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Red meat, Mediterranean diet and lung cancer risk among heavy smokers in the COSMOS screening study
Annals of Oncology Advance Access published August 15, 2013
original article
Annals of Oncology 00: 1–6, 2013 doi:10.1093/annonc/mdt302
Red meat, Mediterranean diet and lung cancer risk among heavy smokers in the COSMOS screening study P. Gnagnarella1*, P. Maisonneuve1, M. Bellomi2,3, C. Rampinelli2, R. Bertolotti4, L. Spaggiari3,4, D. Palli5 & G. Veronesi4 Divisions of 1Epidemiology and Biostatistics; 2Radiology, European Institute of Oncology, Milan; 3School of Medicine, University of Milan, Milan; 4Division of Thoracic Surgery, European Institute of Oncology, Milan; 5Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
Received 15 May 2013; revised 28 June 2013; accepted 2 July 2013
introduction Worldwide, lung cancer is among the most common forms of cancer in men and women and the leading cause of cancer death [1]. Most lung cancers are attributable to exposure to tobacco smoke and a small proportion to exposure to other occupational or environmental carcinogens [2], while the role of diet still remains controversial. The World Cancer Research Fund [3] reported probable risk reduction with increasing fruits consumption and only little evidence of an association with non-starchy vegetables, red and processed meat or butter. In the context of the Italian COSMOS (Continuous Observation of Smoking Subjects) study, a screening programme for the early diagnosis of lung cancer in high-risk asymptomatic individuals using annual low-dose computed tomography (LD-CT) [4], we previously found significant inverse associations with vegetable fat and adherence to the ‘vitamin and fibre’ nutrient pattern [5], supporting a potential protection of dietary antioxidants. Dietary antioxidants may be *Correspondence to: Dr Patrizia Gnagnarella, Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Ramusio 1, 20141 Milano, Italy. Tel: +39-0257489823; Fax: +39-02-94379221; E-mail: [email protected]
particularly important for smokers, because cigarette smoke contains free radicals and causes oxidative DNA damage in lung epithelial cells [6]. According to a recent metaanalysis, Mediterranean diet reduces overall mortality, cancer incidence and mortality [7]. In a large European study, this apparent inverse association was stronger for smoking-related cancers [8]. Our aim was to evaluate whether consumption of specific food items and food groups and adherence to a Mediterranean diet are associated with lung cancer risk in our screened population.
methods and materials The study is based on participants of the COSMOS screening programme. Study details have been published elsewhere [4]. In brief, 5203 asymptomatic volunteers, aged ≥50 years, who were current smokers or had quit smoking for <10 years and had smoked at least 20 pack-years, were enrolled between October 2004 and October 2005 and underwent annual LD-CT. All volunteers gave written consent to participate in the study, which was approved by our institutional ethical committee. At baseline, the validated self-administered food frequency questionnaire (FFQ) developed for the Italian component of the European Prospective
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
original article
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Background: To assess whether intake of selected foods and food groups and adherence to a Mediterranean diet are associated with lung cancer risk in heavy smokers. Patients and methods: In the context of a lung cancer screening programme, we invited asymptomatic volunteers, aged 50 years or more, current smokers or recent quitters, who had smoked at least 20 pack-years, to undergo annual low-dose computed tomography. We assessed participants’ diet at baseline using a self-administered food frequency questionnaire and calculated their average daily food intake using an ad hoc computer program and determined their alternate Mediterranean diet (aMED) score. We used Cox proportional hazards regression to assess the association between selected food items, beverages and the aMED score and lung cancer risk. Results: During a mean screening period of 5.7 years, 178 of 4336 participants were diagnosed with lung cancer. At multivariable analysis, red meat consumption was associated with an increased risk of lung cancer [hazard ratio (HR) Q4 versus Q1, 1.73; 95% confidence interval (CI) 1.15–2.61; P-value for trend 0.002], while tea consumption (HR for one or more cup/day versus none, 0.56; 95% CI 0.31–0.99; P-value for trend 0.04) and adherence to a Mediterranean diet (HR for aMED≥8 versus ≤1, 0.10; 95% CI 0.01–0.77) were significantly associated with reduced lung cancer risk. Conclusions: Among heavy smokers, high red meat consumption and low adherence to a Mediterranean diet are associated with increased risk of lung cancer. Key words: Mediterranean diet, LD-CT screening, lung cancer, food intake
original article Investigation into Cancer and Nutrition (EPIC) study [9, 10] was distributed to the participants. The frequency of the consumption of 188 food items and beverages was collected to assess average daily quantities of foods and energy consumed by participants over the preceding year [10]. Single foods and dishes listed in the FFQ were considered alone and also grouped on the basis of their main ingredient [9]. For each individual, the alternate Mediterranean diet (aMED) score derived from the Mediterranean diet scale developed by Trichopoulou et al. [11] was calculated: intakes above the median value reported by all participants received 1 point for vegetables, fruits, nuts, cereals, legumes and fish; otherwise, they received 0 point. Red and processed meat consumption below the median value received 1 point. Alcohol intake between 5 and 15 g/ day received 1 point. The resulting aMED score values range from 0 (minimal adherence) to 9 (maximal adherence).
Correlation between potential baseline covariates and average daily intake of selected foods (including beverages), food groups and the aMED score was calculated using Pearson correlation coefficients. Cumulative incidence curves of lung cancer according to quartiles of food or food-group consumptions or categories of the aMED score were plotted using the Kaplan– Meier method. Difference between curves was assessed with the log-rank test. Multivariable Cox proportional hazards regression was used to analyse the association between food intake and lung cancer risk, adjusting for baseline lung cancer risk probability and total energy intake. Models included dummy variables to represent missing values for some co-variables (education, body mass index). Energy adjustment was carried out using both the standard and the nutrient-density method [12]. Baseline lung cancer risk probability was calculated for each individual, using information on age, sex, smoking history (smoking duration, average daily cigarettes consumption, years of cessation) and asbestos exposure [13]. We carried out alternative models adjusted for each single variable plus additional variables such as education. Since the results were comparable, we decided to present results from the simplest model. P-values for trend were calculated using the quartile median values. Analysis was carried out with the SAS software version 8.2 (Cary, NC). All P-values are two-sided.
results Completed FFQs were returned by 4336 (84%) of the 5203 participants of the COSMOS study. Data from 27 participants who reported abnormal dietary values (total caloric intake less than or greater than 3 standard deviations) were excluded. Briefly, participants were mostly males (66.1%), current smokers (79.8%), had a median age of 57 years (range 50–84) and had smoked a median of 44 pack-years at enrolment (Table 1). Lung cancer was diagnosed in 178 subjects (127 men, 51 women) after a mean follow-up of 5.7 years and 24 864 person-years of observation, comprising 129 adenocarcinomas (72.5%), 21 squamous-cell carcinomas (11.8%), 14 small-cell lung cancers (7.9%) and 14 other histological subtypes (7.9%). The detection rate of lung cancer significantly increased with increasing age, increasing pack-years and decreasing education.
| Gnagnarella et al.
It was similar across BMI categories for current smokers and recent quitters (Table 1). Correlations between potential confounding variables and average intake of selected foods, food groups and the aMED score are shown in supplementary Table S1, available at Annals of Oncology online. Male gender, current smoking status and number of pack-years were positively correlated with red meat and wine consumption; education was positively correlated with the aMED score; current smoking status and pack-years were also negatively correlated with intakes of fruits and vegetables, fish and with the aMED score. Associations with the 56 major single food items and beverages are available in supplementary Tables S2 and S3, available at Annals of Oncology online. Overall, we found statistically significant decreased risks of lung cancer associated with increasing consumption of total vegetables, total fruits, total fat and olive oil and statistically significant increased risks with increasing consumption of red meat, beef, veal and offal. Cumulative incidence and risk estimates of lung cancer according to the consumption of fruits and vegetables, fish, red meat and olive oil are presented in Table 2 and supplementary
Table 1. Characteristics and incidence of lung cancers diagnosed through repeated annual screening computed tomography among 4336 participants of the COSMOS study who completed a food frequency questionnaire at baseline Baseline characteristics
Participants, N (%)
All participants 4336 (100) Sex Men 2868 (66.1) Women 1468 (33.9) Age 50–54 1491 (34.4) 55–59 1452 (33.5) 60–64 881 (20.3) 65+ 512 (11.8) Educationa Primary school 205 ( 5.1) Secondary school 2532 (62.5) Higher education 1313 (32.4) Body mass indexa (kg/m2) Underweight 45 ( 1.0) (≤18.5) Normal weight 1958 (45.2) (18.5–) Over weight (25–) 1797 (41.4) Obese (≥30) 501 (11.6) Smoking status Former 874 (20.2) Current 3462 (79.8) Pack-years 20–39 1604 (37.0) 40–59 1617 (37.3) 60+ 1115 (25.7) a
Personyears
Lung cancers, N (rate per 100-year)
Log-rank P-value
24 864
178 (0.72)
16 566 8298
127 (0.77) 51 (0.61)
0.18
8633 8438 4987 2806
41 (0.47) 63 (0.75) 44 (0.88) 30 (1.07)
0.003
1117 14 581 7553
19 (1.70) 104 (0.71) 46 (0.61)
0.0003
259
1 (0.39)
11 183
81 (0.72)
10 382 2871
77 (0.74) 15 (0.52)
5035 19 828
30 (0.60) 148 (0.75)
0.26
9239 9380 6245
37 (0.40) 64 (0.68) 77 (1.23)
<0.0001
0.58
Education is missing for 286 participants, body mass index for 35 participants.
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statistical analysis
Annals of Oncology
original article
Annals of Oncology
at Annals of Oncology online). The increased risk was observed in all subgroups considered. High tea and moderate wine consumption were associated with lower lung cancer risk (Table 2, supplementary Figure S1, available at Annals of Oncology online). The association with tea remained statistically significant after further adjustment for fruits and vegetables, fish, red meat, olive oil and wine intake (HR for one or more cup/day versus none, 0.56; 95% CI 0.31– 0.99; P-value for trend 0.04), while the association with moderate wine consumption lost statistical significance at multivariable analysis. To further explore the role of diet on lung cancer risk, we calculated the aMED score (Figure 1). Two hundred and twenty-four participants (5.2%) had a very low score (0–1) and 158 (3.6%) a very high score (8–9). Overall, the aMED score was inversely associated with lung cancer risk (Pvalue for trend 0.045). Participants with aMED score ≥8 had an
Table 2. Risk of lung cancers detected through repeated annual screening computed tomography according to daily quartile food density of fruits and vegetables, fish, red meat and olive oil and according to average daily tea and wine consumption Baseline characteristics Fruits and vegetables Q1 Q2 Q3 Q4 P-value for trend Fish Q1 Q2 Q3 Q4 P-value for trend Red meat Q1 Q2 Q3 Q4 P-value for trend Olive oil Q1 Q2 Q3 Q4 P-value for trend Tea None <1 cup/day 1+ cup/day P-value for trend Wine <1 glass/day 1 glass/day 2 glasses/day 3+ glasses/day P-value for trend
Participants, N
Person-years
Lung cancers, N (rate per 100-year)
Modela, HR (95% CI)
Modelb, HR (95% CI)
1084 1084 1084 1084
6198 6234 6223 6209
58 (0.94) 46 (0.74) 41 (0.66) 33 (0.53)
1.00 0.72 (0.48–1.07) 0.70 (0.47–1.04) 0.62 (0.40–0.95) 0.03
1.00 0.85 (0.56–1.28) 0.89 (0.58–1.37) 0.85 (0.52–1.36) 0.48
1085 1082 1083 1086
6147 6241 6327 6149
54 (0.88) 50 (0.80) 39 (0.62) 35 (0.57)
1.00 0.85 (0.58–1.24) 0.65 (0.42–0.98) 0.65 (0.43–1.00) 0.04
1.00 0.89 (0.61–1.31) 0.71 (0.46–1.08) 0.73 (0.47–1.13) 0.16
1084 1084 1084 1084
6199 6263 6241 6162
35 (0.56) 39 (0.62) 49 (0.79) 55 (0.89)
1.00 0.96 (0.61–1.52) 0.91 (0.58–1.45) 1.81 (1.21–2.70) 0.001
1.00 0.95 (0.60–1.50) 0.91 (0.57–1.44) 1.73 (1.15–2.61) 0.003
1092 1071 1091 1082
6185 6188 6261 6229
52 (0.84) 52 (0.84) 38 (0.61) 36 (0.58)
1.00 0.81 (0.55–1.19) 0.75 (0.50–1.11) 0.57 (0.37–0.89) 0.01
1.00 0.86 (0.58–1.28) 0.77 (0.51–1.18) 0.64 (0.39–1.04) 0.058
2630 1152 554
15 050 6627 3187
121 (0.80) 44 (0.66) 13 (0.41)
1.00 0.93 (0.66–1.32) 0.52 (0.29–0.92) 0.02
1.00 1.01 (0.71–1.44) 0.56 (0.31–0.99) 0.04
1819 531 767 1219
10 309 3066 4487 7002
78 (0.76) 24 (0.78) 21 (0.47) 55 (0.79)
1.00 1.06 (0.67–1.68) 0.61 (0.38–0.99) 0.99 (0.69–1.41) 0.75
1.00 1.14 (0.72–1.80) 0.63 (0.39–1.03) 0.94 (0.65–1.36) 0.42
Hazards ratios (HRs) and 95% confidence intervals (CIs) obtained from multivariable Cox proportional hazards regression model adjusted for abaseline risk probability and total energy adjusted using the nutrient-density method, and bfruits and vegetables, fish, red meat, olive oil, tea and wine intake.
doi:10.1093/annonc/mdt302 |
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Figure S1, available at Annals of Oncology online. High consumption (Q4 versus Q1) of fruit and vegetables [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.40–0.95; P-value for trend 0.03], olive oil (HR 0.57; 95% CI 0.37–0.89; P-value for trend 0.01) and fish (HR Q3 versus Q1 0.65; 95% CI 0.42–0.98; P-value for trend 0.04) was inversely associated with lung cancer risk, while high red meat consumption was associated with an increased risk (HR 1.81; 95% CI 1.21–2.70; P-value for trend 0.001). After further adjustment for other food items, only the association with red meat consumption remained statistically significant (HR 1.73; 95% CI 1.15–2.61; P-value for trend 0.003). The associations for fruit and vegetables, olive oil and fish were attenuated and no longer statistically significant after mutual adjustments. Additional stratified analyses were conducted to test the robustness of the association between red meat and lung cancer risk (supplementary Figure S2, available
original article
Annals of Oncology
Figure 1. Cumulative incidence of lung cancers detected through repeated annual screening computed tomography according to the alternate Mediterranean diet (aMED) score.
discussion The results of the present study suggest that high adherence to a Mediterranean diet in the year preceding enrolment was associated with a lower detection of lung cancers among asymptomatic Italian heavy smokers undergoing annual LD-CT screening. We found that a diet rich in fruits and vegetables, with olive oil as the main source of fat, a moderate consumption of wine and a low consumption of red meat were responsible for the risk reduction. The Mediterranean diet has been recognized for long time as an optimal diet accountable for a better general health status, longer life span [14] and reduced cancer risk [7], which could be ascribed to fatty acids and antioxidants ( polyphenolic compounds, carotenoids, tocopherols, etc.) found in fruits, vegetables and olive oil. Certainly, the effect is not due to single nutrients, but to a complex of components having synergistic and antagonistic interactions. Other studies have found that dietary patterns rich in vegetables were associated with a decreased lung cancer risk [15–17] and that the inverse association was mostly evident for current and former smokers [17]. To date, there is only scarce evidence of an association between olive oil and lung cancer risk, mainly because its consumption is limited to Mediterranean countries where it represents the primary source of dietary fat. A meta-analysis, however, reported a protective effect of olive oil on overall
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cancer risk [18], while exclusive olive oil use was associated with lung cancer risk reduction in an Italian case–control study [19]. Consumption of red and processed meat has often been linked to cancer [20] in part for the fat content but also for the presence of carcinogenic substances (N-nitroso compounds, heterocyclic amines and polycyclic aromatic hydrocarbons) and iron, which may act as a pro-oxidant causing DNA tissue damage [3, 21]. In our study, high red meat consumption was associated with increased lung cancer risk, after multiple adjustments. Excess risk was observed for beef, veal and offal, but not pork or white meat. In a sensitivity analysis, the association was present for all subgroups studied with no evidence of heterogeneity. Our findings confirm results from a meta-analysis in which heterogeneity of risk estimates was attributed to difference in the amount and preparation of red meat across studies [21]. Furthermore, comparison with results from other studies is difficult, as the word ‘meat’ has no standard definition. Results on the association between alcohol consumption and lung cancer risk are controversial. The type of alcohol, the strong correlation with smoking and gender can influence risk estimation [22]. Bagnardi et al. [23] reported higher risk for non- and for heavy drinkers than for light drinkers, suggesting a non-linear, U-shaped, dose–response relation. This may be explained by the potential detrimental effect of heavy ethanol consumption that may outweigh the antioxidant effect at low dose. We also found an inverse association with modest wine consumption, but the association was of borderline statistical significance at multivariable analysis. This protective effect may be due to antioxidant properties of flavonoid and resveratrol contained in red wine [24]. Interestingly, we found a significant reduction of lung cancer among participants drinking tea daily. Tea polyphenols, mainly contained in green tea, may have an inhibitory effect on tumorigenesis [25]. Black tea is the main form consumed in Italy, and a meta-analysis [26] reported possible lung cancer risk reduction with black tea consumption. In a Californian study, tea was associated with a significant decreased lung cancer risk specifically among smokers [27]. The results are, however, heterogeneous since upper tea consumption is variable from one or more cup/day
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HR of 0.10 (95% CI 0.01–0.77) compared with those with a score of 0–1, while the risk was similar for participants with intermediate scores (between 2 and 5). Finally, we carried out stratified analyses by histological subtype (adenocarcinomas versus other subtypes), prevalent (i.e. cancer diagnosed at baseline CT) versus incident (i.e. cancers diagnosed at follow-up CTs) cancers and tumour stage (stage I versus stage II–IV) (supplementary Table S4, available at Annals of Oncology online). The association with red meat (Q4 versus Q1) remained statistically significant for adenocarcinomas, for prevalent and incident cancers and for stage I tumours, while the association with aMED score (8–9 versus 0–1) remained statistically significant only for stage I tumours.
original article
Annals of Oncology
acknowledgements We thank Giovanna Ciambrone for general management of COSMOS volunteers, William Russel-Edu for help with the literature, Simonetta Salvini for help with the decodification of the food frequency questionnaires.
funding This work was supported by the Italian Association for Cancer Research (AIRC), the Italian Foundation for Cancer Research (FIRC) and the European Institute of Oncology (IEO).
disclosure The authors have declared no conflicts of interest.
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in North America and western Europe to five or fewer cups/ day in Asia [26] and since tea blend, manufacturing practices and methods of beverage preparation influence polyphenols content of tea. Our study has several strengths: to our knowledge, it is the first study to examine the relation between diet and lung cancer risk among heavy smokers undergoing annual LD-CT screening. The role of diet on lung cancer risk is particularly important in this setting, as it could help to a better identification and stratification of individuals amenable to screening, being integrated in current risk assessment tools. Subjects undergoing lung cancer screening are also often invited to participate in smoking cessation programmes, but no particular attention is made to their diet. Our findings could, therefore, help defining nutritional recommendations for smokers interested in cancer prevention. Another strength of our study relates to its particular setting: it was conducted in a very well defined population (asymptomatic heavy smokers), with well-assessed smoking and occupational exposure allowing calculation of individualized lung cancer risk probability. Our screening protocol and strict follow-up of the participants also guarantied the completeness of cases detection. Our study had, however, some limitations: despite the large number of participants, the number of lung cancers diagnosed during the study period was relatively small, limiting the statistical power of the study. Second, we recorded nutritional information representative of the year preceding the study baseline; while given the long latency of lung cancer, the relevant exposure period may be decades earlier. Third, we used a widely used FFQ, but such instrument, although validated, is subject to measurement errors and its validity is particularly modest for the evaluation of meat consumption [9]. Finally, we focused our analysis on few foods and beverages often considered in the literature but carried out a systematic analysis of about 50 different food items or food groups, allowing that some of the significant associations found be the result of chance due to multiple testing. Based on the results of the National Lung Screening Trial (NLST), Ma et al. [28] estimated that LD-CT screening could potentially avert approximately 12 000 lung cancer deaths per year in the United States. In its recent lung cancer screening guidelines [29], the American Cancer Society, however, reported that smoking cessation counselling remains a high priority and that screening should not be viewed as an alternative to smoking cessation. Findings from our study add further evidence that diet also modulates lung cancer risk in high-risk population and suggests that current or former heavy smokers should increase vegetable and fruit consumption, preferring olive oil and reducing red meat consumption, and moderate their consumption of wine.
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original article
Annals of Oncology 00: 1–6, 2013 doi:10.1093/annonc/mdt302
Red meat, Mediterranean diet and lung cancer risk among heavy smokers in the COSMOS screening study P. Gnagnarella1*, P. Maisonneuve1, M. Bellomi2,3, C. Rampinelli2, R. Bertolotti4, L. Spaggiari3,4, D. Palli5 & G. Veronesi4 Divisions of 1Epidemiology and Biostatistics; 2Radiology, European Institute of Oncology, Milan; 3School of Medicine, University of Milan, Milan; 4Division of Thoracic Surgery, European Institute of Oncology, Milan; 5Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
Received 15 May 2013; revised 28 June 2013; accepted 2 July 2013
introduction Worldwide, lung cancer is among the most common forms of cancer in men and women and the leading cause of cancer death [1]. Most lung cancers are attributable to exposure to tobacco smoke and a small proportion to exposure to other occupational or environmental carcinogens [2], while the role of diet still remains controversial. The World Cancer Research Fund [3] reported probable risk reduction with increasing fruits consumption and only little evidence of an association with non-starchy vegetables, red and processed meat or butter. In the context of the Italian COSMOS (Continuous Observation of Smoking Subjects) study, a screening programme for the early diagnosis of lung cancer in high-risk asymptomatic individuals using annual low-dose computed tomography (LD-CT) [4], we previously found significant inverse associations with vegetable fat and adherence to the ‘vitamin and fibre’ nutrient pattern [5], supporting a potential protection of dietary antioxidants. Dietary antioxidants may be *Correspondence to: Dr Patrizia Gnagnarella, Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Ramusio 1, 20141 Milano, Italy. Tel: +39-0257489823; Fax: +39-02-94379221; E-mail: [email protected]
particularly important for smokers, because cigarette smoke contains free radicals and causes oxidative DNA damage in lung epithelial cells [6]. According to a recent metaanalysis, Mediterranean diet reduces overall mortality, cancer incidence and mortality [7]. In a large European study, this apparent inverse association was stronger for smoking-related cancers [8]. Our aim was to evaluate whether consumption of specific food items and food groups and adherence to a Mediterranean diet are associated with lung cancer risk in our screened population.
methods and materials The study is based on participants of the COSMOS screening programme. Study details have been published elsewhere [4]. In brief, 5203 asymptomatic volunteers, aged ≥50 years, who were current smokers or had quit smoking for <10 years and had smoked at least 20 pack-years, were enrolled between October 2004 and October 2005 and underwent annual LD-CT. All volunteers gave written consent to participate in the study, which was approved by our institutional ethical committee. At baseline, the validated self-administered food frequency questionnaire (FFQ) developed for the Italian component of the European Prospective
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
original article
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Background: To assess whether intake of selected foods and food groups and adherence to a Mediterranean diet are associated with lung cancer risk in heavy smokers. Patients and methods: In the context of a lung cancer screening programme, we invited asymptomatic volunteers, aged 50 years or more, current smokers or recent quitters, who had smoked at least 20 pack-years, to undergo annual low-dose computed tomography. We assessed participants’ diet at baseline using a self-administered food frequency questionnaire and calculated their average daily food intake using an ad hoc computer program and determined their alternate Mediterranean diet (aMED) score. We used Cox proportional hazards regression to assess the association between selected food items, beverages and the aMED score and lung cancer risk. Results: During a mean screening period of 5.7 years, 178 of 4336 participants were diagnosed with lung cancer. At multivariable analysis, red meat consumption was associated with an increased risk of lung cancer [hazard ratio (HR) Q4 versus Q1, 1.73; 95% confidence interval (CI) 1.15–2.61; P-value for trend 0.002], while tea consumption (HR for one or more cup/day versus none, 0.56; 95% CI 0.31–0.99; P-value for trend 0.04) and adherence to a Mediterranean diet (HR for aMED≥8 versus ≤1, 0.10; 95% CI 0.01–0.77) were significantly associated with reduced lung cancer risk. Conclusions: Among heavy smokers, high red meat consumption and low adherence to a Mediterranean diet are associated with increased risk of lung cancer. Key words: Mediterranean diet, LD-CT screening, lung cancer, food intake
original article Investigation into Cancer and Nutrition (EPIC) study [9, 10] was distributed to the participants. The frequency of the consumption of 188 food items and beverages was collected to assess average daily quantities of foods and energy consumed by participants over the preceding year [10]. Single foods and dishes listed in the FFQ were considered alone and also grouped on the basis of their main ingredient [9]. For each individual, the alternate Mediterranean diet (aMED) score derived from the Mediterranean diet scale developed by Trichopoulou et al. [11] was calculated: intakes above the median value reported by all participants received 1 point for vegetables, fruits, nuts, cereals, legumes and fish; otherwise, they received 0 point. Red and processed meat consumption below the median value received 1 point. Alcohol intake between 5 and 15 g/ day received 1 point. The resulting aMED score values range from 0 (minimal adherence) to 9 (maximal adherence).
Correlation between potential baseline covariates and average daily intake of selected foods (including beverages), food groups and the aMED score was calculated using Pearson correlation coefficients. Cumulative incidence curves of lung cancer according to quartiles of food or food-group consumptions or categories of the aMED score were plotted using the Kaplan– Meier method. Difference between curves was assessed with the log-rank test. Multivariable Cox proportional hazards regression was used to analyse the association between food intake and lung cancer risk, adjusting for baseline lung cancer risk probability and total energy intake. Models included dummy variables to represent missing values for some co-variables (education, body mass index). Energy adjustment was carried out using both the standard and the nutrient-density method [12]. Baseline lung cancer risk probability was calculated for each individual, using information on age, sex, smoking history (smoking duration, average daily cigarettes consumption, years of cessation) and asbestos exposure [13]. We carried out alternative models adjusted for each single variable plus additional variables such as education. Since the results were comparable, we decided to present results from the simplest model. P-values for trend were calculated using the quartile median values. Analysis was carried out with the SAS software version 8.2 (Cary, NC). All P-values are two-sided.
results Completed FFQs were returned by 4336 (84%) of the 5203 participants of the COSMOS study. Data from 27 participants who reported abnormal dietary values (total caloric intake less than or greater than 3 standard deviations) were excluded. Briefly, participants were mostly males (66.1%), current smokers (79.8%), had a median age of 57 years (range 50–84) and had smoked a median of 44 pack-years at enrolment (Table 1). Lung cancer was diagnosed in 178 subjects (127 men, 51 women) after a mean follow-up of 5.7 years and 24 864 person-years of observation, comprising 129 adenocarcinomas (72.5%), 21 squamous-cell carcinomas (11.8%), 14 small-cell lung cancers (7.9%) and 14 other histological subtypes (7.9%). The detection rate of lung cancer significantly increased with increasing age, increasing pack-years and decreasing education.
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It was similar across BMI categories for current smokers and recent quitters (Table 1). Correlations between potential confounding variables and average intake of selected foods, food groups and the aMED score are shown in supplementary Table S1, available at Annals of Oncology online. Male gender, current smoking status and number of pack-years were positively correlated with red meat and wine consumption; education was positively correlated with the aMED score; current smoking status and pack-years were also negatively correlated with intakes of fruits and vegetables, fish and with the aMED score. Associations with the 56 major single food items and beverages are available in supplementary Tables S2 and S3, available at Annals of Oncology online. Overall, we found statistically significant decreased risks of lung cancer associated with increasing consumption of total vegetables, total fruits, total fat and olive oil and statistically significant increased risks with increasing consumption of red meat, beef, veal and offal. Cumulative incidence and risk estimates of lung cancer according to the consumption of fruits and vegetables, fish, red meat and olive oil are presented in Table 2 and supplementary
Table 1. Characteristics and incidence of lung cancers diagnosed through repeated annual screening computed tomography among 4336 participants of the COSMOS study who completed a food frequency questionnaire at baseline Baseline characteristics
Participants, N (%)
All participants 4336 (100) Sex Men 2868 (66.1) Women 1468 (33.9) Age 50–54 1491 (34.4) 55–59 1452 (33.5) 60–64 881 (20.3) 65+ 512 (11.8) Educationa Primary school 205 ( 5.1) Secondary school 2532 (62.5) Higher education 1313 (32.4) Body mass indexa (kg/m2) Underweight 45 ( 1.0) (≤18.5) Normal weight 1958 (45.2) (18.5–) Over weight (25–) 1797 (41.4) Obese (≥30) 501 (11.6) Smoking status Former 874 (20.2) Current 3462 (79.8) Pack-years 20–39 1604 (37.0) 40–59 1617 (37.3) 60+ 1115 (25.7) a
Personyears
Lung cancers, N (rate per 100-year)
Log-rank P-value
24 864
178 (0.72)
16 566 8298
127 (0.77) 51 (0.61)
0.18
8633 8438 4987 2806
41 (0.47) 63 (0.75) 44 (0.88) 30 (1.07)
0.003
1117 14 581 7553
19 (1.70) 104 (0.71) 46 (0.61)
0.0003
259
1 (0.39)
11 183
81 (0.72)
10 382 2871
77 (0.74) 15 (0.52)
5035 19 828
30 (0.60) 148 (0.75)
0.26
9239 9380 6245
37 (0.40) 64 (0.68) 77 (1.23)
<0.0001
0.58
Education is missing for 286 participants, body mass index for 35 participants.
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statistical analysis
Annals of Oncology
original article
Annals of Oncology
at Annals of Oncology online). The increased risk was observed in all subgroups considered. High tea and moderate wine consumption were associated with lower lung cancer risk (Table 2, supplementary Figure S1, available at Annals of Oncology online). The association with tea remained statistically significant after further adjustment for fruits and vegetables, fish, red meat, olive oil and wine intake (HR for one or more cup/day versus none, 0.56; 95% CI 0.31– 0.99; P-value for trend 0.04), while the association with moderate wine consumption lost statistical significance at multivariable analysis. To further explore the role of diet on lung cancer risk, we calculated the aMED score (Figure 1). Two hundred and twenty-four participants (5.2%) had a very low score (0–1) and 158 (3.6%) a very high score (8–9). Overall, the aMED score was inversely associated with lung cancer risk (Pvalue for trend 0.045). Participants with aMED score ≥8 had an
Table 2. Risk of lung cancers detected through repeated annual screening computed tomography according to daily quartile food density of fruits and vegetables, fish, red meat and olive oil and according to average daily tea and wine consumption Baseline characteristics Fruits and vegetables Q1 Q2 Q3 Q4 P-value for trend Fish Q1 Q2 Q3 Q4 P-value for trend Red meat Q1 Q2 Q3 Q4 P-value for trend Olive oil Q1 Q2 Q3 Q4 P-value for trend Tea None <1 cup/day 1+ cup/day P-value for trend Wine <1 glass/day 1 glass/day 2 glasses/day 3+ glasses/day P-value for trend
Participants, N
Person-years
Lung cancers, N (rate per 100-year)
Modela, HR (95% CI)
Modelb, HR (95% CI)
1084 1084 1084 1084
6198 6234 6223 6209
58 (0.94) 46 (0.74) 41 (0.66) 33 (0.53)
1.00 0.72 (0.48–1.07) 0.70 (0.47–1.04) 0.62 (0.40–0.95) 0.03
1.00 0.85 (0.56–1.28) 0.89 (0.58–1.37) 0.85 (0.52–1.36) 0.48
1085 1082 1083 1086
6147 6241 6327 6149
54 (0.88) 50 (0.80) 39 (0.62) 35 (0.57)
1.00 0.85 (0.58–1.24) 0.65 (0.42–0.98) 0.65 (0.43–1.00) 0.04
1.00 0.89 (0.61–1.31) 0.71 (0.46–1.08) 0.73 (0.47–1.13) 0.16
1084 1084 1084 1084
6199 6263 6241 6162
35 (0.56) 39 (0.62) 49 (0.79) 55 (0.89)
1.00 0.96 (0.61–1.52) 0.91 (0.58–1.45) 1.81 (1.21–2.70) 0.001
1.00 0.95 (0.60–1.50) 0.91 (0.57–1.44) 1.73 (1.15–2.61) 0.003
1092 1071 1091 1082
6185 6188 6261 6229
52 (0.84) 52 (0.84) 38 (0.61) 36 (0.58)
1.00 0.81 (0.55–1.19) 0.75 (0.50–1.11) 0.57 (0.37–0.89) 0.01
1.00 0.86 (0.58–1.28) 0.77 (0.51–1.18) 0.64 (0.39–1.04) 0.058
2630 1152 554
15 050 6627 3187
121 (0.80) 44 (0.66) 13 (0.41)
1.00 0.93 (0.66–1.32) 0.52 (0.29–0.92) 0.02
1.00 1.01 (0.71–1.44) 0.56 (0.31–0.99) 0.04
1819 531 767 1219
10 309 3066 4487 7002
78 (0.76) 24 (0.78) 21 (0.47) 55 (0.79)
1.00 1.06 (0.67–1.68) 0.61 (0.38–0.99) 0.99 (0.69–1.41) 0.75
1.00 1.14 (0.72–1.80) 0.63 (0.39–1.03) 0.94 (0.65–1.36) 0.42
Hazards ratios (HRs) and 95% confidence intervals (CIs) obtained from multivariable Cox proportional hazards regression model adjusted for abaseline risk probability and total energy adjusted using the nutrient-density method, and bfruits and vegetables, fish, red meat, olive oil, tea and wine intake.
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Figure S1, available at Annals of Oncology online. High consumption (Q4 versus Q1) of fruit and vegetables [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.40–0.95; P-value for trend 0.03], olive oil (HR 0.57; 95% CI 0.37–0.89; P-value for trend 0.01) and fish (HR Q3 versus Q1 0.65; 95% CI 0.42–0.98; P-value for trend 0.04) was inversely associated with lung cancer risk, while high red meat consumption was associated with an increased risk (HR 1.81; 95% CI 1.21–2.70; P-value for trend 0.001). After further adjustment for other food items, only the association with red meat consumption remained statistically significant (HR 1.73; 95% CI 1.15–2.61; P-value for trend 0.003). The associations for fruit and vegetables, olive oil and fish were attenuated and no longer statistically significant after mutual adjustments. Additional stratified analyses were conducted to test the robustness of the association between red meat and lung cancer risk (supplementary Figure S2, available
original article
Annals of Oncology
Figure 1. Cumulative incidence of lung cancers detected through repeated annual screening computed tomography according to the alternate Mediterranean diet (aMED) score.
discussion The results of the present study suggest that high adherence to a Mediterranean diet in the year preceding enrolment was associated with a lower detection of lung cancers among asymptomatic Italian heavy smokers undergoing annual LD-CT screening. We found that a diet rich in fruits and vegetables, with olive oil as the main source of fat, a moderate consumption of wine and a low consumption of red meat were responsible for the risk reduction. The Mediterranean diet has been recognized for long time as an optimal diet accountable for a better general health status, longer life span [14] and reduced cancer risk [7], which could be ascribed to fatty acids and antioxidants ( polyphenolic compounds, carotenoids, tocopherols, etc.) found in fruits, vegetables and olive oil. Certainly, the effect is not due to single nutrients, but to a complex of components having synergistic and antagonistic interactions. Other studies have found that dietary patterns rich in vegetables were associated with a decreased lung cancer risk [15–17] and that the inverse association was mostly evident for current and former smokers [17]. To date, there is only scarce evidence of an association between olive oil and lung cancer risk, mainly because its consumption is limited to Mediterranean countries where it represents the primary source of dietary fat. A meta-analysis, however, reported a protective effect of olive oil on overall
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cancer risk [18], while exclusive olive oil use was associated with lung cancer risk reduction in an Italian case–control study [19]. Consumption of red and processed meat has often been linked to cancer [20] in part for the fat content but also for the presence of carcinogenic substances (N-nitroso compounds, heterocyclic amines and polycyclic aromatic hydrocarbons) and iron, which may act as a pro-oxidant causing DNA tissue damage [3, 21]. In our study, high red meat consumption was associated with increased lung cancer risk, after multiple adjustments. Excess risk was observed for beef, veal and offal, but not pork or white meat. In a sensitivity analysis, the association was present for all subgroups studied with no evidence of heterogeneity. Our findings confirm results from a meta-analysis in which heterogeneity of risk estimates was attributed to difference in the amount and preparation of red meat across studies [21]. Furthermore, comparison with results from other studies is difficult, as the word ‘meat’ has no standard definition. Results on the association between alcohol consumption and lung cancer risk are controversial. The type of alcohol, the strong correlation with smoking and gender can influence risk estimation [22]. Bagnardi et al. [23] reported higher risk for non- and for heavy drinkers than for light drinkers, suggesting a non-linear, U-shaped, dose–response relation. This may be explained by the potential detrimental effect of heavy ethanol consumption that may outweigh the antioxidant effect at low dose. We also found an inverse association with modest wine consumption, but the association was of borderline statistical significance at multivariable analysis. This protective effect may be due to antioxidant properties of flavonoid and resveratrol contained in red wine [24]. Interestingly, we found a significant reduction of lung cancer among participants drinking tea daily. Tea polyphenols, mainly contained in green tea, may have an inhibitory effect on tumorigenesis [25]. Black tea is the main form consumed in Italy, and a meta-analysis [26] reported possible lung cancer risk reduction with black tea consumption. In a Californian study, tea was associated with a significant decreased lung cancer risk specifically among smokers [27]. The results are, however, heterogeneous since upper tea consumption is variable from one or more cup/day
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HR of 0.10 (95% CI 0.01–0.77) compared with those with a score of 0–1, while the risk was similar for participants with intermediate scores (between 2 and 5). Finally, we carried out stratified analyses by histological subtype (adenocarcinomas versus other subtypes), prevalent (i.e. cancer diagnosed at baseline CT) versus incident (i.e. cancers diagnosed at follow-up CTs) cancers and tumour stage (stage I versus stage II–IV) (supplementary Table S4, available at Annals of Oncology online). The association with red meat (Q4 versus Q1) remained statistically significant for adenocarcinomas, for prevalent and incident cancers and for stage I tumours, while the association with aMED score (8–9 versus 0–1) remained statistically significant only for stage I tumours.
original article
Annals of Oncology
acknowledgements We thank Giovanna Ciambrone for general management of COSMOS volunteers, William Russel-Edu for help with the literature, Simonetta Salvini for help with the decodification of the food frequency questionnaires.
funding This work was supported by the Italian Association for Cancer Research (AIRC), the Italian Foundation for Cancer Research (FIRC) and the European Institute of Oncology (IEO).
disclosure The authors have declared no conflicts of interest.
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in North America and western Europe to five or fewer cups/ day in Asia [26] and since tea blend, manufacturing practices and methods of beverage preparation influence polyphenols content of tea. Our study has several strengths: to our knowledge, it is the first study to examine the relation between diet and lung cancer risk among heavy smokers undergoing annual LD-CT screening. The role of diet on lung cancer risk is particularly important in this setting, as it could help to a better identification and stratification of individuals amenable to screening, being integrated in current risk assessment tools. Subjects undergoing lung cancer screening are also often invited to participate in smoking cessation programmes, but no particular attention is made to their diet. Our findings could, therefore, help defining nutritional recommendations for smokers interested in cancer prevention. Another strength of our study relates to its particular setting: it was conducted in a very well defined population (asymptomatic heavy smokers), with well-assessed smoking and occupational exposure allowing calculation of individualized lung cancer risk probability. Our screening protocol and strict follow-up of the participants also guarantied the completeness of cases detection. Our study had, however, some limitations: despite the large number of participants, the number of lung cancers diagnosed during the study period was relatively small, limiting the statistical power of the study. Second, we recorded nutritional information representative of the year preceding the study baseline; while given the long latency of lung cancer, the relevant exposure period may be decades earlier. Third, we used a widely used FFQ, but such instrument, although validated, is subject to measurement errors and its validity is particularly modest for the evaluation of meat consumption [9]. Finally, we focused our analysis on few foods and beverages often considered in the literature but carried out a systematic analysis of about 50 different food items or food groups, allowing that some of the significant associations found be the result of chance due to multiple testing. Based on the results of the National Lung Screening Trial (NLST), Ma et al. [28] estimated that LD-CT screening could potentially avert approximately 12 000 lung cancer deaths per year in the United States. In its recent lung cancer screening guidelines [29], the American Cancer Society, however, reported that smoking cessation counselling remains a high priority and that screening should not be viewed as an alternative to smoking cessation. Findings from our study add further evidence that diet also modulates lung cancer risk in high-risk population and suggests that current or former heavy smokers should increase vegetable and fruit consumption, preferring olive oil and reducing red meat consumption, and moderate their consumption of wine.
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