consumption tends to
be somewhat more strongly related to the risk of distal colon
cancer and rectal cancer than proximal colon cancer, that
there are only minor differences in relative risk for colorectal
cancer across the major subsites for fiber, milk, and calcium,
and that no statement can be given for garlic due to limited
data. It should be noted that for all exposures the majority of
the analyses showed nonsignificant associations with cancer
risk, the exception being the positive association between
alcohol consumption and rectal cancer.
The pathway of colorectal cancer is complex. The subsite
etiology is rather poorly understood, and the mechanism for
the various dietary factors is likely to differ. Even for red and
processed meat, both established risk factors for colorectal
cancer, the underlying mechanisms are not well defined. One
suggested mechanism for the somewhat stronger association
for rectum and distal colon relative to proximal colon cancer
relates to the enhanced endogenous formation of carcinogenic N-nitroso compounds with a high intake of meat [61].
The level of markers of N-nitroso compounds appears to be
higher in tissue from distal colon and rectum than in that
of the proximal colon [62]. This finding is in keeping with
a previously meta-analyses which implicated processed meat
consumption as a stronger risk factor for cancer occurrence
at the distal colon relative to the proximal colon [22].
A suggested mechanism by which dietary fiber may
decrease the risk of colorectal cancer is linked to the fermentation of fiber. The fermentation produces short-chain
fatty acids and, in particular, acetic, propionic, and butyric
acids. Butyrate is particularly of interest, as it has been
shown to induce apoptosis and to be cytotoxic to both
colorectal adenoma and carcinoma cells [63]. Studies on mice
have shown that the concentration of butyrate is highest
in the distal colon [64]. In humans, fiber is fermented in
the proximal colon, and the total amount of short-chain
fatty acids has been estimated to be considerably higher in
the proximal site compared to the distal [65]. One study
on proximal and distal colonocytes indicates, however, that
butyrate is a more important source of energy for the distal,
than for the proximal, colonic mucosa [66]. If so, this

Journal of Oncology
could be a relevant biological mechanism explaining any
differences in risk between the sites. In addition, fiber may
dilute the concentration of carcinogenic substances in the
distal colon. Despite these findings, a pooled analysis on fiber
reported no convincing differences in colorectal risk for the
various anatomical subsites [25], in line with our own results
published here.
The reduced risk of colorectal cancer with increasing
consumption of milk is likely to be at least partly mediated by
calcium, which is thought to have a protective effect through
its ability to bind bile acids, and its growth-restraining and
differentiation- and apoptosis-inducing effect on colorectal
cells [67]. No convincing site-specific associations regarding
milk and calcium were seen in our review. A former pooled
analysis reported an inverse association for milk limited to
cancer of the distal colon and rectum [24], while the results
from two meta-analysis on site-specific impact of calcium
have been conflicting [20, 21].
The consumption of alcohol is associated with increasing risk of cancer in several organs in the digestive tract,
including the colorectum [18]. Alcohol is not a carcinogen
itself, but acts as a tumor promoter and possibly as a cocarcinogen. Alcohol also acts as a solvent and thus might
increase the exposure to other carcinogens by enhancing the
penetration of carcinogens into the cell [18]. Acetaldehyde
is a metabolite of alcohol and may be the most important
agent responsible for the carcinogenic effect as it is highly
toxic, mutagenic, and carcinogenic [68]. A pooled analyses
on alcohol reported similar risk across all areas of the large
bowel [26]. However, a stronger association with alcohol
for rectal cancer compared with colon cancer as seen in
our paper could possibly be related to a higher degree of
epithelial hyperregeneration in rectum [69]. The number
of sex-specific analysis is presently too low to suggest any
significant interaction by sex at the subsite level.
There are some methodological issues in this study which
may have impacted on the findings. There is considerable
variability in several key characteristics of the assembled
cohort studies: the follow-up time across studies included
in this paper varied from 4 to 22 years, while the total
number of colorectal cancer cases analyzed ranged from
126 to 2974. Short-term follow-up studies tend to accrue a
lower number of cases, and the resulting estimates are subject
to greater uncertainty. The substratification of cases by sex,
tumor location, and exposure categories, as presented here,
inevitably leads to smaller numbers and a greater degree
of imprecision in the estimates, even for relatively large
studies. Statistically significant associations may thus be more
spurious at the subsite-specific level. However, restricting
the evaluation to studies with adequate statistical power did
not change the overall picture. Long-term follow-up studies
will commonly accrue a greater number of cases, but are
more prone to measurement error given that an increasing
follow-up time raises the possibility that exposure status of
the participants will change, leading to misclassification of
exposure and under- or overestimation of the risk estimates.
However, the natural history of colorectal cancer is on average
of long duration, and exposure in the more distant past may
be the most relevant when estimating subsequent risk.

11
Another issue is the difference in risk factor dosages
between studies and that the categories compared sometimes
vary considerably between studies. For instance, for calcium,
in the Swedish study by Larsson et al. [47] daily intake
of 1445 mg or more is compared to an intake of less than
956 mg/day, whereas in the Japanese study by Ishihara et al.
[51] daily intake of 661 mg or more is compared with an intake
of less than 337 mg/day. Careful reading of the exposure
categories (given in the figures) is therefore necessary when
evaluating the findings. In addition, the specific confounding
factors adjusted for at the analysis stage differ between
studies.
Of the studies that were full-text reviewed, 76 were
excluded as they did not reveal information at the level of
subsite location. Given the high proportion of cohort studies
failing to report subsite-specific estimates, the potential
publication bias prohibited a formal meta-analysis [59]. A
further rationale for this decision is the lack of uniformity in
exposure categories within each risk factor.
In summary, the strength of the association between
dietary components and cancer of the large bowel may
partially depend on the anatomic location within the colorectum. The most consistent finding is the stronger association
between alcohol and rectal cancer, compared with alcohol
and proximal and distal colon cancer. Meat (red and processed) is possibly more strongly associated with risk of distal
colon cancer and rectal cancer than the risk of proximal colon
cancer. For fiber, milk, and calcium there seem to be only
minor differences in relative risk across the subsites. However,
caution is required as the number of papers presenting risk
estimates by colorectal subsite is limited, particularly for milk
and garlic. Also, most of the subsite-specific analyses report
non-significant findings.

Conflict of Interests
The authors declare that they have no conflict of interests.

Acknowledgment
The authors thank Lena Leder for her contribution to the data
extraction and paper preparation.

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Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com

Volume 2014

Parkinsons
Disease

Computational and
Mathematical Methods
in Medicine
Hindawi Publishing Corporation
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Volume 2014

AIDS

Behavioural
Neurology
Hindawi Publishing Corporation
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Research and Treatment

Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com

Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com

Volume 2014

Oxidative Medicine and

Cellular Longevity
Hindawi Publishing Corporation
http://www.hindawi.com

Volume 2014