Fruit and vegetable intake and esophageal cancer in a large prospective cohort study
Changing patterns of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) incidence worldwide 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 prospective 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, cigarette 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 relation of fruit and vegetable intake and esophageal cancer risk may vary by histologic type. © 2007 Wiley-Liss, Inc.
Esophageal cancer is the sixth most common cause of cancer death worldwide with ∼386,000 deaths in 20021 and has 2 primary 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, 3, 4 However, in high risk geographic regions, such as northeastern Iran and Linxian, China, ESCC is the predominant form.5, 6, 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.8 Finally, although high body mass index (BMI) is consistently associated with increased EAC risk,9 it may be associated with decreased ESCC risk.7, 10, 11
Whether intake of fruit and vegetables, rich in potentially anti-carcinogenic compounds, protects against ESCC and EAC incidence 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.12 However, 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, 16 and therefore susceptible to the ecological fallacy or recall and selection bias, particularly as esophageal cancer affects the digestive tract and has a 5 year survival rate of just 16%.1 To our knowledge, only 4 prospective studies investigated fruit and vegetable intake and esophageal cancer risk. One study investigated the association between fresh vegetable and fruit intake and ESCC in Linxian, China, a high risk region for esophageal cancer. Though this study lacked comprehensive dietary assessment, a significant protective association was observed with fruit intake.7 Similarly, 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,18 but did not investigate other vegetable types or fruits. The European Prospective Investigation of Cancer using a small number of cases (n = 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 prospective 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.20 Between 1995 and 1996, a questionnaire eliciting information on demographic characteristics, dietary intake, and health-related behaviors was mailed to members of AARP, formerly 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. We excluded subjects with cancer at baseline (n = 51,219), proxy respondents (n = 15,760), those with total energy, total fruit, total vegetable, or total fruit and vegetable intake more than 2 interquartile ranges from the mean (n = 8,616), and those who died or were diagnosed with cancer on the first day of follow-up (n = 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.21 Follow-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).22 We 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-squamous 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 ‘6+ times per day’ for beverages and from ‘never’ to ‘2+ times per day’ for solid foods and 3 categories of portion size. The food items, portion sizes, and nutrient database (Pyramid Servings Database) were constructed23 using data from the US Department of Agriculture's 1994–1996 Continuing Survey of Food Intake by Individuals Survey.24 The 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 Department 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.25 The 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 facilitate analysis, we created quintiles containing equal numbers of cohort participants using the distribution of total fruit and vegetable intake, total fruit intake, total vegetable intake, non-juice fruit intake and fruit juice intake for the whole cohort. Fruit and vegetables were further grouped into botanical groups based on botanical taxonomy to help identify possible chemopreventive phytochemicals.27 For 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 correlation 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.28 We 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 categorical variables of sex, education (< high school education, completion 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 method29 and 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 analyzed data using a standard multivariate model that included fruit and vegetable intake (servings/day), total energy, and other covariates and the results were similar to those obtained with the nutrient 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 conducted by assigning participants the median intake for their categories and entering it as a continuous term in the regression model.
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 variable.
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 individuals 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 participants with low total fruit and vegetable intake, participants with higher intake tended to be women, more educated, drink less alcohol, non-smokers, and participate more frequently in vigorous physical activities. BMI, a strong EAC risk factor,9 did not differ across quintiles of total fruit and vegetable intake (Table I).
Table I. Study Characteristics by Quintiles of Fruit and Vegetable Intake Per 1,000 Calories
|Cohort (Number, %)||98,160||20.0||98,161||20.0||98,160||20.0||98,161||20.0||98,160||20.0|
|Total fruit and vegetable intake2 (Median, interquartile range)||1.5||1.2–1.8||2.4||2.2–2.6||3.2||3.0–3.4||4.1||3.8–4.4||5.8||5.2–6.8|
|Sex (Number, %)|
|Age (Median, interquartile range)||61.6||56.8–66.0||62.4||57.6–66.5||62.8||57.9–66.7||63||58.1–66.8||63.1||58.2–66.9|
|BMI (Median, interquartile range) (kg/m2)||26.6||24.2–29.8||26.6||24.3–29.7||26.5||24.0–29.5||26.3||23.8–29.3||25.8||23.4–28.9|
|Total daily calories (Median, interquartile range)||1,955||1447.0–2600.5||1,802||1377.5–2333.9||1,694||1306.6–2176.6||1,592||1231.8–2046.7||1,445||1105.0–1870.4|
|Education (Number, %)|
| Less than high school||7,941||27.3||5,921||20.3||5,207||17.9||5,018||17.2||5,052||17.3|
| 12 years (completed high school)||22,827||23.8||19,259||20.1||18,227||19.0||17,951||18.7||17,605||18.4|
| Some post-high school training||34,195||21.1||32,565||20.1||32,008||19.7||31,506||19.4||31,934||19.7|
| Completed college||16,889||18.3||19,487||21.1||19,397||21.0||18,867||20.4||17,803||19.3|
| Completed graduate school||13,529||14.0||18,421||19.0||20,659||21.3||22,047||22.8||22,235||22.9|
|Alcohol intake (Number, %)|
| Zero drinks per day||22,190||18.9||21,390||18.2||22,045||18.8||23,725||20.2||28,100||23.9|
| 0< to 1 drinks per day||42,652||16.4||49,926||19.2||53,571||20.6||56,320||21.7||57,509||22.1|
| 1< to 3 drinks per day||14,960||20.1||17,443||23.4||16,749||22.5||14,555||19.6||10,700||14.4|
| > 3 drinks per day||17,959||48.6||9,071||24.5||5,496||14.9||3,146||8.5||1,306||3.5|
|Cigarette Smoking Status (Number, %)|
| Never smoked||24,729||14.2||32,456||18.6||36,076||20.7||39,010||22.4||41,764||24.0|
|Usual activity throughout the day (Number, %)|
| Sit during the day/little walking||9,392||24.2||8,224||21.2||7,579||19.5||7,160||18.5||6,435||16.6|
| Sit during the day/walk a fair amount||31,793||20.1||32,733||20.7||32,401||20.5||31,556||20.0||29,543||18.7|
| Stand/walk a lot—no lifting||34,213||18.5||35,845||19.4||36,930||20.0||38,053||20.6||39,707||21.5|
| Lift/carry light loads, stairs, hills||16,593||19.7||16,469||19.6||16,693||19.9||16,892||20.1||17,372||20.7|
| Do heavy work/carry loads||4,055||28.9||2,961||21.1||2,508||17.9||2,270||16.2||2,220||15.8|
|Vigorous physical activity (Number, %)|
| 1–3 times/month||16,509||24.8||14,869||22.3||13,127||19.7||11,998||18.0||10,161||15.2|
| 1–2 times/week||21,624||20.5||22,750||21.5||22,036||20.9||20,897||19.8||18,379||17.4|
| 3–4 times/week||19,907||15.2||24,859||18.9||27,379||20.9||29,209||22.3||29,895||22.8|
| 5 or more times/week||13,405||14.3||15,652||16.7||18,164||19.4||20,761||22.2||25,625||27.4|
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). Compared 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 contribute to the protective effect observed overall). The association was stronger with whole fruits (Q5 vs. Q1, HR = 0.29, 95% CI: 0.12–0.73) than with fruit juice (Q5 vs. Q1, HR = 0.83, 95% CI: 0.45–1.52). In contrast, neither vegetable intake, nor fruit intake was significantly associated with EAC risk.
Table II. Adjusted Hazard Ratios and 95% Confidence Intervals for Fruit and Vegetable Intake and Esophageal Cancer
|Total fruit and vegetables|
| Continuous variable||103||0.78||0.67–0.91||213||0.98||0.90–1.08|
|Quintiles of intake (median)|
| Q1 (1.52)||40||1.00||(ref)||55||1.00||(ref)|
| Q2 (2.42)||26||0.93||0.56–1.55||41||0.88||0.58–1.32|
| Q3 (3.19)||18||0.74||0.41–1.34||48||1.17||0.78–1.76|
| Q4 (4.14)||10||0.46||0.22–0.96||41||1.17||0.76–1.79|
| Q5 (5.89)||9||0.44||0.20–0.96||28||0.99||0.61–1.61|
| p-value for trend|| ||0.011|| || ||0.683|| |
| Continuous variable||103||0.84||0.66–1.07||213||0.88||0.75–1.04|
|Quintiles of intake (median)|
| Q1 (0.7)||39||1.00||(ref)||51||1.00||(ref)|
| Q2 (1.15)||22||0.78||0.46–1.34||53||1.17||0.79–1.72|
| Q3 (1.55)||17||0.70||0.39–1.25||45||1.08||0.72–1.62|
| Q4 (2.08)||14||0.64||0.34–1.22||36||0.96||0.62–1.49|
| Q5 (3.18)||11||0.57||0.28–1.18||28||0.92||0.57–1.50|
| p-value for trend|| ||0.097|| || ||0.518|| |
| Continuous variable||103||0.73||0.57–0.93||213||1.07||0.94–1.21|
|Quintiles of intake (median)|
| Q1 (0.40)||42||1.00||(ref)||51||1.00||(ref)|
| Q2 (0.98)||21||0.72||0.42–1.23||45||1.03||0.68–1.54|
| Q3 (1.46)||19||0.77||0.44–1.36||41||1.07||0.70–1.64|
| Q4 (2.00)||12||0.56||0.28–1.11||46||1.37||0.90–2.09|
| Q5 (3.25)||9||0.46||0.21–1.00||30||1.04||0.64–1.69|
| p-value for trend|| ||0.033|| || ||0.565|| |
| Continuous variable||103||0.56||0.38–0.82||213||1.08||0.90–1.29|
|Quintiles of intake (median)|
| Q1 (0.22)||42||1.00||(ref)||47||1.00||(ref)|
| Q2 (0.55)||29||0.98||0.60–1.59||52||1.30||0.87–1.94|
| Q3 (0.89)||13||0.52||0.27–0.99||40||1.14||0.74–1.77|
| Q4 (1.35)||13||0.58||0.30–1.13||38||1.25||0.79–1.98|
| Q5 (2.20)||6||0.29||0.12–0.73||36||1.46||0.90–2.36|
| p-value for trend|| ||0.003|| || ||0.195|| |
| Continuous variable||103||0.95||0.68–1.32||213||1.05||0.85–1.29|
|Quintiles of intake (median)|
| Q1 (0.00)||35||1.00||(ref)||49||1.00||(ref)|
| Q2 (0.15)||15||0.59||0.32–1.09||33||0.71||0.46–1.11|
| Q3 (0.39)||20||0.81||0.46–1.41||42||0.87||0.57–1.32|
| Q4 (0.70)||17||0.78||0.43–1.41||54||1.21||0.82–1.80|
| Q5 (1.37)||16||0.83||0.45–1.52||35||0.85||0.55–1.33|
| p-value for trend|| ||0.863|| || ||0.766|| |
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, nectarines, 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, Chenopodiaceae (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, collard, mustard and kale: Q3 vs. Q1, HR = 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 category including both Chenopodiaceae and Cruciferae. The associations of the combined category with EAC and ESCC were similar 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).
Table III. Adjusted Hazard Ratios and 95% Confidence Intervals for Fruit and Vegetable Botanical Groups and Esophageal Cancer
|Chenopodiaceae: raw spinach and cooked spinach||Q1||0||37||1.00||(ref)||92||1.00||(ref)|
|Convolvulaceae: sweet potatoes and yams||Q1||0||36||1.00||(ref)||87||1.00||(ref)|
|Cruciferae: broccoli, cauliflower, brussels sprouts, turnip, cabbage, coleslaw, collard, mustard and kale||Q1||0.06||45||1.00||(ref)||100||1.00||(ref)|
|Cucurbitaceae: cantaloupe, watermelon and honeydew melon||Q1||0.01||42||1.00||(ref)||73||1.00||(ref)|
|Leguminosae: dried beans, string beans and peas||Q1||0.12||49||1.00||(ref)||78||1.00||(ref)|
|Rosaceae: apples, peach, nectarines, plums, pears, and strawberries||Q1||0.06||60||1.00||(ref)||90||1.00||(ref)|
|Rutaceae (citrus): oranges, tangerines, tangelos, and grapefruits||Q1||0.08||49||1.00||(ref)||81||1.00||(ref)|
|Solanaceae: tomatoes, peppers||Q1||0.11||44||1.00||(ref)||74||1.00||(ref)|
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 stratified by these covariates (Table IV). The risk estimates within each group appeared similar, and there was no evidence of residual confounding from these stratified estimates. However, only 7 non-smokers were diagnosed with ESCC.
Table IV. Stratified Estimates for Esophageal Cancer Risk and Total Fruit and Vegetable Intake
|Alcohol use||Never drinker||26||0.75||0.57–0.98||43||1.06||0.90–1.26|
|Education||High School or less||32||0.86||0.66–1.11||48||0.96||0.79–1.17|
|Greater than high school||69||0.73||0.60–0.89||153||1.01||0.90–1.12|
|Vigorous physical activity||<3 times/week||60||0.82||0.66–1.01||117||1.01||0.89–1.15|
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 vegetable 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 histologic 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 mutually adjusted models, the association with ESCC remained significant 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 Chenopodiaceae.
Our results for ESCC and fruit and vegetables are consistent with the results of most previous case–control studies and the limited number of prospective studies that investigated this association.7, 12, 15, 17, 18, 30, 31, 32 Together, these results suggest that fruit and vegetable intake is associated with reduced ESCC risk in both high risk, China and Iran7, 13 and lower risk geographical regions, such as Europe and the United States.12, 16, 30, 31 In contrast, the association between fruit and vegetable intake and EAC risk has been inconsistent. Some previous studies observed significant inverse associations with fruit intake,33, 34 vegetable intake35, 36, 37 and combined fruit and vegetable intake.15 Other studies observed suggestive but nonsignificant inverse associations with fruit35, 36, 37, 38 and vegetables.19, 33, 38 Finally, several studies did not show associations, yet displayed point estimates below 1 for fruit19, 39 and vegetables.39 In comparison to most previous studies of these associations, 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.19 The 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 protect 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 phytochemicals 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 and carotenoids.41, 42
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 lifestyle, 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 associations 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 estimates for fruit and vegetable intake among never smokers, former smokers and current smokers, arguing against residual confounding. Smoking also is a risk factor for EAC,8 yet 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 cruciferae (broccoli, cauliflower, brussels sprouts, turnip, cabbage, coleslaw, collard, mustard and kale), showed a suggestive or significant inverse association with risk of EAC. One previous case–control study observed a significant association between dark green vegetables and EAC risk39 and suggestive but not significant associations were observed in one case–control study38 and one prospective study19, that examined leafy vegetables (excluding cabbage). These results suggest that nutrients at high concentrations in dark green vegetables such as isothiocyanates may protect against the development of EAC.43, 44 We also observed a suggestive, 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 prospective examinations of fruit and vegetable intake and esophageal cancer. The very large size of the cohort allowed us to evaluate 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, alcohol use, BMI, education and physical activity. We also evaluated whether the associations with total fruit and vegetable intake varied by levels of other esophageal cancer risk factors. This study also had several limitations. Fruit and vegetable intake was measured at baseline via a food frequency questionnaire which is subject to measurement error.45 It is possible, therefore, that a true yet moderate association between EAC risk and total fruit and vegetable 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.8 Reflux 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.46 Finally, 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.
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 University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer 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 Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology 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, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically 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.
Table AI. Pearson Correlation Coefficients for Intake1 of Different Botanical Groups
|Convol-vulaceae|| || ||1.00||0.17||0.10||0.08||0.14||0.10||0.11||0.06||0.07||0.09||0.07|
|Cruciferae|| || || ||1.00||0.16||0.12||0.31||0.11||0.21||0.09||0.20||0.29||0.12|
|Cucur-bitaceae|| || || || ||1.00||0.16||0.10||0.11||0.23||0.14||0.13||0.12||0.22|
|Gramineae|| || || || || ||1.00||0.22||0.03||0.08||0.03||0.09||0.06||0.08|
|Legumi-nosae|| || || || || || ||1.00||0.07||0.14||0.03||0.14||0.23||0.08|
|Musaceae|| || || || || || || ||1.00||0.26||0.15||0.07||0.11||0.09|
|Rosaceae|| || || || || || || || ||1.00||0.18||0.13||0.21||0.19|
|Rutaceae|| || || || || || || || || ||1.00||0.09||0.07||0.11|
|Solanaceae|| || || || || || || || || || ||1.00||0.15||0.09|
|Umbelli-ferae|| || || || || || || || || || || ||1.00||0.09|
|Vitaceae|| || || || || || || || || || || || ||1.00|