Abstract

OBJECTIVES:

• To review all prospective studies which provided data about total fruits or vegetables, their subgroups, and specific types of vegetables and fruits, in relationship with lung cancer risk, disease progression and mortality/survival.
• To define the amount of consumption found to be related with the described effects on cancer.
• To define possible effect modification by confounders.

DATA SOURCE: The Pubmed database was searched (No start date - Feb 10, 2009) for relevant articles using the keywords "cancer, neoplasm, or neoplasms" combined with "vegetables, vegetable, fruit, or fruits" and a fair amount of other keywords. The exact search term is described in the methods.
Prospective studies published in the English language were included. Reference lists were searched for additional articles.
RESULTS: 61 articles were found which provided information about 31 different cohorts.
Of these, two articles were excluded because the full text articles are published in Chinese (13, 15b).
Results are described when any evidence for an association - as defined in the Methods - was found. In addition, data about total vegetables or fruits is described

• Total disease risk.
  -Total vegetables: 32 articles providing information about 20 different cohorts were found. Vegetables possibly protect against lung cancer risk among men. This effect was found at the level of consumption of ≥ 170 g/day. No association was found among women. No evidence was found for a modifying effect of smoking status on the relation between vegetables and lung cancer risk. In a pooled analysis of 8 cohorts (data for men + women combined), the protective effect was restricted to cancer cases diagnosed at age < 65.
  -Total fruits: 34 articles, providing information about 20 different cohorts were found. Convincing evidence was found for a protective effect of fruit against lung cancer risk. Stratified by sex, probable evidence for an effect was found among men, while among women this evidence was suggestive. Levels of consumption for this effect were ≥ 127 g/day among men, but could not be defined among women. No consistent or convincing effects were found by smoking status. But results look most promising for current smokers.
  -Suggestive evidence for a protective effect of the following variables was found: lettuce (≥ 1.26 servings/week), tomatoes (≥ 0.5 tomato/day), green leafy vegetables ≥ 0.5 serving/day, and cruciferous vegetables.
  -Possible protective effects of the following items were found: apples (> 1 apple/week), oranges/tangerines (> 1 orange/tangerine/week) and tomato sauce (no level of consumption could be defined).
  -Possible protective effects of intermediate levels of consumption were found of carrots (0.5 to < 1 serving/week), and - among women - of citrus fruit (7 servings/week).
  -Orange/grapefruit juice probably protects against lung cancer risk at an intermediate level of consumption (24-55 g/day). A possible protective effect was found with higher consumption.
• Advanced stage/metastatic disease risk or disease progression.
  No data was found.
• Mortality risk.
  -Total vegetables: Data about 4 cohorts was found. No association was found in any cohort.
  -Total fruits: 11 articles providing information about 9 different cohorts were found. Total fruit probably protects against lung cancer mortality. Stratified by sex, probable evidence for an effect was found among men, while little data is available about women. The level of consumption for this effect was found at daily consumption.
• Oranges possibly protect against lung cancer mortality among men (> 3 oranges/wk).
• Suggestive evidence was found for a protective effect of citrus fruit among men. No level of consumption could be defined for this effect.

CONCLUSION:
Total vegetables possibly protect against lung cancer risk among men (≥ 170 g/day), but not women. This protective effect might be restricted to cancer cases diagnosed at age < 65 years. Convincing evidence was found for a protective effect of fruit. Stratified by sex, probable evidence was found for a protective effect of fruit among men (≥ 127 g/day), while the evidence was only suggestive for an association among women. Suggestive evidence of a protective effect was found of green leafy vegetables and cruciferous vegetables, and among women citrus fruit is possibly protective (median 7 servings/wk).
Among specific vegetable or fruit items, apples (> apple/wk), oranges/tangerines (> 1 orange/tangerine/wk), tomato sauce (no level of consumption could be defined) and an intermediate level of carrot consumption (0.5-< 1 serving/wk) possibly protect against lung cancer risk. Orange/grapefruit juice probably protects against lung cancer risk at an intermediate level of consumption (24-55 g/day), and a possible protective effect was found with higher consumption. Suggestive evidence was found for a protective effect of lettuce (≥ 1.26 servings/week), and tomatoes (≥ 0.5 tomato/day). For lung cancer mortality, no evidence was found for an effect of vegetables, but among men, a probable protective effect of total fruit (at daily consumption), a possible protective effect of oranges (> 3 oranges/wk), and suggestive evidence of a protective effect of citrus fruit (no level of consumption could be defined) were found.
LIMITATIONS: Though this review suggests a probable protective effect of fruit against lung cancer mortality, it should be noted that in most cohorts consumption was measured prior to cancer diagnosis. Little is known about the effect of fruit consumption following cancer diagnosis.

Total vegetables and lung cancer risk. Stratified by sex.

32 articles, providing information about 20 different cohorts were found.

About the male analysis: In 2003 a pooled analysis of 8 prospective studies was published (Smith-Warner SA). The analysis included data from a total of 1,808 men of which 298 were from The ATBC Study. In 2002 another publication about The ATBC Study included data from 1,644 men, which is nearly as much as the total amount of cases from the pooled analysis. A similar finding was done with The Netherlands Cohort Study. For this systematic review it was chosen not to include data about men from the pooled analysis as a whole, but from the individual cohorts.
As a consequence of this decision, data about men from The New York State Cohort (including 392 men) can not be included in this review, since no data is published about this specific cohort.

Results:

• Men: Data about 11 cohorts including a total of 8,107 cases was found. A significant protective effect was found in 3 cohorts (11, 18, 29) including 7,162 cases (88% of all cases). No associations were found in the remaining 8 cohorts.
• Women: Data about 9 cohorts including a total of 3,863 cases was found. No significant associations were found.
• In three other cohorts including a total of 2,294 cases, risk was not stratified by sex. No associations were found.

Inclusion of intermediate levels of consumption:
The figure below included RRs among men from all cohorts in which any (non)significant association was found at any level of consumption. The level at which a significant protective effect could be found differed among the cohorts (≥ 110 g/day; both 170-235 and ≥ 424 g/day; and 294 g/day for Holick CN, George SM, and , Balder HF, respectively). Overlapping effects were found at the level of ≥ 170 g/day.

Effect modification by variables other than sex and smoking status:
A significant protective effect among cancer cases diagnosed at age < 65 years, but not ≥ 65 years was found in a pooled analysis of 8 cohorts (24). In the same analysis, no evidence of effect modification was found by the number of fruit and vegetable questions included on a study's FFQ.
No evidence of effect modification was found by alcohol intake or multivitamin use in two cohorts (14), or by use of beta carotene/vitamin A supplements in another cohort (22).

Conclusion: For men, a significant protective effect was found in 3 out of 11 cohorts, and no (non)significantly increased risks were found in the remaining cohorts. Though these 3 cohorts included 88% of all male cases, consistency is low. Total vegetables possibly protect against lung cancer risk amon men. Levels of consumption for this effect were ≥ 170 g/day, and the effect may be restricted to cancer cases diagnosed at age < 65 years. No association was found among women.

Total vegetables and lung cancer risk. Stratified by smoking status.

About the analysis: For this systematic review, data is stratified by smoking status into current smokers, former smokers, and never smokers.
The JPHC Study (25) and CARET Study (22) provided data about "ever smokers" without stratifying into former vs current smokers. Likewise, The Finnish Mobile clinic Health Cohort (8) provided data about "current nonsmokers" without stratifying into nonsmokers vs former smokers. It was chosen not to include this data in the following tables.

Results: In general, few significant associations were seen. RRs varied from < 1 to > 1 across all categories of smoking status. Further stratification by sex is lacking, apart from data from The NIH-AARP Diet and Health Study.
In addition, no associations were found with current nonsmokers (8), or ever smokers (22, 25) in the aforementioned 3 cohorts. And no interaction was found with smoking duration in another cohort (16) (results shown in extended version of tables).

Conclusion: No evidence was found for a modifying effect of smoking status on the relation between vegetables and lung cancer risk.

Total vegetables and lung cancer mortality.

Data about lung cancer mortality is provided by 4 cohorts. Three of these cohorts measured food intake prior to cancer diagnosis (5, 9, 16), and another one following diagnosis (19). No associations were found.

Conclusion: Little is known about the effect of vegetables on lung cancer mortality. No evidence was found for an association.

Total fruit and lung cancer risk. Stratified by sex.

34 articles, providing information about 20 different cohorts were found.

About the male analysis: In 2003 a pooled analysis of 8 prospective studies was published (Smith-Warner SA). The analysis included data from a total of 1,808 men of which 298 were from The ATBC Study. In 2002 another publication about The ATBC Study included data from 1,644 men, which is nearly as much as the total amount of cases from the pooled analysis. A similar finding was done with The Netherlands Cohort Study. For this systematic review it was chosen not to include data about men from the pooled analysis as a whole, but from the individual cohorts.
As a consequence of this decision, data about men from The New York State Cohort (including 392 men) can not be included in this review, since no data is published about this specific cohort.

Results:

• Men: Data was found about 11 cohorts including a total of 8,116 cases. A significant protective association was found in 4 cohorts including 7,300 cases (8, 11, 18, 29), and a nonsignificant trend of a protective effect was found in one other study (1). No associations were found in the remaining 6 cohorts).
• Women: Data was found about 9 cohorts including a total of 3,862 cases. A nonsignificant protective effect was found in a pooled analysis of 6 cohorts (24), and a nonsignificant trend of a protective effect was found in one other cohort (27) including 1,145 cases. No other associations were found, but all RRs were < 1.
• In five cohorts including a total of 2,397 cases, risk was not stratified by sex. Significant protective effects were found in 2 cohorts (7, 19), and in the placebo arm of another cohort (22) including 1,504 cases. No other associations were found.

Inclusion of intermediate levels of consumption:
The figure below included RRs among men from all cohorts in which any (non)significant association was found at any level of consumption. Results from one cohort of small size could not be included since levels of consumption were not clearly defined (8):
Though a significant trend of a protective effect was found in one cohort (George SM), no significant effect was found at any level of consumption.
Significant effects in the other cohorts were found at the level of consumption of ≥ 88 g/day (Balder HF), and ≥ 127 g/day (Holick CN).

Effect modification by variables other than sex and smoking status:
No evidence of effect modification was found by age of diagnosis, or by the number of fruit and vegetable questions included on a study's FFQ according to a pooled analysis of 8 cohorts (24). And no evidence of effect modification was found by alcohol intake or multivitamin use in two cohorts (14).
But in one cohort, the protective effect of fruit was restricted to non-users of beta carotene/vitamin A supplements (22).

Conclusion: Significant protective associations were found in 7 cohorts - two of which are of very large size (19, 29). These 7 cohorts included a total of 61% of all cases. In addition, nonsignificant protective associations were found in several other studies including another 10% of all cases, and no (non)significantly increased risk was found in the remaining cohorts.
Convincing evidence was found for a protective effect of total fruit against lung cancer risk. Stratified by sex, evidence was fairly strong for a protective effect among men, but only suggestive for a protective effect among women. Levels of consumption for this effect were ≥ 127 g/day among men, but could not be defined among women.

Total fruit and lung cancer risk. Stratified by smoking status.

About the analysis: For this systematic review, data is stratified by smoking status into current smokers, former smokers, and never smokers.
The JPHC Study (25) and CARET Study (22) provided data about "ever smokers" without stratifying into former vs current smokers. Likewise, The Finnish Mobile clinic Health Cohort (8) provided data about "current nonsmokers" without stratifying into nonsmokers vs former smokers. It was chosen not to include this data in the following tables.

Results:

• Current smokers: Data was found about a pooled analysis of 8 studies and 3 other studies including a total of 5,518 cases. Significant protective effects were found in the pooled analysis (24) and another study (19) including 2,646 cases. No associations were found in the remaining cohorts.
• Former smokers: No (non)significant associations were found, but all RRs were slightly < 1.
• Never smokers: No (non)significant associations were found, and RRs ranged widely.

Conclusion: No consistent or convincing effects were found by smoking status. But results look most promising for current smokers.

Total fruit and lung cancer mortality.

11 articles, providing information about 9 different cohorts were found. Only in one cohort food measurement was conducted following cancer diagnosis (19).

Results:

• Men: Data was found about 7 cohorts including 4,057 cases. Significant protective associations were found in 5 studies including 3,797 cases (3, 5, 17, 20, 21). RRs were below 1 in both remaining cohorts.
  Risk was often presented in frequency of consumption (times or days/week: 3, 17, 20, 21).
• Women: Data was found about 3 cohorts. No (non)significant associations were found, but RRs were < 1.
• Two other cohorts did not stratify risk by sex. No signficant associations were found, but RRs were < 1.

Conclusion: Significant protective associations were found in 5 cohorts - one of which of very large size (3). These 5 cohorts included a total of 84% of all cases. In addition, all RRs were below 1.
Total fruit probably protects against lung cancer mortality. Stratified by sex, a probable protective effect was found among men, while little data is available about women. The level of consumption for this effect was found at daily consumption.