Abstract

BACKGROUND: Early articles often found protective effects of vegetables and fruits against various types of cancer, but results were mostly based on data from case-control studies (1). Later reviews which could be based on more data from prospective studies found little association with most types of cancer.
The WCRF recently published a systematic review providing information about various dietary items in relation to various types of cancer (2). A protective effect of vegetables and fruits was found against few cancer types. Since no information was provided about the relation with total cancer, information may still be difficult to translate to recommendations, because vegetables and fruits may negatively impact other - less studied - cancer sites. This theory is strenghtened by a recent article examining a large cohort, and providing information about > 50,000 cancer cases (3). In this cohort, protective effects were found for some cancer sites, but increased risks were found for other types of cancer by high consumption of vegetables or fruits. The balance in these effects resulted in (almost) no association with total cancer risk.
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 total 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 - Sep 11, 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.
r> Prospective studies published in the English language were included. Reference lists were searched for additional articles.
RESULTS: 33 articles were found which provided information about 24 different cohorts.
Of these, 0 articles needed to be excluded because of language restrictions. And no articles were excluded for any other reasons.
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.
  -For total vegetables, 15 articles providing information about 11 different cohorts were found, including 70,570 incident cancer cases. Among men, significant protective effects were found in 2 cohorts including 90% of all cases, and no (non)significantly increased risks were found. Possible evidence was found for a protective effect of total vegetables against total cancer risk among men. No level of consumption could be defined for this effect. Results among women are inconsistent and do not provide evidence for an association. Stratification by smoking status showed that the protective effect was only found in male smokers. Dietary supplement use may be an effect modifier, but results are inconsistent.
  -For total fruits, 21 articles providing information about 16 different cohorts were found, including 70,802 incident cancer cases. Hardly any association was found among men, and inconsistent findings were done among women. Though some nonsignificant trends of protective effects were found among women, the power of the effect is very weak, and the weight of the evidence does not justify the label of a possible association. No evidence was found for an association of total fruit with total cancer risk. Dietary supplement use may be an effect modifier, but results are inconsistent.
  -A significantly increased cancer risk of citrus fruit juice among multivitamin supplement users was found in a pooled analysis of 2 cohorts. No other associations were found. Citrus fruit juice possibly increases total cancer risk among multivitamin supplement users.
• Advanced stage/metastatic disease risk or disease progression.
  No article provided information about any of the dietary variables in this review in relation to advanced/metastatic stage disease, or disease progression.
• Mortality risk.
  -For total vegetables, 6 articles providing information about 6 different cohorts were found. No associations were found in any cohort. In addition, no evidence was found for an association when 5 cohorts examining green-yellow vegetables were added to this model.
  -For total fruits, 11 articles providing information about 10 cohorts were found. Significant protective effects were found in 2 cohorts. Evidence was judged suggestive for a protective effect of total fruits against total cancer mortality. This effect was found at the level of daily vs less frequent consumption.

CONCLUSION: Among men, total vegetables possibly protect against total cancer risk. This effect was limited to male smokers, and no evidence was found for an association among women. The level of consumption for this effect could not be defined. Suggestive evidence was found for a protective effect of total fruits against total cancer mortality. This effect was found for (almost) daily vs less frequent consumption. No evidence was found for an effect of total fruit with total cancer risk, or total vegetables with total cancer mortality. Multivitamin/dietary supplements may modify the effect of total vegetables or total fruit with total cancer risk, but results are inconsistent. Citrus fruit juice possibly increases cancer risk among multivitamin supplement users. No further evidence was found for an association between any vegetable/fruit subgroup or item and total cancer risk or mortality.
LIMITATIONS: Most associations in this review came from examining consumption as a continuous variable, which makes it impossible to define the amount of consumption necessary to find an association, making possible recommendations difficult.
Information from a lot of cohorts - which are currently being followed-up - is not yet available in relation to total cancer. Some cohorts are very large, and future information from these populations may differ from the findings in this review. In the coming decades information will be provided from hundreds of thousands of cancer cases and cancer deaths, and this review should be seen in that perspective.
AUTHORS NOTE: Though current evidence does not support a strong role of vegetables & fruits in cancer prevention, the author supports the current recommendations on fruits and vegetables because of possible protective effects against risk of coronary heart disease (4) and stroke (5).
REFERENCES:
1) Riboli E. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr. 2003 Sep;78(3 Suppl):559S-569S. Full text
2) World Cancer Research Fund / American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR, 2007. Full text
3) George SM. Fruit and vegetable intake and risk of cancer: a prospective cohort study. Am J Clin Nutr. 2009 Jan;89(1):347-53. Abstract
4) He FJ. Increased consumption of fruit and vegetables is related to a reduced risk of coronary heart disease: meta-analysis of cohort studies. J Hum Hypertens. 2007 Sep;21(9):717-28. Abstract
5) He FJ. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet. 2006 Jan 28;367(9507):320-6. Abstract

Total vegetables and total cancer risk.

15 articles, providing information about 11 different cohorts were found (The EPIC Cohort was counted as 1 cohort, though data from 3 different populations was available). The sum of these cohorts provided information about a total of 70,570 incident cancer cases.
Associations are stratified by sex:

Men: Data for men was provided by 7 cohorts, including a total of > 40,520 cases.
Significant protective effects were found in 2 cohorts including 36,590 cases (18, 22). No associations were found in the remaining 7 cohorts (2, 9, 11, 15, 20). The protective effects were once published as a categorized variable and once as a continuous variable. Therefore, no level of consumption could be defined for this effect.
Women: Data for women was provided by 5 cohorts, combining > 25,340 cases.
A significant protective effect was found in 1 cohort, including 430 cases (18 [Benetou V.]), but a nonsignificant trend of an increased risk was found in another cohort, including 15,792 cases (22). No associations were found in the remaining cohorts (2, 11, 18 [Olsen A.], 20).

Inclusion of intermediate levels of consumption:
Significant protective effects at any level of consumption were restricted to 2 cohorts: One cohort among women only at 3 different levels of consumption (Benetou V; at ≥ 414 g/day), and one cohort among men only (George SM; at 235-312 g/day, and at ≥ 424 g/day).
A nonsignificant trend of an increased risk was found in one cohort among women (George SM;, but no (non)significantly increased risks were found at any level of consumption in any cohort.

Conclusion: Among men, significant protective effects were found in 2 cohorts including 90% of all cases, and no (non)significantly increased risks were found. Total vegetables possibly protect against total cancer risk among men. No level of consumption could be defined for this effect. Results among women are inconsistent and do not provide evidence for an association.

Total vegetables and total cancer mortality.

6 articles, providing information about 6 different cohorts were found. No associations were found in any cohort.

Conclusion: No evidence was found for an association between total vegetables and total cancer mortality.

Total fruit and total cancer risk.

21 articles, providing information about 16 different cohorts were found (The EPIC Cohort was counted as 1 cohort, though data from 3 different populations was available). The sum of these cohorts provided information about a total of 70,802 incident cancer cases.
Associations are stratified by sex:

Men: Data for men was provided by 8 cohort, including a total of > 40,621 cases.
A significant protective effect was only found in the smallest cohort, including 138 cases (15). No other associations were found, but RRs were ≤ 1.
Women: Data for women was provided by 6 cohorts, including a total of > 25,471 cases.
A significant protective effect was found in one small cohort, including 690 cases (2). A nonsignificant trend of a protective effect was found in one other cohort, including 131 cases (10). And a nonsignicant trend of a protective effect was found in another cohort, but the strength of the association is extremely weak: a 1% decreased risk (22).

Inclusion of intermediate levels of consumption:
Significant protective effects at any level of consumption were as follows: Among men > 200 g/day (Jansen MC), among women > 192 g/day (Shibata A), and 335 g/day (Benetou V), and among men & women combined ≥ 12.6 g/day (Maynard M). No (non)significantly increased risk at any level of consumption was found in any cohort.

Conclusion: Hardly any association was found among men, and inconsistent findings were done among women. Though some nonsignificant trends of a protective effect were found among women, the power of the effect was very weak, and the weight of the evidence does not justify the label of a possible association. No evidence was found for an association of total fruit with total cancer risk.

Total fruit and total cancer mortality

11 articles, providing information about 10 different cohorts were found including a total of > 4,938 cases (no data was available from 2 cohorts: Hung HC; 2004).
Significant protective effects were found in 2 cohorts, including 3,816 cases (4, 14), though in one cohort the association was significant for men only (4). No other associations were found.

Conclusion: Significant protective effects were found in 2 cohorts. Within one cohort, an effect was found for daily vs less frequent consumption (4), and in the other one for (almost) daily consumption vs < 2 servings/wk (14), indicating that a protective effect may only be found compared with very low or infrequent consumption. Since no data about the amount of cancer cases was available from 2 cohorts, evidence was judged suggestive for a protective effect of total fruits against total cancer mortality for daily vs less frequent consumption.

Total fruit & Vegetables and total cancer.

Primary variables of interest were either total fruits, or total vegetables consumption.
Two articles did not stratify the association by consumption variables, but only provided information about the combined effect of total vegetables & total fruits. Both articles examined the relation with total cancer mortality, and both showed a nonsignificant trend of a protective effect.

Both cohorts were small. Within the first cohort (Hertog 1996), the highest level of consumption was defined as > 258 g/day (> 3.3 servings/day), and within the second cohort (Genkinger 2004), The strength of the association differed little between the 2nd and 5th quintile of consumption (Table).

Conclusion: Both articles do not provide strong evidence for a protective effect of high consumption, but show a possible increased risk of low levels of consumption.

Effect modification:

Effect modification is discussed if a modifying effect by any variable is examined in any amount of cohorts.

Vegetables:

• Smoking status:
  -One article pooled the results of 2 cohorts (Hung HC; 2004) and found no significant difference between smokers, past smokers and nonsmokers (RRs: 0.94, 1.01, and 1.02, respectively).
  -In another cohort (Takachi R; 2007), also no difference was found between ever smokers and nonsmokers (HRs: 0.94 and 0.97, respectively).
  -In the largest cohort (George SM; 2008) a significant protective effect was found among men (RR = 0.94; P = 0.004), but no association was found among never-smokers (RR = 0.97; P = 0.474).
• Dietary supplement use:
  -One article pooled the results of 2 cohorts (Hung HC; 2004) and found a stronger inverse association among non-vitamin users than among multivitamin users (RRs: 0.93 and 1.01, respectively).
  -In another cohort (Olsen A; 2005), risk tended to be lower among non-users of dietary supplements than among users of dietary supplements (RRs: 0.90 vs 1.02 among women, and 0.87 vs 0.93 among men, respectively).
  -In a fourth cohort (Benetou V; 2008), no difference in effect was found among dietary supplement users vs nonusers. If anything, the inverse association was slightly more evident among the users.
• BMI, age or alcohol: One article provided information about analyses stratified by BMI, age and alcohol (Takachi R; 2007). Results were similar.

Fruit:

• Smoking status:
  -One article pooled the results of 2 cohorts (Hung HC; 2004) and found no significant difference between smokers, past smokers and nonsmokers (RRs: 1.07, 0.97, and 1.03, respectively).
  -In another cohort (Takachi R; 2007), risk tended to be higher among nonsmokers than among smokers (HRs: 1.12 and 0.95, respectively).
• Dietary supplement use:
  -One article pooled the results of 2 cohorts (Hung HC; 2004) and found a stronger inverse association among non-vitamin users than among multivitamin users (RRs: 0.94 and 1.06, respectively).
  -In another cohort (Olsen A; 2005), no difference was found between non-users of dietary supplements vs users of dietary suppements (RRs: 0.97 vs 1.00 among women, and 1.00 vs 0.97 among men, respectively).
  -In a fourth cohort (Benetou V; 2008), no difference in effect was found among dietary supplement users vs nonusers. If anything, the inverse association was slightly more evident among the users.
• Age: Two articles provided information about analyses stratified by age (Maynard M; 2003, and Takachi R; 2007). Results were similar.
• BMI or alcohol: One article provided information about analyses stratified by BMI and alcohol (Takachi R; 2007). Results were similar.
• Season of consumption: One article provided information about fruit consumption in winter vs summer (Cox BD; 2000). Results were similar.

Conclusion: Evidence for a protective effect of vegetables against total cancer risk is limited to effects in 2 cohorts. Within the largest of these cohorts the protective effect was not found in nonsmokers. In addition, all RRs were higher in nonsmokers than in smokers. Weak evidence was found for a protective effect of total vegetables against total cancer risk among male smokers, but no evidence was found for nonsmokers. Further stratification of ever smokers into current vs former smokers is not possible because little data is available.
Evidence suggests that dietary supplement use may be an effect modifier, especially among vegetables, but results are inconsistent.