Fruit and vegetable intake and esophageal cancer in a large prospective
Neal D. Freedman1*, Yikyung Park2, Amy F. Subar3, Albert R. Hollenbeck4, Michael F. Leitzmann2,
Arthur Schatzkin2and Christian C. Abnet2
1Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute,
National Institutes of Health, Bethesda, MD
2Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute,
NIH, DHHS, Rockville, MD
3Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, DHHS, Rockville, MD
4AARP, Washington, DC
Changing patterns of esophageal squamous cell carcinoma
(ESCC) and esophageal adenocarcinoma (EAC) incidence world-
wide suggest distinct etiologies. Although associations between
fruit and vegetable intake and both ESCC and EAC have been
found in multiple ecological and case–control studies, few prospec-
tive studies have investigated these associations. We prospectively
examined these associations in 490,802 participants of the National
Institutes of Health (NIH)-AARP Diet and Health Study using
Cox models adjusted for age, alcohol intake, body mass index, cig-
arette smoking, education, physical activity and total energy
intake. We present hazard ratios and 95% confidence intervals
per serving per 1,000 calories. During 2,193,751 person years of
follow-up, 103 participants were diagnosed with ESCC and 213
participants with EAC. We found a significant inverse association
between total fruit and vegetable intake and ESCC risk (HR: 0.78,
95% CI: 0.67–0.91), but not EAC risk (0.98, 0.90–1.08). In models
mutually adjusted for fruit and vegetable intake, the protective
association with ESCC was stronger for fruits (0.73, 0.57–0.93)
than for vegetables (0.84, 0.66–1.07). When we examined botanical
subgroups, we observed significant protective associations for
ESCC and intake of Rosacea (apples, peaches, nectarines, plums,
pears and strawberries) and Rutaceae (citrus fruits). A significant
inverse association between EAC and Chenopodiaceae (spinach)
intake was observed. Results from our study suggest that the rela-
tion of fruit and vegetable intake and esophageal cancer risk may
vary by histologic type.
' 2007 Wiley-Liss, Inc.
Key words: esophageal cancer; fruits; vegetables; cohort
Esophageal cancer is the sixth most common cause of cancer
death worldwide with ?386,000 deaths in 20021and has 2 pri-
mary histologic types, esophageal squamous cell carcinoma
(ESCC) and esophageal adenocarcinoma (EAC). EAC rates are
increasing in many countries worldwide. For example, in the
United States, the rates of EAC have increased by over 350% over
the past 30 years, while the rates of ESCC have decreased by
35%.2–4However, in high risk geographic regions, such as north-
eastern Iran and Linxian, China, ESCC is the predominant form.5–7
Concordant with these differences in incidence rates, ESCC and
EAC share common but also independent risk factors. Cigarette
smoking appears to be a risk factor for both cancer types, whereas
gastric reflux disease is thought to be a strong risk factor for EAC
but not ESCC. Studies consistently show associations between
heavy alcohol consumption and increased ESCC risk; studies with
alcohol and EAC do not suggest a consistent association.8Finally,
although high body mass index (BMI) is consistently associated
with increased EAC risk,9it may be associated with decreased
Whether intake of fruit and vegetables, rich in potentially anti-
carcinogenic compounds, protects against ESCC and EAC inci-
dence is not known. An IARC report of fruit and vegetable intake
and cancer risk indicated that the intake of fruit and vegetables
‘‘probably’’ lowers the risk of esophageal cancer.12However, this
report did not distinguish by histolgic type in its recommendations.
Most previous studies of this association have been ecological13,14
or case–control in design,12,15,16and therefore susceptible to the
ecological fallacy or recall and selection bias, particularly as
esophageal cancer affects the digestive tract and has a 5 year sur-
vival rate of just 16%.1To our knowledge, only 4 prospective
studies investigated fruit and vegetable intake and esophageal can-
cer risk. One study investigated the association between fresh veg-
etable and fruit intake and ESCC in Linxian, China, a high risk
region for esophageal cancer. Though this study lacked compre-
hensive dietary assessment, a significant protective association
was observed with fruit intake.7Similarly, a borderline significant
inverse association between fruit intake and ESCC risk was
observed in the Japanese Hiroshima Life Span study17; this study
did not examine total vegetable intake. An analysis of data from 6
prefectures in Japan observed decreased risk for ESCC with
increased consumption of Green-yellow vegetables,18but did not
investigate other vegetable types or fruits. The European Prospec-
tive Investigation of Cancer using a small number of cases (n 5
65), reported a suggestive but not significant inverse association
between total vegetable intake, citrus fruit intake and EAC risk.19
To our knowledge, no previous prospective study compared the
association between fruit and vegetable intake and EAC risk with
that for ESCC risk.
As fruit and vegetable intake may protect against esophageal
cancer incidence, we examined this association in a large US pro-
spective cohort, the National Institutes of Health (NIH)-AARP
Diet and Health Study. Fruit and vegetable intake was assessed
via a comprehensive 124 item food frequency questionnaire and
esophageal cancer sub-types were distinguished by histology.
Material and methods
The NIH-AARP Diet and Health study has previously been
described.20Between 1995 and 1996, a questionnaire eliciting in-
formation on demographic characteristics, dietary intake, and
health-related behaviors was mailed to members of AARP, for-
merly known as the American Association of Retired Persons—a
US organization whose membership is open to those greater than
50 years of age, who resided in 6 US states (California, Florida,
Louisiana, New Jersey, North Carolina and Pennsylvania) and 2
metropolitan areas (Atlanta, Georgia and Detroit, Michigan).
566,407 respondents (339,671 men and 226,736 women) filled out
the survey in satisfactory detail and consented to be in the study.
Grant sponsor: National Cancer Institute, NIH (Intramural Research Pro-
*Correspondence to: Nutritional Epidemiology Branch, Division of
Cancer Epidemiology and Genetics, 6120 Executive Blvd, EPS/320, MSC
7232, Rockville, MD 20852, USA. Fax: 11-301-496-6829.
Received 4 April 2007; Accepted after revision 1 June 2007
Published online 9 August 2007 in Wiley InterScience (www.interscience.
Int. J. Cancer: 121, 2753–2760 (2007)
' 2007 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
We excluded subjects with cancer at baseline (n 5 51,219), proxy
respondents (n 5 15,760), those with total energy, total fruit, total
vegetable, or total fruit and vegetable intake more than 2 inter-
quartile ranges from the mean (n 5 8,616), and those who died or
were diagnosed with cancer on the first day of follow-up (n 5 10).
The resulting cohort included 490,802 participants: 292,898 men
and 197,904 women.
Cohort follow-up and case identification
Cohort follow-up methods have been described previously.21Fol-
low-up time extended from study baseline (between 1995 and 1996)
to diagnosis of the first upper-gastrointestinal tract cancer (head and
neck, esophageal or stomach cancer, as a diagnosis of one of these
cancers would be associated with increased surveillance of the other
sites), date of death, end of study (December 31, 2000), or the date
moved out of registry ascertainment area. Ending follow-up time at
the first cancer diagnosis, regardless of site, reduced case numbers
slightly but did not appreciably affect the results. Incident cases of
cancer were identified by probabilistic linkage between the NIH-
AARP cohort membership and 8 state cancer registry databases.21
Cancer sites were identified by anatomic site and histologic code of
the International Classification of Disease for Oncology (ICD-O,
third edition).22We classified tumors with site codes C15.0–C15.9
as EAC or ESCC based on squamous or adenocarcinoma histology.
We excluded 22 cancers with non-adenocarcinoma or non-squa-
mous diagnoses. The NIH-AARP Diet and Health Study was
approved by the Special Studies Institutional Review Board of the
US National Cancer Institute (NCI).
Assessment of fruit and vegetable intake
The baseline questionnaire included a 124 item food frequency
questionnaire and questions about demographics, alcohol intake,
tobacco use and physical activity. Participants were asked to
report their usual frequency of intake and portion size over the last
12 months, using 10 frequency categories ranging from ‘never? to
‘61 times per day? for beverages and from ‘never? to ‘21 times
per day? for solid foods and 3 categories of portion size. The food
items, portion sizes, and nutrient database (Pyramid Servings
Database) were constructed23using data from the US Department
of Agriculture’s 1994–1996 Continuing Survey of Food Intake by
Individuals Survey.24The Pyramid Servings Database utilized a
recipe file to disaggregate food mixtures into their component
ingredients and assign them to the appropriate food group. One
pyramid serving corresponded to one serving in the US Depart-
ment of Agriculture’s food guide Pyramid. For example, 1 fruit
serving equaled one medium sized fresh fruit, [1/2] cup cut fruit,
or 6 oz juice, while a vegetable serving might refer to 1 cup leafy
vegetables, [1/2] cup other vegetables, or 6 oz juice.25The FFQ
was calibrated using 2 non-consecutive 24-hr recalls in 1953
participants. For fruit and vegetable intake, the energy-adjusted
Pearson correlation between FFQ and the 24-hr recalls for men
and women respectively was 0.72 and 0.61.26
We excluded white potatoes from the vegetable group. To facil-
itate analysis, we created quintiles containing equal numbers of
cohort participants using the distribution of total fruit and vegeta-
ble intake, total fruit intake, total vegetable intake, non-juice fruit
intake and fruit juice intake for the whole cohort. Fruit and vegeta-
bles were further grouped into botanical groups based on botanical
taxonomy to help identify possible chemopreventive phytochemi-
cals.27For analysis of botanical groups, tertiles were used due to
the large number of participants who did not regularly consume
food items from some of the botanical groups. The Pearson corre-
lation coefficients for intake of each botanical group ranged from
0.03 to 0.46 (Appendix Table AI).
Hazard ratios and 95% confidence intervals were calculated
using Cox proportional hazards regression.28We tested for and
found no deviations from the proportional hazards assumption.
Follow-up time was used as the underlying time metric. Using age
as the underlying time metric did not change our results.
All models included adjustment for continuous age, and cate-
gorical variables of sex, education (< high school education, com-
pletion of high school, some post-high school training, completion
of college, and completion of graduate school), BMI (<18.5,
18.5–<25, 25–<30, 30–<35 and ?35), alcohol intake (none, >0–
1 drink per day, >1–3 drinks per day and >3 drinks per day),
smoke-quit-dose (never cigarette smokers, quit ? 1 pack/day, quit
>1 pack per day, currently smoking ?1 pack/day, and currently
smoking >1 pack/day), vigorous physical activity (never, rarely,
1–3 times/month, 1–2 times/week, 3–4 times/week, 5 or more
times per week), usual activity throughout the day (sit all day, sit
much of the day/walk some, stand/walk often/no lifting, lift/carry
light loads and carry heavy loads).
We did not include race/ethnicity in models, as more than 93%
of the subjects that developed ESCC and EAC were non-Hispanic
white and adding categorical variables of race/ethnicity to the
models did not affect estimates. To adjust for energy intake, we
used the nutrient density method29and divided fruit and vegetable
servings by total energy intake (per 1,000 calories) and included
total energy in the model. As a sensitivity analysis, we also ana-
lyzed data using a standard multivariate model that included fruit
and vegetable intake (servings/day), total energy, and other cova-
riates and the results were similar to those obtained with the nutri-
ent density method (data not shown). In further models, fruit and
vegetable intake were also mutually adjusted. Missing values for
adjusting covariates were included as dummy variables in the
models. Linear trend tests across categories of intake were con-
ducted by assigning participants the median intake for their cate-
gories and entering it as a continuous term in the regression
We also examined interactions between total fruit and vegetable
intake and sex (male versus female), alcohol (ever versus never),
smoking (current versus former versus never), vigorous physical
activity (? than 3 times per week versus < 3 times per week, and
education (high school or less versus greater than high school) by
stratifying the continuous intakes of fruits and vegetables by each
Analyses were performed with SAS version 8.2. An alpha level
of less than 0.05 was considered statistically significant and all
tests were 2-sided.
During 5 years of follow-up (2,193,751 person-years), 103 indi-
viduals were diagnosed with ESCC and 213 with EAC. Those in
the cohort had a median age of 62.6 years; the majority were male
(59.7%) and non-Hispanic white (92.6%). Compared to partici-
pants with low total fruit and vegetable intake, participants with
higher intake tended to be women, more educated, drink less alco-
hol, non-smokers, and participate more frequently in vigorous
physical activities. BMI, a strong EAC risk factor,9did not differ
across quintiles of total fruit and vegetable intake (Table I).
Using multivariate-adjusted Cox regression, we examined the
association between total fruit and vegetable intake and ESCC or
EAC cancer risk. Increasing consumption of fruit and vegetables
was significantly associated with decreased ESCC risk (HR per
serving per 1,000 calories, 0.78, 95% CI: 0.67–0.91) but not EAC
risk (HR per serving per 1,000 calories 0.98, 0.90–1.08). Com-
pared to those with lowest intake (first quintile), those with the
highest intake of fruit and vegetables were at significantly reduced
risk for ESCC (HR: 0.44, 95% CI: 0.20–0.96) but not EAC (HR:
0.99, 95% CI: 0.61–1.61). In mutually adjusted models separating
fruit and vegetable intake (Table II), fruit intake (HR per serving
per 1,000 calories, 0.73, 0.57–0.93) but not vegetable intake (HR
per serving per 1,000 calories, 0.84, 0.66–1.07 was significantly
associated with decreased ESCC risk), though both seemed to con-
tribute to the protective effect observed overall). The association
FREEDMAN ET AL.
TABLE I – STUDY CHARACTERISTICS BY QUINTILES OF FRUIT AND VEGETABLE INTAKE PER 1,000 CALORIES
Quintiles of fruit and vegetable intake1
Cohort (Number, %)
Total fruit and vegetable intake2
(Median, interquartile range)
Sex (Number, %)
Age (Median, interquartile range)
BMI (Median, interquartile
Total daily calories (Median,
Education (Number, %)
Less than high school
12 years (completed high school)
Some post-high school training
Completed graduate school
Alcohol intake (Number, %)
Zero drinks per day
0< to 1 drinks per day
1< to 3 drinks per day
> 3 drinks per day
Cigarette Smoking Status (Number, %)
Usual activity throughout the day (Number, %)
Sit during the day/little walking
Sit during the day/walk a fair amount
Stand/walk a lot—no lifting
Lift/carry light loads, stairs, hills
Do heavy work/carry loads
Vigorous physical activity (Number, %)
5 or more times/week
1Categories may not add up to 490,802 persons due to missing data.–2Servings/day per 1,000 kcal.
ESOPHAGEAL CANCER AND FRUIT AND VEGETABLE INTAKE
was stronger with whole fruits (Q5 vs. Q1, HR 5 0.29, 95% CI:
0.12–0.73) than with fruit juice (Q5 vs. Q1, HR 5 0.83, 95% CI:
0.45–1.52). In contrast, neither vegetable intake, nor fruit intake
was significantly associated with EAC risk.
To examine the association between fruit and vegetable intake
and esophageal cancer in further detail, we examined associations
using 13 subgroups based on botanical classifications (Table III).
For ESCC, HR were below 0.9 for 9 of the 13 botanical groups
examined. Statistically significant associations were observed
between ESCC risk and intake of Rosacea (apples, peach, nectar-
ines, plums, pears and strawberries: Q3 vs. Q1, HR: 0.34, 95%
CI: 0.18–0.65) and Rutaceae (citrus fruits: Q3 vs. Q1, HR: 0.58,
95% CI: 0.34–0.99). Suggestive but not significant associations
were observed between the intake of Umbelliferae (carrots: Q3
vs. Q1, HR: 0.61, 95% CI: 0.35–1.07) and Compositae (lettuce:
Q3 vs. Q1, HR: 0.62, 95% CI: 0.36–1.06) and ESCC risk. The
majority of hazard ratios for the association between botanical
groups and EAC risk centered around one. However, Chenopo-
diaceae (spinach) intake was significantly associated with reduced
EAC risk (Q3 vs. Q1, HR: 0.66, 95% CI: 0.46–0.95). Suggestive
but not significant associations between intake of Cruciferae
(broccoli, cauliflower, brussels sprouts, turnip, cabbage, coleslaw,
TABLE II – ADJUSTED HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR FRUIT AND VEGETABLE
INTAKE AND ESOPHAGEAL CANCER
Fruit and vegetable groups1,2
Cases HR95% CI CasesHR95% CI
Total fruit and vegetables
Quintiles of intake (median)
p-value for trend
Quintiles of intake (median)
p-value for trend
Quintiles of intake (median)
p-value for trend
Quintiles of intake (median)
p-value for trend
Quintiles of intake (median)
p-value for trend
1030.78 0.67–0.91 2130.98 0.90–1.08
1030.84 0.66–1.072130.88 0.75–1.04
103 0.73 0.57–0.932131.07 0.94–1.21
1030.560.38–0.82 2131.08 0.90–1.29
1030.95 0.68–1.32 2131.050.85–1.29
1Fruit and vegetable constituents–Total Fruit 1 vegetables: total fruits 1 vegetables; Total vegetables:
spinach, turnip, collard greens, mustard, kale, cole slaw, cabbage, sauerkraut, carrots, string beans, dried
beans, peas, corn, broccoli, cauliflower, brussels sprouts, mixed vegetables, tomatoes, sweet papers, let-
tuce salad, sweet potatoes, yams, tomato juice, tomato sauce, chili and salsa; Total fruits: Whole fruits
1 Fruit Juice; Whole fruits: apples, apple sauce, pears, bananas, dried fruit excluding apricots, peaches,
nectarines, plums, cantaloupe, other melons, strawberries, oranges, tangerines, tangelos, grapefruit and
grapes; Fruit Juice: orange and grapefruit juice, and other fruit juices and drinks.–2Servings per 1,000 cal-
ories.–3Adjusted for sex, age at entry into cohort, BMI, education, alcohol intake, cigarette-smoke-dose,
vigorous physical activity, usual activity throughout the day and total energy.–4Additionally adjusted for
continuous fruit intake.–5Additionally adjusted for continuous vegetable intake.–6Additionally adjusted
for continuous vegetable intake and continuous fruit juice intake.–7Additionally adjusted for continuous
vegetable intake and continuous fruit (no juice) intake.
FREEDMAN ET AL.
collard, mustard and kale: Q3 vs. Q1, HR 5 0.69, 95% CI: 0.48–
1.00) and Gramineae (corn: Q3 vs. Q1, HR: 1.38, 95% CI: 0.99–
1.92) and EAC risk were also observed. As Chenopodiaceae and
Cruciferae had a correlation of 0.46 (Appendix Table AI) and
both contain dark green vegetables, we examined a combined cat-
egory including both Chenopodiaceae and Cruciferae. The associ-
ations of the combined category with EAC and ESCC were simi-
lar to that observed for the separate botanical groups (EAC: Q3
vs. Q1, HR: 0.69, 95% CI: 0.48–0.99; ESCC: 0.73, 0.44–1.22).
As fruit and vegetable intake was correlated with alcohol use,
cigarette smoking, education, sex and vigorous physical activity
(Table I), we examined the association observed between total
fruit and vegetable consumption and ESCC and EAC when strati-
fied by these covariates (Table IV). The risk estimates within each
group appeared similar, and there was no evidence of residual con-
founding from these stratified estimates. However, only 7 non-
smokers were diagnosed with ESCC.
As symptoms of esophageal cancer might affect eating habits
even before cancer diagnosis, we examined risk estimates after
excluding different amounts of initial follow-up. Risk estimates
did not change. For example, after excluding the first 3 years of
follow-up, the HR per serving per 1,000 calories of fruit and vege-
table intake for ESCC (41 cases: 0.75, 0.58–0.97) and EAC (91
cases: 0.96, 0.83–1.11) remained similar to those estimates
observed for all 5 years of follow-up.
In this large prospective study of esophageal cancer in a United
States population, we found that the association between total fruit
and vegetable intake and risk of esophageal cancer differed by his-
tologic type: total fruit and vegetable intake was significantly
associated with decreased risk of ESCC, but not EAC. When
intake of fruit and vegetables were examined separately in mutu-
ally adjusted models, the association with ESCC remained signifi-
cant with fruit but not vegetables, though both fruit and vegetable
intake contributed to the observed reduction in risk. We observed
significant associations between ESCC risk and intake of 2 fruit
groups: Rosacea (apples, peach, nectarines, plums, pears and
strawberries) and Rutaceae (citrus fruits). In contrast, we found a
significant protective association between EAC risk and intake of
Our results for ESCC and fruit and vegetables are consistent
with the results of most previous case–control studies and the lim-
ited number of prospective studies that investigated this associa-
tion.7,12,15,17,18,30–32Together, these results suggest that fruit and
vegetable intake is associated with reduced ESCC risk in both
high risk, China and Iran7,13and lower risk geographical regions,
such as Europe and the United States.12,16,30,31In contrast, the
association between fruit and vegetable intake and EAC risk has
been inconsistent. Some previous studies observed significant
TABLE III – ADJUSTED HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR FRUIT AND VEGETABLE
BOTANICAL GROUPS AND ESOPHAGEAL CANCER
Cases HR95% CI CasesHR 95% CI
Chenopodiaceae: raw spinach
and cooked spinach
Convolvulaceae: sweet potatoes
Cruciferae: broccoli, cauliflower,
brussels sprouts, turnip, cabbage,
coleslaw, collard, mustard and kale
Cucurbitaceae: cantaloupe, watermelon
and honeydew melon
Leguminosae: dried beans, string
beans and peas
Rosaceae: apples, peach, nectarines,
plums, pears, and strawberries
Rutaceae (citrus): oranges, tangerines,
tangelos, and grapefruits
Solanaceae: tomatoes, peppers
1Servings per 1,000 calories.–2Adjusted for sex, age at entry into cohort, BMI, education, alcohol intake, cigarette-smoke-dose, vigorous
physical activity, usual activity throughout the day, and total energy.–3ap for trend 5 0.023;–3bp for trend 5 0.001;–3cp-for trend 5 0.046; all
other p-for trends were >0.05.
ESOPHAGEAL CANCER AND FRUIT AND VEGETABLE INTAKE
inverse associations with fruit intake,33,34vegetable intake35–37
and combined fruit and vegetable intake.15Other studies observed
suggestive but nonsignificant inverse associations with fruit35–38
and vegetables.19,33,38Finally, several studies did not show associ-
ations, yet displayed point estimates below 1 for fruit19,39and veg-
etables.39In comparison to most previous studies of these associa-
tions, our study had a prospective design. Retrospective case–control
studies are subject to several types of bias, including recall bias
where cases potentially recall intake differently than controls and
selection bias where controls in the study are different from the
underlying population of the cases. Only one previous study with a
prospective design investigated the association between fruit and
vegetables intake and EAC risk.19The associations between fruit
and vegetable intake and EAC risk in that study were not significant
(Q3 vs. Q1 of intake: fruit: HR: 0.94, 95% CI: 0.49–1.80; vegetables:
HR: 0.71, 95% CI: 0.34–1.48), but with 65 cases had low power.
The mechanism by which fruit and vegetable intake might pro-
tect against ESCC risk is unclear. In our analysis, 2 botanical
groups showed associations with decreased risk, consistent with a
role for multiple phytochemicals and/or a role for a few phyto-
chemicals common to multiple foods. Carotenoids, flavonoids,
folate, fiber, isothiocyanates and selenium, among other nutrients,
are found in many fruits and vegetables, and could protect against
ESCC. Though we observed a significant association with whole
fruit intake, we did not observe an association with fruit juice.
Fruit juice typically contains high concentrations of Vitamin C,
but low concentrations of nutrients found in the fruit pulp or skin,
such as fiber, flavonoids and carotenoids. Protective associations
have been observed between ESCC risk and intake of fiber37,40
As in all observational studies, it is possible that confounding
by other unmeasured or insufficiently controlled risk factors
explains these associations. Fruit and vegetable intake could also
be a surrogate for other markers of a healthy or privileged life-
style, such as smoking behavior or SES. We adjusted our models
for alcohol consumption, BMI, education, physical activity and
smoking status. Stratifying the analysis by markers of lifestyle
associated with fruit and vegetable intake in this cohort (Table I:
alcohol, education, sex, smoking and vigorous physical activity)
also did not affect the risk estimates (Table IV). Previous studies
of smoking and alcohol, in particular, consistently indicate associ-
ations with ESCC. Residual confounding by alcohol consumption
is unlikely to explain the observed protective association between
fruit and vegetable intake, as the risk estimates were similar in the
26 non-drinkers with ESCC in our study. Though only 7 non-
smokers were diagnosed with ESCC, we observed similar esti-
mates for fruit and vegetable intake among never smokers, former
smokers and current smokers, arguing against residual confound-
ing. Smoking also is a risk factor for EAC,8yet we did not observe
significant associations between total fruit and vegetable intake
and EAC risk, further suggesting against residual confounding by
smoking as an explanation for the protective association observed
between fruit and vegetable intake and ESCC risk.
In contrast to the results for ESCC, total fruit and vegetable
intake was not significantly associated with a lower risk for EAC.
Two sub-groups of vegetables, chenopodiaceae (spinach) and cru-
ciferae (broccoli, cauliflower, brussels sprouts, turnip, cabbage,
coleslaw, collard, mustard and kale), showed a suggestive or sig-
nificant inverse association with risk of EAC. One previous case–
control study observed a significant association between dark
green vegetables and EAC risk39and suggestive but not significant
associations were observed in one case–control study38and one
prospective study19, that examined leafy vegetables (excluding
cabbage). These results suggest that nutrients at high concentra-
tions in dark green vegetables such as isothiocyanates may protect
against the development of EAC.43,44We also observed a sugges-
tive, yet not significant positive association between Gramineae
(fresh or frozen corn) intake and EAC risk. This might be the
result of chance, or intake of such foods may be associated with
an unknown confounder in our analysis.
This study has a number of strengths. It is one of the first pro-
spective examinations of fruit and vegetable intake and esopha-
geal cancer. The very large size of the cohort allowed us to evalu-
ate the association by histological type. Cancer diagnoses were
ascertained prospectively reducing the likelihood of recall bias.
To limit confounding, we adjusted our models for many important
esophageal cancer risk factors, including cigarette smoking, alco-
hol use, BMI, education and physical activity. We also evaluated
whether the associations with total fruit and vegetable intake var-
ied by levels of other esophageal cancer risk factors. This study
also had several limitations. Fruit and vegetable intake was meas-
ured at baseline via a food frequency questionnaire which is sub-
ject to measurement error.45It is possible, therefore, that a true yet
moderate association between EAC risk and total fruit and vegeta-
ble intake might have been attenuated resulting in the observed
null association. Also, separating fruit and vegetable intake into
botanical groups resulted in multiple comparisons increasing the
likelihood of Type I error. We lacked information on gastric
reflux, an important EAC risk factor.8Reflux symptoms might
lead to dietary modification in the years before EAC diagnosis. A
recent cross sectional study in the United States, however, did not
observe differences in fruit and vegetable intake by gastric reflux
status.46Finally, we lacked assessment of smoking duration,
though did assess years of smoking cessation.
In conclusion, total fruit and vegetable intake was significantly
associated with decreased ESCC risk but not with EAC risk. Our
findings suggest that fruit and vegetables may play distinct roles
in ESCC and EAC pathogenesis, and further suggest different
etiologies for these 2 esophageal cancer sub-types.
TABLE IV – STRATIFIED ESTIMATES FOR ESOPHAGEAL CANCER RISK AND TOTAL FRUIT AND VEGETABLE INTAKE
95% CI Cases1
High School or less
Greater than high school
Vigorous physical activity
1Case numbers may not add up to 103 or 213 based on missing data for stratifying factors.–2Continuous variable, servings per 1,000 calories
of total fruit and vegetable intake.
FREEDMAN ET AL.
Cancer incidence data from the Atlanta metropolitan area were
collected by the Georgia Center for Cancer Statistics, Department
of Epidemiology, Rollins School of Public Health, Emory Univer-
sity. Cancer incidence data from California were collected by the
California Department of Health Services, Cancer Surveillance Sec-
tion. Cancer incidence data from the Detroit metropolitan area were
collected by the Michigan Cancer Surveillance Program, Commu-
nity Health Administration, State of Michigan. The Florida cancer
incidence data used in this report were collected by the Florida Can-
cer Data System under contract to the Department of Health
(DOH). The views expressed herein are solely those of the authors
and do not necessarily reflect those of the contractor or DOH.
Cancer incidence data from Louisiana were collected by the Louisi-
ana Tumor Registry, Louisiana State University Medical Center in
New Orleans. Cancer incidence data from New Jersey were col-
lected by the New Jersey State Cancer Registry, Cancer Epidemiol-
ogy Services, New Jersey State Department of Health and Senior
Services. Cancer incidence data from North Carolina were collected
by the North Carolina Central Cancer Registry. Cancer incidence
data from Pennsylvania were supplied by the Division of Health
Statistics and Research, Pennsylvania Department of Health, Harris-
burg, Pennsylvania. The Pennsylvania Department of Health specif-
ically disclaims responsibility for any analyses, interpretations or
conclusions. We are indebted to the participants in the NIH-AARP
Diet and Health Study for their outstanding cooperation.
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TABLE AI – PEARSON CORRELATION COEFFICIENTS FOR INTAKE1OF DIFFERENT BOTANICAL GROUPS
Chenopodiaceae Compositae Convolvulaceae Cruciferae Cucurbitaceae Gramineae Leguminosae Musaceae Rosaceae Rutaceae Solanaceae Umbelliferae Vitaceae
0.180.10 0.46 0.09 0.04 0.190.060.12 0.060.14 0.170.08
1Intake of botanical groups per 1,000 calories.
FREEDMAN ET AL.