Skip Navigation


Japanese Journal of Clinical Oncology Advance Access originally published online on April 7, 2009
Japanese Journal of Clinical Oncology 2009 39(6):352-359; doi:10.1093/jjco/hyp028
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
39/6/352    most recent
hyp028v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Tang, N.-P.
Right arrow Articles by Ma, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tang, N.-P.
Right arrow Articles by Ma, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


© The Author (2009). Published by Oxford University Press. All rights reserved

Flavonoids Intake and Risk of Lung Cancer: A Meta-analysis

Na-Ping Tang1, Bo Zhou2, Bin Wang2, Rong-Bin Yu3 and Jing Ma1

1 National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai
2 Department of Pharmacology, Nanjing Medical University
3 Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China

For reprints and all correspondence: Na-Ping Tang or Jing Ma, National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, 199 Guoshoujing Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China. E-mail: naping.tang{at}gmail.com (N.-P.T.) or jma{at}ncdser.com (J.M.)

Received November 15, 2008; accepted March 12, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Objective: A number of studies have evaluated the association between flavonoids intake and lung cancer risk. However, results were inconsistent. To clarify the role of flavonoids in lung cancer, we conducted a meta-analysis on this topic.

Methods: Two authors independently searched PubMed and EMBASE for studies regarding the association of flavonoids intake with lung cancer risk. Summary relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated by using random-effects model.

Results: Eight prospective studies and four case–control studies involving 5073 lung cancer cases and 237 981 non-cases were included in this meta-analysis. The combined results indicated a statistically significant association between highest flavonoids intake and reduced risk of developing lung cancer (RR = 0.76, 95% CI = 0.63–0.92). Furthermore, an increase in flavonoids intake of 20 mg/day was associated with a 10% decreased risk of developing lung cancer (RR = 0.90, 95% CI = 0.83–0.97). In stratified analyses, the highest flavonoids intake was significantly associated with decreased lung cancer risk in prospective studies, studies conducted in Finnish population, studies without adjustment for fruits and vegetables or vitamins, males, smokers and studies using dietary history interview for flavonoids intake estimation. Most subclasses of flavonoids were inversely associated with lung cancer except for hesperetin.

Conclusions: Our data indicate that high or an increased intake of flavonoids is associated with reduced risk of lung cancer in some population but not in other population.

Key Words: flavonoids • lung cancer • meta-analysis


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Lung cancer is one of the leading causes of death in both developed and developing countries (1,2). Although incremental improvements are made regularly in the ways in which all treatment modalities including surgery, radiation and medical therapies are applied to patients with lung cancer, the prognosis from this disease has only marginally improved, and the 5-year survival rates have remained under 20% (3). Therefore, efforts toward primary prevention in addition to early detection have come under the spotlight.

Increasing evidence suggests that high fruits and vegetables intake decreases the risk of lung cancer, but it is unclear which bioactive compounds are responsible (4). Considerable attention has been paid to vitamins such as vitamin A, C and E from fruits and vegetables because of their roles as regulators of cell differentiation or antioxidants (5,6). However, recent findings have not demonstrated the expected protective effects of these micronutrients (7,8), suggesting that other plant compounds may be responsible for the observation of an inverse association between high fruits and vegetables intake and decreased risk of lung cancer.

Flavonoids are part of a large group of polyphenolic compounds abundant in fruits and vegetables. Previous study by Cao et al. (9) has demonstrated that some flavonoids have much stronger antioxidant activities against peroxyl radicals than vitamin C and E. In addition, a number of epidemiologic studies have reported a protective effect of flavonoids against lung cancer. However, the results were inconsistent. Therefore, we performed a meta-analysis of published epidemiologic studies to derive a precise estimation of the association.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Search Strategy
We performed a literature search in PubMed and EMBASE (last search was updated on 1 January 2009) for all relevant papers using the following keywords ‘lung neoplasm’, ‘lung cancer’, ‘lung tumor’ or ‘lung carcinoma’ combined with ‘flavonoids’, ‘flavanols’, ‘flavanones’, ‘flavones’, ‘flavonols’, ‘catechin’, ‘flavan-3-ols’, ‘isoflavones’ or ‘anthocyanidins’. Furthermore, we reviewed the reference lists of retrieved articles to search for more studies. No language restrictions were imposed. Searching was performed in duplicate by two independent authors (N.-P.T and B.Z).

Study Selection
To be included in our meta-analysis, studies had to fulfill the following criteria. First, they had to be prospective or case–control studies. Second, the exposure of interest was flavonoids intake. Third, the outcome of interest was primary lung cancer. Fourth, the study had to enroll unrelated subjects. Last, the relative risk (RR) estimates [or odds ratios (ORs) in case–control studies] with their corresponding 95% confidence intervals (CIs) were reported (or sufficient data to calculate them). If data were duplicated in more than one study, the most recent and complete study was included in the meta-analysis.

Data Extraction
All data were extracted independently and in duplicate by two authors (N.-P.T and B.Z) who used a standardized data extraction form. The following data were extracted: the first author’s last name, year of publication, study design, study population, type of controls for case–control studies (population-based or hospital-based controls), follow-up time for prospective studies, sample size (cases and controls or prospective cohort size), the exposure of flavonoids intake, the RR or OR estimates with corresponding 95% CIs for each category of flavonoids intake, variables adjusted for in the analysis and estimation method of flavonoids intake. If a study provided several risk estimates, the most completely adjusted estimate was extracted.

Statistical Analysis
The measure of interest was the RR for prospective studies, approximated by the OR in case–control studies, and the corresponding 95% CI. Study-specific risk estimates and 95% CIs for highest versus non/lowest flavonoids intake level were extracted from each study, and log risk estimates were weighted by inverse of their variances to obtain a pooled risk estimate. Studies were combined by using DerSimonian and Laird random-effects model, which considers both within- and between-study variations (10).

For dose–response analysis, we used the method proposed by Greenland and Longnecker (11) and Orsini et al. (12) to estimate study-specific slopes from the natural logarithm of the RR across categories of flavonoids intake, assigning to each class the dose corresponding to the midpoint of upper and lower boundaries. The highest open-ended category was assumed to have the same amplitude as the preceding category (11). Because this method requires the risk estimates with their variance estimates for three or more quantitative exposure categories, studies with only two categories were not included in this analysis. In addition, if studies did not provide the number of cases and non-cases in each exposure category, the variance-weighted least square regression models were used to estimate the slopes. Then, we calculated the pooled RR estimates by pooling the study-specific slopes, using the inverse of the corresponding variances as weights.

Statistical heterogeneity among studies was estimated using Q and I2statistics (13). To avoid type II errors resulting from low power, statistical significance was defined as P < 0.10 rather than the traditional 0.05 (14). The causes of heterogeneity were explored through stratified analyses. Publication bias was evaluated through visual inspection of funnel plots, and the Egger weighted regression method with P < 0.10 was considered representative of statistical significance (15). A sensitivity analysis was also conducted in which one study was removed at a time and the rest analyzed to estimate whether the results could have been affected markedly by a single study. All statistical analyses were performed with Stata (version 9.0; StataCorp, College Station, TX, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
The process of study selection was shown in Fig. 1. We identified 15 potentially relevant studies concerning flavonoids intake and lung cancer (16–30). One study (16) was excluded because it did not report data regarding flavonoids intake and lung cancer independently. Two studies (17,18) were excluded because they did not provide data on lung cancer risk for highest flavonoids intake versus non/lowest flavonoids intake or an increment of 20 mg/day of flavonoids intake. Thus, a total of 12 studies (19–30) with 8 prospective studies (19–26) and 4 case–control studies (27–30) regarding the association of flavonoids intake with lung cancer risk were included in our meta-analysis (Table 1). Among these studies, three were conducted in the Netherlands (16,19,20), three in Finland (22,24,26), four in the USA (23,25,29,30), one in Spain (27) and one in Uruguay (28). Among case–control studies, two used hospital-based controls (27,28) and two used population-based controls (29,30).


Figure 1
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. Summary of study assessment and exclusion stages.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Characteristics of studies included in the meta-analysis

 
The risk estimates of lung cancer for highest flavonoids intake versus non/lowest flavonoids intake are shown in Fig. 2 and Table 2. Overall, we found that highest flavonoids intake was statistically significantly associated with reduced risk of lung cancer (RR = 0.76, 95% CI = 0.63–0.92). Statistically significant heterogeneity was observed among the study results (Q = 28.74, P = 0.002, I2 = 61.7%). When subgroup analysis was conducted by study design, a statistically significant 27% decreased risk of developing lung cancer was observed among prospective studies (RR = 0.73, 95% CI = 0.57–0.93), whereas no such effect was observed among case–control studies (RR = 0.83, 95% CI = 0.60–1.15). Heterogeneity was significantly reduced among case–control studies (Q = 5.68, P = 0.128, I2 = 47.2%) but not in prospective studies (Q = 22.36, P = 0.002, I2 = 68.7%).


Figure 2
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2. Forest plot of RRs of lung cancer risk for highest flavonoids intake versus non/lowest flavonoids intake. Squares indicated study-specific risk estimates (size of square reflects the study-statistical weight); horizontal lines indicate 95% CIs; and diamond indicates summary RR estimate with its corresponding 95% CI. RR, relative risk; CI, confidence interval.

 

View this table:
[in this window]
[in a new window]

  		Table 2. Meta-analysis of risk estimates of flavonoids intake (highest versus lowest) and lung cancer risk

 
We also examined if study population affected the pooled RR and degree of heterogeneity (Table 2). The pooled RR for studies conducted in Finland was 0.54 (95% CI = 0.40–0.73). However, no statistically significant association was noted in the USA (RR = 0.95, 95% CI = 0.82–1.10), the Netherlands (RR = 0.81, 95% CI = 0.55–1.21) and other populations (RR = 0.67, 95% CI = 0.44–1.03). The heterogeneity was significantly reduced among these populations (P values for heterogeneity in Finland, the Netherlands, the USA and others were 0.245, 0.764, 0.215 and 0.265, respectively).

We also stratified the various studies by adjustment for fruits and vegetables or vitamins (Table 2). The overall results in studies without adjustment for fruits and vegetables or vitamins indicated a statistically significant protective effect of flavonoids intake on lung cancer risk (RR = 0.69, 95% CI = 0.50–0.96). No such association was seen in studies adjusted for these factors (RR = 0.84, 95% CI = 0.69–1.02). Heterogeneity was significantly reduced in studies adjusted for fruits and vegetables or vitamins (Q = 10.46, P = 0.164, I2 = 33.1%), but not in studies without adjustment for these factors (Q = 10.95, P = 0.012, I2 = 72.6%).

When we stratified studies by sex, a stronger finding was noted among males (RR = 0.57, 95% CI = 0.49–0.67) compared with females (RR = 0.94, 95% CI = 0.79–1.11). Heterogeneity was significantly reduced among both men (Q = 4.29, P = 0.509, I2 = 0.0%) and women (Q = 0.02, P = 0.992, I2 = 0.0%) (Table 2).

We also did a subgroup analysis by smoking status (Table 2). The inverse association between flavonoids intake and lung cancer risk was observed only in smokers (RR = 0.70, 95% CI = 0.51–0.95), but not among non-smokers (RR = 0.74, 95% CI = 0.26–2.12). In addition, the data indicated that the heterogeneity across studies was observed regardless of smoking status (smoking: Q = 13.29, P = 0.010, I2 = 69.9%; non-smoking: Q = 8.58, P = 0.014, I2 = 76.7%).

A subgroup analysis was also performed according to estimation method of flavonoids intake (Table 2). The summary estimate based on the results from four studies using dietary history interview for flavonoids intake estimation showed that flavonoids intake was statistically significantly associated with reduced risk of lung cancer (RR = 0.58, 95% CI = 0.49–0.70; Q = 1.59, P = 0.662, I2 = 0.0%). However, no such association was noted based on the results from seven studies using food frequency questionnaire for flavonoids intake estimation (RR = 0.91, 95% CI = 0.79–1.04; Q = 6.50, P = 0.370, I2 = 7.7%).

We also conducted a subgroup analysis by subclasses of flavonoids (Table 2). Most subclasses of flavonoids are inversely associated with lung cancer risk except for hesperetin. In addition, we noted that kaempferol was statistically significantly associated with reduced risk of lung cancer (RR = 0.77, 95% CI = 0.60–0.98; Q = 1.40, P = 0.706, I2 = 0.0%).

Given the wide array of measurement categories reported among studies, we also conducted dose–response analysis of flavonoids intake for lung cancer risk (Fig. 3). Our data indicated that an increase in flavonoids intake of 20 mg/day was statistically significantly associated with a 10% decreased risk of developing lung cancer (RR = 0.90, 95% CI = 0.83–0.97).


Figure 3
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3. Forest plot of RRs of lung cancer risk for an increase in flavonoids intake of 20 mg/day Squares indicated study-specific risk estimates (size of square reflects the study-statistical weight); horizontal lines indicate 95% CIs; diamond indicates summary RR estimate with its corresponding 95% CI.

 
There was no indication of publication bias from either visualization of the funnel plot (Fig. 4) or Egger’s test (P = 0.695). A sensitivity analysis which one study was removed at a time was performed to evaluate the stability of the results (Fig. 5). The summary RR ranged from 0.73 (95% CI = 0.60–0.89) [when excluding the study by Cui et al. (30)] to 0.81 (95% CI = 0.68–0.97) [when excluding the study by Hirvonen et al. (22)], indicating the stability of our results.


Figure 4
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 4. Funnel plot indicating publication bias in the studies included in this meta-analysis. No indication of publication bias was noted from both visualization of the funnel plot and Egger’s test (P = 0.695).

 

Figure 5
View larger version (22K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 5. Sensitivity analysis which one study was removed at a time was performed to evaluate the stability of the results. The summary RR ranged from 0.73 (95% CI = 0.60–0.89) [when excluding the study by Cui et al. (29)] to 0.81 (95% CI = 0.68–0.97) [when excluding the study by Hirvonen et al. (21)].

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
This is the first meta-analysis evaluating the potential association between flavonoids intake and lung cancer risk. Eight prospective studies and four case–control studies involving 5073 lung cancer cases and 237 981 non-cases were included in our analysis. Our data suggest that high flavonoids intake have a protective effect against lung cancer. Furthermore, an increase in flavonoids intake of 20 mg/day was statistically significantly associated with a 10% decreased risk of developing lung cancer.

Flavonoids influence several important biological functions, which may explain the observed inverse associations of flavonoids intake with lung cancer risk (31). In experimental system, the free radical scavenging ability of flavonoids has been fairly well characterized. In addition, in animal models and in vitro system, flavonoids have also been shown to modulate enzymatic activity, induce cell cycle arrest and apoptosis, promote differentiation, regulate host-immune function and inhibit inflammation, cellular proliferation and angiogenesis (31–33).

There was statistically significant heterogeneity among the studies on flavonoids intake and lung cancer. When subgroup analysis was conducted by study design, we noted that statistically significant inverse association was only noted among prospective studies but not in case–control studies. It is possible that the negative findings reported from case–control studies may have been wrongly estimated, because of recall bias and possibly because early symptoms in patients may have led to a change in dietary habits.

Our data also showed that the association between flavonoids intake and reduced lung cancer risk was more evident among Finland population but not among the USA, the Netherlands or other populations. The different observations may be explained, at least in part, by the variations of flavonoids or subclasses of flavonoids consumption among different countries (34). In addition, a possible role of ethnic differences in genetic backgrounds and the environment they lived in should also be taken into consideration.

The subgroup analysis by adjustment for fruits and vegetables or vitamins revealed that the protective effect of flavonoids on lung cancer was significant in studies without adjustment for these factors but not in studies with adjustment for these factors, suggesting that the association between flavonoids and lung cancer might be confounded by the vegetables and vitamins. It remains us that it is important to control the confounding of fruits and vegetables or vitamins intake in future research.

In subgroup analysis by sex, we found that high flavonoids intake was associated with a reduced lung cancer risk among males but not among females, which suggested that gender might be an important modifier of the effects of flavonoids. The reasons for this remain unclear. It is probably because that the protective effect of flavonoids on lung cancer might be masked by the effect of estrogen, which has been suggested to be a potential risk factor for lung cancer (35,36).

When subgroup analysis was conducted by smoking status, we found that an inverse association between flavonoids intake and lung cancer risk was stronger among smokers than non-smokers. Smoking has been strongly implicated as a risk factor for lung cancer. Multiple evidences support the major pathological mechanism of oxidative stress linking smoking to lung cancer. Thus, the function of flavonoids as antioxidants may explain the reduction of lung cancer risk seen in smokers.

In the subgroup analysis by estimation method of flavonoids intake, we also found that flavonoids intake was statistically significantly associated with decreased lung cancer risk among studies using dietary history interview for flavonoids intake estimation but not among studies using food frequency questionnaire for flavonoids intake estimation. The different observation can be a consequence of response bias due to different assessment techniques or to chance alone.

We also stratified studies by subclasses of flavonoids, since flavonoids contain many types of chemicals with various type of biological activity. Our data indicated that most subclasses of flavonoids were inversely associated with lung cancer risk except for hesperetin. Our results were consistent with the findings by Cui et al. (30) which suggested that high intake or an increased intake of hesperetin was positively associated with lung cancer risk (≥30 versus <10 mg/day: OR = 1.6, 95% CI = 1.1–2.2; an increase intake of 80 mg/day: OR = 1.7, 95% CI = 1.0–2.9, Ptrend = 0.044). The estimated effect differences between hesperetin and other flavonoid compounds may have been caused by differences in their chemical structure, bioavailability, distribution and metabolism (37). Considerable differences in antioxidative effect between hesperetin and other flavonoid compounds have also been demonstrated in vitro studies (37). In addition, it is also likely that the results in the subgroup analysis may be due to chance because only two studies were included in the analysis.

Several studies also estimated the potential effect of flavonoids intake on subtypes of lung cancer, since the subtypes of lung cancer are etiologically and histologically clearly distinct (22). However, the results were inconsistent (28,29). In this meta-analysis, the number of studies on the association of flavonoids intake with subtypes of lung cancer was relatively small. Therefore, we could not draw a conclusion.

Several limitations should be taken into account when interpreting the results in our study. First, as in all observational studies, the possibility of bias and confounding can not be excluded. However, prospective studies, which are less susceptible to bias because of the prospective design, also showed a statistically significant inverse association between flavonoids intake and lung cancer, suggesting that the finding is not likely attributable to recall and selection bias. Second, only published studies were included in our meta-analysis. Therefore, publication bias may have occurred, although no publication bias was indicated from both visualization of the funnel plot and Egger’s test. Finally, studies included in our meta-analysis were mainly conducted in Finland, the Netherlands, the USA, Spain and Uruguay; therefore, the data should be extrapolated to other populations with caution.

In conclusion, our results based on eight prospective studies and four case–control studies suggest that flavonoids intake have a protective effect on the risk of developing lung cancer in some population but not in other population. Given the relative paucity of human data, prospective cohort studies with larger sample size, well-controlled confounding factors, more accurate measurement of flavonoids intake and longer duration of follow-up are needed to affirm the protective effect of flavonoids on lung cancer.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This work was supported by grants from the Major Projects Foundation of the National Science and Technology of China (No.2008ZX09305-006) and the National Natural Science Foundation of China (No.90709036).


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
1 Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet (2003) 362:847–52.[CrossRef][Web of Science][Medline]

2 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin (2005) 55:74–108.[Abstract/Free Full Text]

3 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin (2008) 58:71–96.[Abstract/Free Full Text]

4 Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc (1996) 96:1027–39.[CrossRef][Web of Science][Medline]

5 Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer (2001) 1:181–93.[CrossRef][Medline]

6 Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA (2002) 287:3116–26.[Abstract/Free Full Text]

7 Voorrips LE, Goldbohm RA, Brants HA, van Poppel GA, Sturmans F, Hermus RJ, et al. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev (2000) 9:357–65.[Abstract/Free Full Text]

8 Cho E, Hunter DJ, Spiegelman D, Albanes D, Beeson WL, van den Brandt PA, et al. Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: a pooled analysis of 8 prospective studies. Int J Cancer (2006) 118:970–8.[CrossRef][Web of Science][Medline]

9 Cao G, Sofic E, Prior RL. Antioxidant and prooxidant behavior of flavonoids: structure–activity relationships. Free Radic Biol Med (1997) 22:749–60.[CrossRef][Web of Science][Medline]

10 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials (1986) 7:177–88.[CrossRef][Web of Science][Medline]

11 Greenland S, Longnecker MP. Methods for trend estimation from summarized dose–response data, with applications to meta-analysis. Am J Epidemiol (1992) 135:1301–9.[Abstract/Free Full Text]

12 Orsini N, Bellocco R, Greenland S. Generalized least squares for trend estimation of summarized dose–response data. Stata J (2006) 6:40–57.

13 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med (2002) 21:1539–58.[CrossRef][Web of Science][Medline]

14 Hedges LV, Pigott TD. The power of statistical tests in meta-analysis. Psychol Methods (2001) 6:203–17.[CrossRef][Web of Science][Medline]

15 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (1997) 315:629–34.[Abstract/Free Full Text]

16 Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary flavonoids and cancer risk in the Zutphen Elderly Study. Nutr Cancer (1994) 22:175–84.[Web of Science][Medline]

17 Wright ME, Mayne ST, Stolzenberg-Solomon RZ, Li Z, Pietinen P, Taylor PR, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol (2004) 160:68–76.[Abstract/Free Full Text]

18 Lagiou P, Samoli E, Lagiou A, Katsouyanni K, Peterson J, Dwyer J, et al. Flavonoid intake in relation to lung cancer risk: case–control study among women in Greece. Nutr Cancer (2004) 49:139–43.[CrossRef][Web of Science][Medline]

19 Knekt P, Järvinen R, Seppänen R, Hellövaara M, Teppo L, Pukkala E, et al. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol (1997) 146:223–30.[Abstract/Free Full Text]

20 Goldbohm RA, Hertog MGL, Brants HAM, van Poppel G, van der Brandt PA. Intake of flavonoids and cancer risk: a prospective cohort study. In: Polyphenols in Foods—Amado R, Andersson H, Bardosz S, Serra F, eds. (1998) Luxembourg: Office for Official Publications of the European Community. 159–66.

21 Arts IC, Hollman PC, Bueno De Mesquita HB, Feskens EJ, Kromhout D. Dietary catechins and epithelial cancer incidence: the Zutphen elderly study. Int J Cancer (2001) 92:298–302.[CrossRef][Web of Science][Medline]

22 Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes Control (2001) 12:789–96.[Web of Science][Medline]

23 Arts IC, Jacobs DR Jr, Gross M, Harnack LJ, Folsom AR. Dietary catechins and cancer incidence among postmenopausal women: the Iowa Women’s Health Study (United States). Cancer Causes Control (2002) 13:373–82.[CrossRef][Web of Science][Medline]

24 Knekt P, Kumpulainen J, Järvinen R, Rissanen H, Heliövaara M, Reunanen A, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr (2002) 76:560–8.[Abstract/Free Full Text]

25 Cutler GJ, Nettleton JA, Ross JA, Harnack LJ, Jacobs DR Jr, Scrafford CG, et al. Dietary flavonoid intake and risk of cancer in postmenopausal women: the Iowa Women’s Health Study. Int J Cancer (2008) 123:664–71.[CrossRef][Web of Science][Medline]

26 Mursu J, Nurmi T, Tuomainen TP, Salonen JT, Pukkala E, Voutilainen S. Intake of flavonoids and risk of cancer in Finnish men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Int J Cancer (2008) 123:660–3.[CrossRef][Web of Science][Medline]

27 Garcia-Closas R, Agudo A, Gonzalez CA, Riboli E. Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain. Nutr Cancer (1998) 32:154–8.[Web of Science][Medline]

28 De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Carzoglio JC, Ronco A, et al. Dietary antioxidants and lung cancer risk: a case–control study in Uruguay. Nutr Cancer (1999) 34:100–10.[CrossRef][Web of Science][Medline]

29 Le Marchand L, Murphy SP, Hankin JH, Wilkens LR, Kolonel LN. Intake of flavonoids and lung cancer. J Natl Cancer Inst (2000) 92:154–60.[Abstract/Free Full Text]

30 Cui Y, Morgenstern H, Greenland S, Tashkin DP, Mao JT, Cai L, et al. Dietary flavonoid intake and lung cancer—a population-based case–control study. Cancer (2008) 112:2241–8.[CrossRef][Web of Science][Medline]

31 Neuhouser ML. Dietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer (2004) 50:1–7.[CrossRef][Web of Science][Medline]

32 Ren W, Qiao Z, Wang H, Zhu L, Zhang L. Flavonoids: promising anticancer agents. Med Res Rev (2003) 23:519–34.[CrossRef][Web of Science][Medline]

33 Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr (2002) 22:19–34.[CrossRef][Web of Science][Medline]

34 Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr (2003) 133:3248–54S.

35 Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nat Rev Cancer (2007) 7:778–90.[CrossRef][Web of Science][Medline]

36 Schwartz AG, Wenzlaff AS, Prysak GM, Murphy V, Cote ML, Brooks SC, et al. Reproductive factors, hormone use, estrogen receptor expression and risk of non-small-cell lung cancer in women. J Clin Oncol (2007) 25:5785–92.[Abstract/Free Full Text]

37 Rice-Evans CA, Miller NJ, Paganga G. Structure–antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med (1996) 20:933–56.[CrossRef][Web of Science][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
39/6/352    most recent
hyp028v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Tang, N.-P.
Right arrow Articles by Ma, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tang, N.-P.
Right arrow Articles by Ma, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?