IJC

International Journal of Cancer

Dietary total antioxidant capacity and colorectal cancer:

A large casecontrol study in Italy
Carlo La Vecchia1,2, Adriano Decarli2,3, Mauro Serafini4, Maria Parpinel5, Rino Bellocco6,7, Carlotta Galeone1,2,
Cristina Bosetti1, Antonella Zucchetto2,8, Jerry Polesel8, Pagona Lagiou9,10, Eva Negri1 and Marta Rossi1,2
1

Department of Epidemiology, Istituto di Ricerche Farmacologiche Mario NegriIRCCS, Milan, Italy

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
3
Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCSS Istituto Nazionale Tumori di Milano, Milan, Italy
4
Agricultural Research Council, CRA Ex-INRAN, Rome, Italy
5
Unit of Hygiene and Epidemiology, Department of Biological and Medical Sciences, University of Udine, Udine, Italy
6
Department of Statistics, University of Milano-Bicocca, Milan, Italy
7
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden
8
Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, Aviano, Italy
9
Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
10
Department of Epidemiology, Harvard School of Public Health, Boston, MA
2

A diet rich in vegetables and fruit has been associated with a

reduced risk of various common cancers, particularly of the
respiratory and digestive tracts.16 It is unclear whether such
a favorable effect may be attributed to specic micronutrients
or bioactive compounds contained in plant foods. Among
them, various antioxidants, such as vitamin C and E and avonoids have been inversely associated to cancer risk.710
Key words: colorectal cancer, total antioxidant capacity, risk, diet,
non enzymatic antioxidant capacity
Grant sponsor: Italian Association of Cancer Research (AIRC);
Grant numbers: IG10068, IG10415; Grant sponsor: Italian Ministry
of Education; Grant number: PRIN 2009X8YCBN; Grant sponsor:
ASSOMELA
DOI: 10.1002/ijc.28133
History: Received 22 Aug 2012; Accepted 7 Feb 2013; Online 27 Feb
2013
Correspondence to: Dr. Marta Rossi, Department of Epidemiology,
Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, 19,
20156 Milano, Italy, Tel: [1390239014541],
Fax: [1390233200231], E-mail marta.rossi@marionegri.it

C 2013 UICC
Int. J. Cancer: 133, 14471452 (2013) V

Total antioxidant capacity (TAC) rather than individual antioxidants has been suggested as a relevant factor for cancer
risk.1113 TAC has been dened as the moles of oxidants
neutralized by one litre of plasma, food extracts or single
molecules, and represents a biomarker of antioxidant potential, including redox synergistic interactions.14,15
With reference to colorectal cancer, an inverse association
between dietary TAC and rectal cancer risk has been
reported in the Health Professionals Follow-up Study.16 In
that study, TAC was evaluated by ferric reducing-antioxidant
power (FRAP) assay, which measures in vitro the reduction
of the Fe31 (ferric ion) to Fe21 (ferrous ion) in the presence
of antioxidants.
Since antioxidants may act in vivo through different
mechanisms, other assays are also used to evaluate TAC.17,18
These include Trolox equivalent antioxidant capacity
(TEAC), which measures the ability of antioxidant molecules
to quench the long-lived ABTS1 compared with that of 6hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, Trolox, and total radical-trapping antioxidant parameter (TRAP),
which measures the protection provided by antioxidants on

Epidemiology

A favorable role of fruit and vegetables on colorectal cancer risk has been related to the antioxidant properties of their
components. We used data from an Italian casecontrol study including 1,953 patients with incident, histologically confirmed
colorectal cancer (1,225 colon and 728 rectal cancers). Controls were 4,154 patients admitted to hospital for acute,
non-neoplastic conditions. A reproducible and valid food frequency questionnaire was used to assess subjects usual diet.
Total antioxidant capacity (TAC) was measured using Italian food composition tables in terms of ferric reducing-antioxidant
power (FRAP), Trolox equivalent antioxidant capacity (TEAC) and total radical-trapping antioxidant parameter (TRAP). We estimated the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) through multiple logistic regression models, including terms for potential confounding factors, and energy intake. TAC was inversely related with colorectal cancer
risk: the OR for the highest versus the lowest quintile was 0.68 (95% CI, 0.570.82) for FRAP, 0.69 (95% CI, 0.570.83) for
TEAC and 0.69 (95% CI, 0.570.83) for TRAP. Corresponding values, excluding TAC deriving from coffee, were 0.75 (95% CI,
0.610.93) for FRAP, 0.76 (95% CI, 0.610.93) for TEAC and 0.71 (95% CI, 0.570.89) for TRAP. The inverse association was
apparentlythough not significantlystronger for rectal than for colon cancer. This is the first casecontrol study indicating
consistent inverse relations between dietary TAC and colorectal cancer risk.

1448

Total antioxidant capacity and colorectal cancer

Whats new?
A diet rich in fruit and vegetables has been associated with a reduced risk of common cancers, including colorectal cancer. Total
antioxidant capacity (TAC), rather than individual components, has been suggested as a relevant factor for cancer risk. In this
case-control study of over 6,000 patients, the authors used several different techniques to measure the dietary TAC of subjects
usual diet, and found a consistent inverse relationship between dietary TAC and colorectal cancer risk.

the uorescence decay of R-phycoerythrin (lag-phase) during

a controlled peroxidation reaction.
The aim of this study is to investigate the relation between
dietary TAC and colorectal cancer riskthrough FRAP,
TEAC and TRAPusing data from a large Italian study.

Epidemiology

Material and Methods

Between 1992 and 1996 in six Italian area, we conducted a
multicentric casecontrol study including 1,953 cases with
colorectal cancer and 4,154 controls.19
Cases were subjects with histologically conrmed colorectal cancer diagnosed no longer than 1 year prior to the
interview and no previous diagnoses of cancer at other sites.
Overall, 1,225 subjects with cancer of the colon and 728 with
cancer of the rectum and recto-sigmoid junction were
included. Controls were patients admitted to the same hospitals as cases for acute, non-neoplastic conditions unrelated to
digestive tract diseases: 23% were admitted for traumas, 28%
for other orthopedic disorders, 20% for acute surgical conditions, 19% for eye diseases and 10% for miscellaneous other
illnesses, such as ear-nose-and-throat, skin or dental conditions. This allowed to exclude controls with digestive/abdominal, non-neoplastic problems that may be predictors of
colorectal cancer and inuence food habits. About 5% of subjects approached for interview (cases and controls) refused to
participate.
Centrally trained interviewers administered a standard
questionnaire to cases and controls during their hospital stay.
The questionnaire included personal and socio-demographic
characteristics, anthropometric measures and lifestyle habits,
including tobacco smoking and alcohol consumption. A reproducible20 and valid21 food frequency questionnaire (FFQ)
was used to assess the patients usual diet in the 2 years preceding cancer diagnosis (for cases) or hospital admission (for
controls). The FFQ included the average weekly consumption
of 78 food items or food groups and of 5 alcoholic beverages.
Intakes lower than once a week, but at least once per month
were coded as 0.5 per week.
We developed a food composition database for our FFQ
using TAC measurements, which were assessed in terms of
FRAP, TEAC and TRAP by Italian food tables.17,22 We then
translated the frequency of consumption of each food item of
the FFQ into average cumulative daily TAC, also taking portion size into account. To this purpose, we standardized the
units of measures as mmol of Fe21 equivalents per 100 g
(solid foods) or 100 ml (beverages) for FRAP and mmol of
Trolox per 100 g (solid foods) or 100 ml (beverages) for

TEAC and TRAP, and obtained average mmol per day

(mmol/day) of TAC for each subject.23
We computed both overall TAC and TAC excluding the
contribution of coffee in order to estimate the risk for TAC
that are not inuenced by coffee consumption. In fact, coffee
has been inversely related to colorectal cancer risk24,25 and
the contribution of coffee represented about half of the total
amount of TAC in our controls (56% for FRAP, 48% for
TEAC and 62% for TRAP) with a high correlation between
coffee and TAC. TAC without the contribution of coffee
mainly derived from the consumption of fruit and vegetables
(40% for FRAP, 42% for TEAC and 35% for TRAP), including citrus fruit (11% for FRAP, 12% for TEAC and 8% for
TRAP) and apple and pears (5% for FRAP, 6% for TEAC
and 8% for TRAP), and the consumption of wine (38% for
FRAP, 36% for TEAC and 47% for TRAP). The three indexes
were strongly correlated, with correlation coefcients between
0.97 and 0.99.
We also computed the intake of avonoids by using food
composition data published by the US Department of Agriculture (USDA).2628 Nutrient and energy intakes were computed using an Italian food composition database,
supplemented with other published data.29
We computed energy-adjusted FRAP, TEAC and TRAP
using the residual method.30 The energy-adjusted FRAP, TEAC
and TRAP were categorized into quintiles based on the control
distribution, and the corresponding odds ratios (ORs) and 95%
condence intervals (CIs) were estimated using unconditional
multiple logistic regression models. All models included terms
for age (quinquennia, categorically), sex, study centre, years of
education (<7, 711, > 11, categorically), alcohol consumption
(quartiles, categorically), body mass index (BMI) (quintiles, categorically), family history of colorectal cancer (yes/no), occupational physical activity (low, medium, and high, categorically)
and FRAP, TEAC or TRAP from coffee alone (when considering TAC without the contribution of coffee). We also examined
additional models including terms for the intakes of fruit, vegetables, red meat, avonoids, vitamin C, beta-carotene, vitamin
E, vitamin D, calcium and folates.
ORs per an increment of intake equal to the difference
between the upper cut-off points of the IV and the I quintiles
were also computed.

Results
Table 1 gives the correlation coefcients between FRAP,
TEAC and TRAPwithout the contribution of coffeeand
other selected dietary covariates, including fruit, vegetables
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Int. J. Cancer: 133, 14471452 (2013) V

1449

Vecchia et al.

Fruit

Vegetables

Flavonoids

Anthocyanidins

Flavones

FRAP

TEAC

TRAP

0.27

0.29

0.19

0.11

0.12

0.03

0.21

0.24

0.16

0.00

0.02

20.03

0.73

0.72

0.66

0.65

0.64

0.56

0.88

0.88

0.91

0.86

0.86

0.89

0.27

0.28

0.19

colorectal cancer risk: the OR was 0.71 (95% CI, 0.590.86)

for FRAP, 0.72 (95% CI, 0.590.87) for TEAC and 0.71 (95%
CI, 0.580.86) for TRAP.
When we studied cancers of the colon and rectum separately,
the OR for colon cancer was 0.81 (95% CI, 0.631.05; p-trend,
0.082) for FRAP, 0.86 (95% CI, 0.671.10; p-trend, 0.094) for
TEAC and 0.77 (95% CI, 0.621.00; p-trend, 0.018) for TRAP.
Corresponding values for rectal cancer were 0.69 (95% CI, 0.51
0.94; p-trend, 0.002) for FRAP, 0.64 (95% CI, 0.480.87; p-trend,
0.001) for TEAC and 0.65 (95% CI, 0.480.89; p-trend, 0.002)
for TRAP. Tests for heterogeneity were not signicant.
ORs changed little toward the null after adjustment for
fruit, vegetables and other dietary factors, but more so after
adjustment for some classes of avonoids, particularly anthocyanidins. The OR for FRAP became 1.06 (95% CI, 0.80
1.42) adjusting for anthocyanidins, 0.88 (95% CI, 0.701.10)
adjusting for avonols and 0.84 (95% CI, 0.671.05) adjusting
for proanthocyandins with more than 10 mers.

0.05

0.04

20.02

Flavonols

0.49

0.50

0.48

0.30

0.30

0.27

Proanthocyanidins  10 mers

0.52

0.55

0.48

0.32

0.35

0.30

Discussion

0.33

0.35

0.21

In our study, dietary TAC was inversely related with the risk
of colorectal cancer. Associations were somewhat stronger for
rectal cancer, though the results were not signicantly heterogeneous. Our results are in line with those from the Health
Professional Follow-up Study that found an inverse association between FRAP and rectal cancer (relative risk, RR, 0.58,
95% CI, 0.350.96) on a cohort of 47,399 men including 201
rectal cancers.16 However, in that study, the association was
essentially explained by TAC from coffee, decaffeinated coffee
and tea combined (RR: 0.62; 95% CI: 0.331.14, ptrend 5 0.02), and dietary TAC from other food sources was
not associated with the risk of rectal cancer (RR: 0.92; 95%
CI: 0.531.60, p-trend 5 0.84). In our study, not only TAC
from coffee, but also TAC from other food sources was associated to colorectal cancer risk. We did not consider tea separately because the contribution of tea to total dietary TAC
was very low in our data (1%).
With reference to the few available data on other cancer
sites, dietary TRAP was inversely associated to the risk of
gastric cancer in a Spanish13 and a Swedish study.12
TAC mainly derives from vegetables and fruit. A favorable
effect of fruit and vegetables on cancer risk was reported by
the Greek EPIC Cohort study,1 which found a 33% reduction
in cancer incidence for subjects in the highest compared to
the lowest quintile of fruit and vegetable consumption, as
well as by a network of Italian casecontrol studies.2,31 High
consumption of fruit and vegetables in Mediterranean populations, where seasonal and fresh vegetables and fruit are
widely available, may facilitate the documentation of an
inverse relation in those populations and explain, at least in
part, the apparent discrepancy with American results.1 Mediterranean diet has been inversely associated to the risk of
selected cancers,4,32,33 and a recent intervention study found
that a Mediterranean diet was associated with high plasma
antioxidant capacity.34

Vitamin C

0.09

0.10

20.03

Carotene

0.19

0.21

0.13

20.04

20.03

20.09

Vitamin E

0.32

0.39

0.25

20.22

20.15

20.24

Vitamin D

0.14

0.17

0.10

20.16

20.14

20.17

Total energy

0.59

0.63

0.53

20.10

20.09

20.08

Partial correlation coefficients adjusted for sex. The top value is for
crude covariates and the bottom value is for energy-adjusted covariates.
FRAP: Ferric reducing antioxidant-power; TEAC: Trolox equivalent antioxidant capacity; TRAP: Total radical-trapping antioxidant parameter.

and avonoids, among controls. A strong positive correlation

was found between the three TAC indexes and total avonoids (r 0.7), especially anthocyanidins (r 0.9).
Table 2 gives the mean daily TAC without the contribution of coffee among controls, and the ORs of colorectal cancer according to quintiles of the three TAC indices. The
mean was 11.45 mmol for FRAP, 4.47 mmol for TEAC, 4.56
mmol for TRAP. We found inverse associations between
TAC and colorectal cancer risk. The OR estimates were very
similar for the three TAC estimates: the OR for the highest
versus the lowest quintile was 0.75 (95% CI, 0.610.93; ptrend, 0.002) for FRAP, 0.76 (95% CI, 0.610.93; p-trend,
0.001) for TEAC and 0.71 (95% CI, 0.570.89; p-trend,
<0.001) for TRAP. Corresponding values for overall TAC
(considering both diet and coffee) were 0.68 (95% CI, 0.57
0.82), 0.69 (95% CI, 0.570.83) and 0.69 (95% CI, 0.570.83).
TAC deriving from coffee alone was also inversely related to

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Int. J. Cancer: 133, 14471452 (2013) V

Epidemiology

Table 1. Correlation1 of three non-coffee total antioxidant capacity

indices with selected dietary covariates among 4,154 controls. Italy,
19921996

1450

Total antioxidant capacity and colorectal cancer

Table 2. Odds ratios (ORs)1 of colorectal cancer among 1,953 cases with colorectal cancer and 4,154 controls, and corresponding 95%
confidence intervals (CIs) according to quintiles2 (IV) of three energy-adjusted non-coffee total antioxidant capacity indices. Italy, 1992
1996.
OR1 (95% CI), Quintiles
Mean (SD)2

I4

II

III

IV

7.93

9.93

11.75

14.34

0.86
(0.721.03)

0.77
(0.640.93)

0.73
(0.600.88)

3.17

3.93

4.59

5.54

0.93
(0.781.11)

0.77
(0.640.92)

0.75
(0.620.91)

2.88

3.78

4.61

5.94

0.82
(0.680.98)

0.75
(0.630.90)

0.68
(0.560.83)

p for trend

OR continuous3

0.75
(0.610.93)

0.002

0.88
(0.810.97)

0.76
(0.610.93)

0.001

0.88
(0.810.96)

0.71
(0.570.89)

<0.001

0.89
(0.820.97)

FRAP (mmol/d)
Upper cut off-points5
11.45 (6.65)
TEAC (mmol/d)
Upper cut off-points5
4.47 (2.55)
TRAP (mmol/d)
Upper cut off-points5
4.56 (3.09)
1

Epidemiology

Estimated using multiple logistic regression models adjusted for sex, age, study centre, education, alcohol consumption, body mass index, family history, physical activity, TAC from coffee, and energy intake, according to the residual method. 2Mean and standard deviation (SD) among controls. 3Estimated for an increment of intake equal to the difference between the upper cut-off points of the IV and the I quintiles. 4Reference category.
5
Computed as the sum of the upper cut off-points of energy-adjusted TAC quintiles plus the mean of TAC.
FRAP: Ferric reducing-antioxidant-power; TEAC: Trolox equivalent antioxidant capacity; TRAP: Total radical-trapping antioxidant parameter.

Results from observational studies and clinical trials on

the inuence of single antioxidants on cancer risk are inconclusive,3 but compatible with the hypothesis that multiple
antioxidants jointly act for preventing adverse consequences
of oxidative stress, including carcinogenesis. A nested case
control study in the EPIC cohort35 on biomarkers of oxidative stress and colorectal cancer found a positive association
between prediagnostic serum levels of oxidative stress indicators (i.e., reactive oxygen metabolites) and colorectal cancer.
The estimation of the overall antioxidant activity of foods in
vitro allows to take into account the activity of all antioxidants and their potential synergistic and redox interactions.36
With reference to possible sources of bias, the interview setting and catchment areas were the same for cases and controls,
and the participation rate was almost complete, thus limiting
the size of selection bias. We excluded from the control group
all admission diagnoses that might have involved long-term
changes in diet. With reference to information bias, diagnosis
of colorectal cancer is usually made after a period of symptoms
that may inuence food habits. However, our FFQ refers to
the 2 years previous to disease diagnosis, thus limiting this
possible source of bias. Moreover, our FFQ was satisfactorily
reproducible20 and valid,21 though information on vitamin
supplements was not available. Further, our dietary FRAP,
TEAC and TRAP were comparable with those presented in a
previous Italian study.23 The main food contributors of TAC
were wine, citrus fruits, apples and pears, as well as coffee, in
our data. Given the favorable effect of coffee on colorectal cancer risk24,25 and the high contribution of coffee consumption
to TAC, we also examined dietary TAC not deriving from coffee consumption in order to control for the possible confounding effect of coffee on the risk estimates.

Among the strengths of the study are the large sample

size, and the use of a reproducible and valid FFQ in terms of
specic food items and nutrients.20,21 We were able to adjust
for major recognized risk factors for colorectal cancer, as well
as for total energy intake, and the study has generated results
on other colorectal cancer risk factors that were in line with
other investigations,19,37 providing reassurance that major
biases were not operating.
In previous investigations,27,28,38 we found signicant
inverse associations between various micronutrients and avonoids and colorectal cancer risk. Adjustment for avonoids
and particularly anthocyanidins reduced the strength of the
inverse relations between TAC and colorectal cancer risk, but
the high correlation between TAC and anthocyanidin intake
made the models difcult to interpret. Anthocyanidins are
poorly absorbed antioxidants. This suggests that not absorbed
antioxidants may contribute to the protective effect, but the
data were too limited for any additional inference. Likewise,
although TAC assays may not adequately reect antioxidant
activity in vivo because the bioavailability of antioxidants is
highly variable, TAC may exert important local activity in
the gastrointestinal tract.39
This is to our knowledge the rst report from a casecontrol study indicating consistent inverse relations between dietary TAC and colorectal cancer. Further studies, also based
on plasma TAC assessments, are needed to provide stronger
evidence on the role of antioxidants on the risk of colorectal
and other digestive tract cancers.

Acknowledgement
M.R. was supported by a fellowship from Fondazione Umberto Veronesi

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References