Fruit and Vegetable Intake in Relation to Lung Cancer Risk: A Systematic Review and Dose-response Meta-analysis of Prospective Cohort Studies

Abstract

The objective of this study was to consolidate the mounting evidence related to the association between fruit and vegetable intake and lung cancer risk by conducting a systematic review of prospective studies and a dose-response meta-analysis. A systematic search was conducted on major online databases (PubMed, Scopus, and Web of Science) from inception up to January 2024. The exposures included daily intake of total fruits and vegetables (FVs), vegetables, fruits, and their subclasses (including cruciferous and green leafy vegetables, and citrus fruits). The main outcome was lung cancer and its subclasses (incidence and mortality). Out of 31,819 records initially retrieved, 41 eligible studies were included. Significant inverse associations were observed between lung cancer and daily consumption of total FVs (risk ratios [RR]: 0.81, 95% CI: 0.74-0.90), vegetables (RR: 0.87, 95% CI: 0.83-0.91), fruits (RR: 0.78, 95% CI: 0.72-0.85), cruciferous vegetables (RR: 0.82, 95% CI: 0.75-0.91), green leafy vegetables (RR: 0.85, 95% CI: 0.76-0.94), and citrus fruits (RR: 0.80, 95% CI: 0.73-0.88). Non-linear dose-response associations were observed regarding lung cancer and all of the exposures, except for cruciferous vegetables. The consumption of FVs may decrease the risk of lung cancer incidence and mortality. The type of lung cancer, biological sex of individuals, and smoking status can alter this association.

INTRODUCTION

Lung cancer has the highest mortality rate among solid-tumor cancers [1]. The disease is categorized into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with distinctive etiological background and histopathological signs [2]. Even though the prevalence of the disease is decreasing worldwide [3], it poses a great risk to health systems of countries with various economic growth. In the year 2022, it has been estimated that 2.5 million individuals have been newly diagnosed with lung cancer; moreover, a harrowing 1.8 million deaths have been attributed to lung cancer [4]. As is the case with other types of cancer, patterns of the epidemiology, the pathophysiology of the disease, and the methods of diagnosis and treatment are rapidly changing [5]. Moreover, these changes are greatly affected by countries’ economic and development status, such as ‘human development index’ (an index incorporating gross domestic index, life expectancy, and education) [6,7]. In this light, while a decline in tobacco use (still, by far, the most significant cause of lung cancer) has been observed in most economically developed countries, the pattern is inconsistent among ‘emerging economies’ and low- and middle-income countries [8].

Tobacco smoking is the most potent predictor of lung cancer [9]. However, there still exists a discrepancy between the trends of smoking and the prevalence of lung cancer [10]. Also, a noticeable percentage of cases are never-smokers, a pattern more frequently observed in females and younger individuals [11]. To explain the residual gap, other factors have been introduced as note-worthy players, including dietary/lifestyle determinants, other environmental pollutions (e.g. products of unprocessed biomass combustion, arsenic, radon, and occupational exposure to carcinogens), infectious/chronic disorders (e.g. chronic obstructive pulmonary disease and human immunodeficiency virus, diabetes, and obesity), and genetic variations [12].

At the individual level, dietary modifications have been highlighted as easy-to-apply and potentially effective methods in cancer prevention [13]. Among dietary factors, the intake of fruits and vegetables (FVs) have been extensively studied [14]. In addition to their micronutrients content (vitamins and minerals that can act both as potential risk or protective factors), FVs provide the organism with various bioactive compounds which modify the individuals’ risk to lung cancer [15].

Even though the national guidelines still stress the increased use of FVs [16], the role of micronutrients seems to be controversial with regard to the risk of lung cancer. For instance, carotenoids, vitamin E, and calcium have been enlisted both as protective and risk factors for lung cancer [17-19]. Moreover, since the calorie intake might function as an independent risk for cancer [20] and given that fruit intake can be a significant provider of calories in dietary regimens, the delicate threshold by which the protective role of FVs outbalances the negative impact of additional calories, gains surplus importance.

In the present systematic review and meta-analysis of prospective observational studies, a comprehensive search, accompanied by extensive subgroup and dose-response analyses, was conducted to both update and further develop the association between FVs and the risk of various types of lung cancer.

METHODS

The results of this systematic review and meta-analysis were reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) criteria [21]. The protocol was registered in International Prospective Register of Systematic Reviews under the following code: CRD42024506978.

Search strategy

A thorough search (from inception up to January 2024) was carried out in the online databases, including PubMed, Scopus, and ISI Web of Science, to find relevant studies. The association between consumption of fruits, vegetables, total FVs, citrus fruits, green leafy vegetables, and cruciferous vegetables and the risk of lung cancer was investigated. Table S1 lists the MeSH (medical topic heading phrases) and non-MeSH terms used in the search strategy. Two reviewers, MA and MR, independently screened the titles and abstracts of the records. The literature search was conducted regardless of the language or publication date of the articles. Moreover, the reference list of the included papers and recent reviews was screened and hand-searched to avoid missing any possible articles.

Study selection

The study inclusion criteria were (i) prospective observational studies (cohort, case-cohort or nested case–control) conducted on adults aged 18 years or more; (ii) studies that reported adjusted estimates (e.g., hazard ratios [HRs] and risk ratios [RRs] with 95% CIs) for the association between exposure(s) (fruit, vegetable, total fruit and vegetable, cruciferous vegetables, green leafy vegetables and citrus fruits) and outcome (incidence or mortality of lung cancer). In the case where findings from one dataset were reported in more than one paper, studies with the more complete data were selected. Moreover, some records did not meet the inclusion criteria, due to irrelevant title and abstract (letters, comments, reviews, ecological studies or studies performed on children or adolescences and those studies that investigated other types of cancer).

Data extraction

Two reviewers (MA and MR) independently extracted the fully adjusted RRs or HRs with 95% CIs, from the included studies. The extracted information was the first author’s name, publication year, study location, sample size, number of cancer incidences, age range, sex, methods used to assess dietary intake and lung cancer, type of fruit and/or vegetable and amount of intake, study name, duration of follow-up, and adjustment variables. Moreover, for dose–response meta-analysis, at least 3 quantitative categories of exposure intake were extracted.

Quality assessment

The Newcastle Ottawa Scale (NOS) was used to assess the quality of the included studies [22]. This scale serves as a valuable tool in discerning the rigor and reliability of findings of a research. The scale score ranged from 0 up to 9. This tool considers parameters such as participant selection (4 points), comparability (2 points), and outcome assessment (3 points). Studies scoring 0 to 3, 4 to 6, and 7 to 9 points are categorized as low-, medium-, and high-quality, respectively.

Statistical methods

The risk estimates (HRs and RRs) and 95% CIs of lung cancer was calculated to compare the association between the highest and the lowest intakes of exposures and the final outcome. The natural log form of these RRs was calculated and then pooled using a random-effects model to estimate the overall RR of lung cancer regarding consumption of FVs [23]. If studies reported findings by sex, these estimates were combined using a fixed-effects model and then the pooled values were considered for the main analysis. Due to anticipated heterogeneity among the included studies (e.g., differences in populations, dietary assessment tools, and confounder adjustments), random-effects models were applied to provide more conservative and generalizable estimates. Cochran’s Q test and I2 were used to assess the between-study heterogeneity [24]. Heterogeneity was explored in subgroup analysis, using a fixed-effect model, based on several pre-defined variables such as study location (USA vs. non-USA), participants’ sex (male, female, male and female), follow-up duration (< 10 years vs. ≥ 10 years), dietary assessment methods (food frequency questionnaire vs. food recall and record), and adjustments for energy intake (adjusted vs. non-adjusted), outcome type (incidence vs. mortality), type of lung cancer (adenocarcinoma, small cell carcinoma, large cell carcinoma, and squamous cell carcinoma), smoking status (never smokers vs. current smokers), and sample size (< 10,000 subjects vs. ≥ 10,000 subjects). Publication bias was evaluated using Egger’s test and Begg’s test [25]. A trim and fill method was applied to find the impact of probable missing studies on the overall estimate. The sensitivity analysis was performed to assess the influence of each study on the overall effect. We applied the generalized least squares trend calculation method for the linear dose-response analysis, reported by Greenland and Longnecker [26] and Orsini et al. [27]. In this method, study-specific slopes were calculated and then, the slopes were merged using a random-effects model to provide a total average slope. Through this approach, the total number of participants, the distribution of lung cancer cases, and the RRs with the variance estimates for at least three categories of intake were required. The mean or median intake of fruit/vegetable was assigned to the corresponding RR for each study. For studies that described a range of intakes by category, the midpoint in each category was estimated. When the highest category of intake was open-ended, it was assumed that the length of the open-ended interval was the same as the adjacent category. For studies that reported in servings, based on previous studies, the conversion unit of 80 g as a serving size was used for fruit and vegetable intake [28,29].

To assess possible non-linear associations, a two-stage random effects dose-response meta-analysis was applied, using restricted cubic splines with 3 knots at 10%, 50% and 90% of the distribution, and combined them using the restricted maximum likelihood method in a multivariate meta-analysis [27,30]. Null hypothesis testing was used to estimate the probability value for non-linearity, in which the coefficient of the second spline was considered equal to zero. Statistical analyses were performed using STATA version 14.0 (StataCrop LP). A two-tailed P < 0.05 was considered statistically significant for all tests.

RESULTS

Study selection

We identified and screened 31,819 records in our initial search. Afterwards, duplicate papers (n = 9,500) were excluded. Of the remaining articles, after evaluating the titles and abstracts of 22,319 records, 22,126 irrelevant articles were eliminated. One hundred and ninety-three papers were remained for more comprehensive full-text verification. Among those, 89 studies were excluded due to reporting no exposure or outcome of interest. Moreover, nine pooled analysis and 52 case-control studies were discarded. Also, the study of Anic et al. [31] was excluded, because they reported dietary patterns rather than fruit/vegetable in relation to lung cancer. In addition, another study by Cai et al. [32], which assessed the association between dietary fiber intake and lung cancer, was excluded. Furthermore, to avoid double-counting data, we did not include the study conducted in the highest to lowest intake analysis, because the study reported the results of the two cohorts (European Prospective Investigation into Cancer and Nutrition [EPIC] and Nurses’ Health Study/National Lung Cancer Screening Trial [NLC] studies) regarding fruit intake that was already reported by EPIC study and NLC study. Additionally, another study [33] which seemed to overlap with other included studies, was discarded. Finally, 41 eligible prospective papers [34-74] were included in the current systematic review and meta-analysis. Among these, 36 studies (30 papers) investigated fruit intake [34-36,38,40-45,47-52,54,56-61,63-65,67-70], 30 studies (25 papers) vegetable intake [34-36,38,40,42,43,45,47,48,50-52,54,56,57,60,61,63-68,70], 20 studies (16 papers) intake of FVs [37,40,43,45,51,54,56,57,61-63,65,68,71,72,74], 11 studies (8 papers) cruciferous vegetables intake [38,40,53,55-57,64,73], 11 studies (8 papers) citrus fruits intake [39-41,43,46,57,65,68], 11 studies (8 papers) green leafy vegetables intake [40,43,59,61,63-65,68] in Figure 1.

Figure 1.

Flow diagram of study selection.

Characteristics of the included studies

Table S2 shows the details of the included prospective studies. The number of participants in the studies varied between 730 and 483,338 individuals, with a total sample size of 4,298,280 participants, aged between 18 and 103 years, and 41,567 cases of lung cancer. The 41 included prospective studies published between 1983 and 2022, with a follow-up period ranging between 4 and 25 years. Seven articles included only males [38,45,47,48,51,62,65], six studies included only females [39,57,58,63,64,73], and eight studies had reported results for males and females separately [40,42,46,50,55,59,61,72]. Overall, 18 studies were conducted in the USA [34,36,38-42,53,56-58,61-63,67,69,72,74], and 23 studies in non-USA countries [35,37,43-52,54,55,59,60,64-66,68,70,71,73]. All of the included studies used a study-specific food frequency questionnaire to assess fruit/vegetable intake, except in three publications [48,71,74] that used dietary records or recalls as a dietary assessment tool. Lung cancer incidence/mortality was diagnosed using medical records or cancer registries in all of the included studies. Some important confounders including energy intake (n = 25), smoking (n = 40), age (n = 39), body mass index (n = 11), physical activity (n = 10), and alcohol consumption (n = 12) were controlled in the analysis of fruit/vegetable intake with lung cancer risk in the included studies. Most included studies, based on NOS (Table S3), were considered high-quality studies, except seven publications [34,36,43,46,61,62,69].

Meta-analyses of the highest compared with the lowest intakes

In total, 29 papers with a total sample size of 2,613,657 participants and 24,167 cases of lung cancer investigated the association between fruit intake and lung cancer [34-36,38,40-43,45,47-52,54,56-61,63-65,67-70]. The comparison between the highest and the lowest categories of total fruit intake, showed a significant inverse association between fruits intake and lung cancer risk (RR: 0.78, 95% CI: 0.72 to 0.85, I2= 55.7%, P-heterogeneity ≤ 0.001; Fig. 2). Twenty-five articles examined the association between intake of vegetables and lung cancer risk [34-36,38,40,42,43,45,47,48,50-52,54,56,57,60,61,63-68,70], with a pooled population of 2,297,787 participants and 22,270 lung cancer cases. A meaningful inverse association was observed between consumption of vegetables and risk of lung cancer (RR: 0.87, 95% CI: 0.83 to 0.91, I2= 28.9%, P-heterogeneity = 0.072; Fig. 3).

Figure 2.

Forest plot for the association between fruits consumption and risk of lung cancer. Horizontal lines represent 95% CIs. Diamonds represent pooled estimates from random-effects analysis. ES, Epidemiologic Study; ACSC, Adventist Cardiac and Stroke Cohort; LBS, Leisure World Cohort Study; LWS, Leisure World Study; IWHS, Iowa Women’s Health Study; FMCHES, First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study; NHS, Nurses’ Health Study; HPFS, Health Professionals Follow-Up Study; NLCS, Netherlands Cohort Study on Diet and Cancer; NHIS, National Health Interview Survey; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CARET, Beta-Carotene and Retinol Efficacy Trial; AHS, Adventist Health Study; HGCS, Health Guidance Cohort Study; JPHC, Japan Public Health Center-based Prospective Study; JACC, Japan Collaborative Cohort Study; NIH-AARP, NIH–AARP Diet and Health Study; SWHS, Shanghai Women’s Health Study; COSMOS, COsmos Study of Mobile phone use and health; EPIC, European Prospective Investigation into Cancer and Nutrition; BWHS, Black Women’s Health Study; PLCO, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; M, men; W, women.

Figure 3.

Forest plot for the association between vegetables consumption and risk of lung cancer. Horizontal lines represent 95% CIs. Diamonds represent pooled estimates from fixed-effects analysis. ES, Epidemiologic Study; LBS, Leisure World Cohort Study; LWS, Leisure World Study; IWHS, Iowa Women’s Health Study; FMCHES, First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study; NHS, Nurses’ Health Study; HPES, Health Professionals Follow-Up Study; NLCS, Netherlands Cohort Study on Diet and Cancer; NHIS, National Health Interview Survey; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CARET, Beta-Carotene and Retinol Efficacy Trial; AHS, Adventist Health Study; HGCS, Health Guidance Cohort Study; JPHS, Japan Public Health Center-based Prospective Study; NIH-AARP, NIH–AARP Diet and Health Study; SWHS, Shanghai Women’s Health Study; COSMOS, COsmos Study of Mobile phone use and health; EPIC, European Prospective Investigation into Cancer and Nutrition; BWHS, Black Women’s Health Study; PLCO, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; M, men; W, women.

Regarding the association between intake of total fruit and vegetable and lung cancer risk, 16 papers were included [37,40,43,45,51,54,56,57,61-63,65,68,71,72,74], including 1,603,887 participants and 14,628 cases. Comparing the highest versus lowest categories of total FVs intake indicated a summary RR of 0.81 (95% CI: 0.74 to 0.90, I2= 48.1%, P-heterogeneity = 0.009; Fig. 4), showing a significant inverse association in this regard. Eight papers assessed the association between cruciferous vegetables intake and lung cancer [38,40,53,55-57,64,73], with a total sample size of 453,021 individuals and 4,676 cases. The summary effect size for lung cancer risk, comparing the highest and lowest cruciferous vegetables intakes, was 0.82 (95% CI: 0.75 to 0.91, I2= 13.4%, P-heterogeneity = 0.317; Fig. 5), indicating an inverse association between cruciferous vegetables intake and lung cancer risk.

Figure 4.

Forest plot for the association between total fruits and vegetables consumption and risk of lung cancer. Horizontal lines represent 95% CIs. Diamonds represent pooled estimates from random-effects analysis. ES, Epidemiologic Study; LWS, Leisure World Study; IWHS, Iowa Women’s Health Study; NHANES-I, National Health and Nutrition Examination Survey I; FMCHES, First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study; NHS, Nurses’ Health Study; HPES, Health Professionals Follow-Up Study; NLCS, Netherlands Cohort Study on Diet and Cancer; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CARET, Beta-Carotene and Retinol Efficacy Trial; JPHC, Japan Public Health Center-based Prospective Study; VITAL, VITamins And Lifestyle Study; NIH-AARP, NIH–AARP Diet and Health Study; EPIC, European Prospective Investigation into Cancer and Nutrition; COSMOS, COsmos Study of Mobile phone use and health; SWHS, Shanghai Women’s Health Study; BWHS, Black Women’s Health Study; M, men; W, women.

Figure 5.

Forest plot for the association between cruciferous vegetables consumption and risk of lung cancer. Horizontal lines represent 95% CIs. Diamonds represent pooled estimates from fixed-effects analysis. ES, Epidemiologic Study; LBS, Leisure World Cohort Study; HPFS, Health Professionals Follow-Up Study; CARET, Beta-Carotene and Retinol Efficacy Trial; CLUE II, CLUE II (Give Us a CLUE to Cancer and Heart Disease) Study; SWHS, Shanghai Women’s Health Study; JPHC, Japan Public Health Center-based Prospective Study; BWHS, Black Women’s Health Study; M, men; W, women.

Eight articles containing 531,960 participants and 4,163 lung cancer cases were included in the analysis of citrus fruits intake and lung cancer [39-41,43,46,57,65,68]. An inverse association was seen between intake of citrus fruits and lung cancer risk (RR: 0.80, 95% CI: 0.73 to 0.88, I2= 1.5%, P-heterogeneity = 0.427; Fig. 6). Eight publications evaluated the association between green leafy vegetables intake and lung cancer risk [40,43,59,61,63-65,68], including 531,471 participants and 3,706 cases. The results, comparing the highest and lowest green leafy vegetables intake, showed an inverse association between green leafy vegetables intake and risk of lung cancer (RR: 0.85, 95% CI: 0.76 to 0.94, I2= 25.8%, P-heterogeneity = 0.198; Fig. 7).

Figure 6.

Forest plot for the association between citrus fruits consumption and risk of lung cancer. Horizontal lines represent 95% CIs. Diamonds represent pooled estimates from fixed-effects analysis. ES, Epidemiologic Study; NHS, Nurses’ Health Study; HPFS, Health Professionals Follow-Up Study; NLCS, Netherlands Cohort Study on Diet and Cancer; JACC, Japan Collaborative Cohort Study; IWHS, Iowa Women’s Health Study; COSMOS, COsmos Study of Mobile phone use and health; SWHS, Shanghai Women’s Health Study; BWHS, Black Women’s Health Study; M, men; W, women.

Figure 7.

Forest plot for the association between green leafy vegetables consumption and risk of lung cancer. Horizontal lines represent 95% CIs. Diamonds represent pooled estimates from fixed-effects analysis. ES, Epidemiologic Study; LWS, Leisure World Study; IWHS, Iowa Women’s Health Study; NHS, Nurses’ Health Study; HPFS, Health Professionals Follow-Up Study; NLCS, Netherlands Cohort Study on Diet and Cancer; JACC, Japan Collaborative Cohort Study; SWHS, Shanghai Women’s Health Study; COSMOS, COsmos Study of Mobile phone use and health; M, men; W, women.

Subgroup analysis

Subgroup analyses were performed to examine the robustness of the results and find possible sources of heterogeneity between studies (Table S4). In terms of total fruit and vegetable intake, a significant inverse association was seen with lung cancer risk among the studies that performed in the USA and non-USA countries, those conducted on both males and females and those carried out on males only, studies with a follow-up duration of more or less than 10 years, studies that applied a food frequency questionnaire or food recall and record for dietary assessment, studies that controlled their analysis for energy intake, those with current-smokers participants, and studies with a sample size more or less than 10,000 participants.

For fruits intake, a significant inverse association was seen with lung cancer risk in studies that reported squamous cell carcinoma as a lung cancer type, but not in other types of lung cancer (adenocarcinoma, small cell carcinoma, and large cell carcinoma). Moreover, we found this inverse association in all other subgroups regarding fruits intake.

We found a significant inverse association between vegetables intake and lung cancer risk in studies that conducted in the USA and non-USA countries, those that performed on both biological sex and studies that included only males, those with a follow-up duration of more or less than 10 years, studies that used food frequency questionnaire as a dietary assessment tool, those that adjusted their analysis for energy intake or those did not include that as a confounder, studies that considered incidence of lung cancer as an outcome, those reported large cell carcinoma as a type of lung cancer, studies that performed on current-smokers individuals, and those with a sample size more or less than 10,000 participants.

An inverse association between citrus fruits intake and risk of lung cancer was observed in studies that were done in the USA and non-USA countries, those conducted on males, females and both sexes, studies with a follow-up of more than 10 years and less than 10 years, those that controlled energy intake in their analysis, studies that selected lung cancer incidence or mortality as an outcome, studies mentioned squamous cell carcinoma as a subtype of lung cancer, those that were done on participants with current smoking status, and studies that their participants were equal or more than 10,000.

We observed an inverse association between cruciferous vegetables and lung cancer risk in studies that were performed in the USA and non-USA countries, those conducted on both genders and studies that involved only females, studies that controlled energy intake as a confounder in their analysis, those reported incidence of lung cancer, and studies with a sample size equal or more than 10,000 individuals.

Green leafy vegetables intake was inversely associated with risk of lung cancer in studies that carried out in non-USA countries, those performed on male participants, those with a follow-up of less than 10 years, studies that considered energy intake as a confounder, studies that mentioned lung cancer incidence, and those with a sample size equal or more than 10,000 participants.

Publication bias and sensitivity analyses

In terms of publication bias, both Egger’s test and Begg’s showed a publication bias for total fruit and vegetable intake and lung cancer; however, after using the trim-and-fill method, the overall estimate did not change, indicating the findings were not influenced by publication bias. Moreover, there was no evidence of publication bias regarding other types of fruit/vegetable intake. Sensitivity analysis showed the overall effect size corresponding to the inverse association between different types of fruit/vegetable intake and lung cancer risk did not depend on any studies.

Linear and non-linear dose-response analysis

Twenty-two publications [34,36,38,41,43,45,47,48,51,54,57-61,63-66,68,70,72] on the association between fruits intake and lung cancer risk were included in the dose-response analysis. There was a non-linear association with a reduction in cancer risk from no intake of fruits up to 120 g/day (P ≤ 0.001 for non-linearity; Fig. 8A), however, the non-linear association showed a slight decrease in cancer risk with fruits intake above 120 g/day. The risk of lung cancer was 0.94 (0.92, 0.97), 0.87 (0.83, 0.91), 0.84 (0.80, 0.90), 0.82 (0.74, 0.90), and 0.80 (0.67, 0.92) for 50, 150, 250, 350, and 450 g/day of fruits consumption, respectively. Moreover, linear dose-response meta-analysis showed an inverse significant association between fruits intake and lung cancer risk (RR per 100 g/day: 0.94, 95% CI: 0.91-0.96, I2 = 52.1%; Figure S1), indicating a 6% reduction in lung cancer risk in each 100 g/day increment in fruits intake.

Figure 8.

Non-linear dose-response association of consumption (based on g/day) of fruits (A), vegetables (B), total fruits and vegetables (C), citrus fruits (D), cruciferous vegetables (E) and green leafy vegetables (F) with risk of lung cancer. The solid lines indicate the spline model (non-linear association). The dashed lines present the 95% CI. Short-dashed lines show the best model for the linear association.

Regarding the association between vegetables intake and lung cancer risk, nineteen papers [34,36,38,43,45,47, 48,51,54,57,60,61,63-66,68,70,72] had a complete data for inclusion in the dose-response analysis. A non-linear association (P ≤ 0.001 for non-linearity; Fig. 8B) was found between vegetables intake and lung cancer risk, with a significant reduction in cancer risk up to 140 g/day intake of vegetables but at higher than 140 g/day of vegetable intake, the descend in cancer risk occurred moderately. The risk of lung cancer was 0.97 (0.95, 0.99), 0.92 (0.87, 0.96), 0.89 (0.84, 0.94), 0.86 (0.79, 0.94), 0.84 (0.72, 0.96), and 0.82 (0.66, 0.98) for 50, 150, 250, 350, 450, and 550 g/day of vegetables consumption, respectively. Furthermore, the linear dose-response analysis revealed that for every 100 g/day increase in vegetables intake, there was a 6% reduction in lung cancer risk (RR per 100 g/day: 0.94, 95% CI: 0.91-0.97, I2 = 15.9%; Figure S2).

Combining data from twelve papers [40,43,45,51,54,57,61-63,65,68,72] in the dose-response analysis of total fruit and vegetable intake and lung cancer risk, a decreasing non-linear trend (P ≤ 0.001 for non-linearity; Fig. 8C) was seen up to 900 g/day of total fruit and vegetable intake. The risk of lung cancer was 0.97 (0.95, 0.99), 0.93 (0.89, 0.96), 0.89 (0.86, 0.94), 0.85 (0.81, 0.91), 0.82 (0.78, 0.89), 0.79 (0.72, 0.87), 0.76 (0.65, 0.87), 0.73 (0.60, 0.86), and 0.70 (0.53, 0.95) for 100, 200, 300, 400, 500, 600, 700, 800, and 900 g/day of FVs consumption, respectively. Moreover, the linear dose-response showed that with each additional intake of 100 g/day of total fruit and vegetable intake, the risk of lung cancer decreased by 5% (RR per 100 g/day: 0.95, 95% CI: 0.93-0.97, I2 = 34.3%; Figure S3).

Five publications [39,43,57,65,68] relating to the association between citrus fruits intake and lung cancer risk were included in the dose-response analysis. We found a non-linear trend between citrus fruits intake and lung cancer risk, with a significant reduction in cancer risk up to 60 g/day, but unexpectedly an increasing non-linear trend was observed above the 60 g/day intake of citrus fruits intake (P ≤ 0.001 for non-linearity; Fig. 8D). The risk of lung cancer was 0.78 (0.67, 0.89), 0.77 (0.67, 0.87), 0.84 (0.65, 1.02), and 0.91 (0.61, 1.21) for 50, 100, 150, and 200 g/day of citrus fruits consumption, respectively. In addition, the linear dose-response showed that for every 50 g increase in citrus fruits intake per day, there was a 15% decrease in the risk of developing lung cancer (RR per 50 g/day: 0.85, 95% CI: 0.76-0.94, I2 = 8.0%; Figure S4).

In terms of cruciferous vegetables and lung cancer risk, six papers [38,53,55,57,64,65] were considered for the dose-response analysis. We found no significant association between cruciferous vegetables and lung cancer risk corresponding to non-linear dose-response analysis (P = 0.221 for non-linearity; Fig. 8E), but we detected a linear trend regarding the mentioned association (RR per 50 g/day: 0.92, 95% CI: 0.85-0.99, I2 = 0.0%; Figure S5). The risk of lung cancer was 0.96 (0.88, 1.04), 0.93 (0.83, 1.02), 0.90 (0.78, 1.01), and 0.86 (0.68, 1.04) for 50, 100, 150, and 200 g/day of cruciferous vegetables consumption, respectively.

Seven publications [43,59,61,63-65,68] about the association between green leafy vegetables and lung cancer risk were pooled for dose-response analysis. There was a descending non-linear trend in cancer risk, up to 50 g/day of green leafy vegetables intake (P = 0.005 for non-linearity; Fig. 8F). The risk of lung cancer was 0.88 (0.78, 0.97), 0.81 (0.69, 0.92), and 0.74 (0.56, 0.93) for 50, 100, and 150 g/day of green leafy vegetables consumption, respectively. Also, we observed an inverse linear association between an increase of 50 g per day green leafy vegetables and a 13% decrease in chance of developing lung cancer (RR per 50 g/day: 0.87, 95% CI: 0.80-0.95, I2 = 45.2%; Figure S6).

DISCUSSION

The most prominent findings of the present study can be highlighted in five axes: (1) there exists an inverse association between total daily consumption of total FVs, vegetables, fruits, and their subclasses (cruciferous and green leafy vegetables and citrus fruits) and lung cancer; (2) daily consumption of 140 g/day vegetables, 120 g/day of fruits, and up to 900 g/day of FVs can protect against the risk of lung cancer; (3) the consumption of FVs, fruits, vegetables, and their subclasses seem to exert a stronger protective effect on males and smoking individuals (for the exception of cruciferous vegetables); (4) daily consumption of FVs appears more likely to protect against NSCLC, rather than SCLC; and (5) calorie adjustment seems to be determining in defining the association between FVs intake and lung cancer.

As previously stated, lung cancer is divided into two major categories of SCLC and NSCLC. Whilst NSCLC comprises the most diagnosed type (85% of all diagnosed with lung cancer), SCLC seems to be the deadliest with stronger predilection towards distant metastasis and a weaker prognosis [10]. Even though smoking is associated with a significantly higher tumor mutation burden in both kinds, the mutations are usually distinctive: the most commonly mutated oncogenes in NSCLC are Kirsten rat sarcoma virus (KRAS) and epidermal growth factor receptor (EGFR); whereas, the majority (95%) of SCLC cases are signified with a loss of function of tumor suppressors, such as p53 and retinoblastoma protein [5].

SCLC has also been defined as a ‘neuroendocrine’ tumor which, accompanied by its other characteristics, makes its clinical management more challenging; in fact, an Food and Drug Administration-approved targeted therapy has yet to be introduced for the disease [75]. Despite the more aggressive nature of SCLC, the NSCLC incidence rate are higher. The findings of the present study suggest that the consumption of FVs and their subclasses are more likely to protect against the risk of NSCLC. In epidemiological terms, this observation suggests that by increasing the daily consumption of FVs, the accumulated burden of the disease could be ameliorated. Moreover, studies have suggested that this risk reduction is expected to be more pronounced in NSCLC patients with EGFR mutations, as compared to the EGFR wild-type [76]. Nonetheless, the mechanisms are yet to be elucidated.

Regardless of the type of the disease, lung cancer seems to flourish in a tumor microenvironment (TME) whose properties could be targeted by a dietary modification of increasing the intake of FVs. The TME for lung cancer includes the development of extracellular matrix, vast angiogenesis, the intrusion of fibroblasts, and the infiltration of host immune cells into the tumor site [77]. The latter phenomenon, that is the incorporation of innate and adaptive immune responses, is believed to play a dichotomous role in the development and progression of lung cancer; in which they could either help halt the unhinged circle of tumorigenesis and the augmentation of circulating tumor cells responsible for metastasis (a process known as ‘immune surveillance’) or favor the already flourishing TME [78]. In the condition that the latter (called ‘cells-avoiding immunity’) be selected, a plethora of aberrant inflammatory cascades will be ensued; all in favor of a progressive in-site/distant tumorigenesis [79]. The most important of these include augmented expression of the following TGFs and cytokines: TGF-β, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-22 [80]. Subsequently, other inflammatory processes, such as increased expression of NF-κB and COX-2 will be triggered which further develop a pro-inflammatory milieu to facilitate tumor growth [81,82]. Furthermore, once established, cancer cells will remodel the TME by deriving immunosuppressive response [83].

It is now well-established to the daily consumption of vegetables and fruits could disrupt the aforementioned cycle to both prevent or hinder further tumorigenesis [84]. FVs contain an abundance of bioactive compounds which can prevent the crucial stage of mutations for cancer initiation and the following inflammatory pathways for the development of tumor and its distant metastasis [85,86]. Even though each subclass of FVs contain vastly distinctive groups of phytochemicals, the findings of the present study suggest that, apart from the number of the required servings, their impact is hardly differentiable, at least in the context of an observational study.

Biological sex is another factor that needs to be taken into account. It appears that multiple biological, social, and psychological factors differentiate males and females in the way they pursue smoking (as the main predictor of lung cancer) [87]. These factors, accompanied by distinctive impact of smoking on male and female smokers, have led to a gap in lung cancer epidemiology between the two sexes; whilst there is a decrease in lung cancer in males, it holds an increasing figure in females, especially in the form of adenocarcinoma [88].

The findings of the present study also indicate that consumption of FVs might yield a different impact on females than on their male counterparts. The subgroup analyses of the present study show that consumption of FVs and their subclasses might be more beneficial for males in the prevention of lung cancer, except for cruciferous vegetables. This observation might be explained by the different way that the two sexes metabolize carcinogens, such as those present in tobacco smoke [89]. For instance, the activity of CYP1A1, a cytochrome P450 enzyme involved in phase II detoxification, has been shown to be comparatively lower in females [90]. Moreover, there is some evidence that cruciferous vegetables and/or their extracted bioactive compounds may positively alter the activity of CYP1A1 [91,92]. However, further evidence, preferably in the form of human controlled trials, are needed to confirm such claims.

Another noteworthy factor that needs to be accounted for is the effect of calorie consumption. Restriction of energy intake has been suggested both as a preventive measure and a complementary method to chemotherapy and radiotherapy once a tumor has been developed [93]. Similar claims have been made with regard to lung cancer [94,95]. Subgroup analyses of the present study show that adjustment for the possible confounding impact of energy consumption is not a determinant factor, except for the total FVs, citrus fruits, and cruciferous and green and leafy vegetables.

However, owing to the significant fewer studies which did not adjust for calorie consumption, compared to the vast majority which did, measuring the impact of calorie intake on the association between these food groups and lung cancer is quite challenging. In clearer terms, the association was rendered insignificant only when there was a remarkable gap between the number of studies in each subgroup; thus, increasing the risk of bias in the subgroup with fewer included studies. Nonetheless, due to growing body of evidence which suggest the impact of energy consumption/restriction on the development and progression of lung cancer, it is highly advised that the findings of prospective interventional studies be seriously considered. The findings of the current study indicate that consumption of 120 g/day of fruits, as the main source of energy among the included exposures, is probably the best cutoff for cancer/mortality prevention which seems to provide an amount of energy not excessive enough to nullify its beneficial impact.

The association between the consumption of FVs have been already investigated in previous studies [96-98]; however, in addition to updating the evidence, the present study holds the following distinctive features: (1) the comprehensiveness of the search which resulted in a noteworthy pooled population which make the findings rather conclusive; (2) a thorough subgroup analysis which envisions the impact of further sources of heterogeneity, including the unprecedented inclusion of calorie adjustment to explore the otherwise neglected residual confounding; (3) the inclusion of both incidence and mortality as the final outcomes, and (4) extensive investigation of dose-response association which yielded cutoffs for each food group/subgroup, different from previous studies.

CONCLUSION

The daily consumption of FVs is associated with a significantly reduced risk of lung cancer incidence/mortality. Our findings suggest that daily consumption of 140 g/day vegetables, 120 g/day of fruits, and up to 900 g/day of FVs significantly reduces the risk of lung cancer. Furthermore, calorie intake seems to be an important determinant regarding this association. The impact of FVs intake seems to be more prominent on NSCLC, male individuals, and smokers. Future studies need to focus on establishing a clear cut-off for biological sex and smokers vs. non-smokers.

SUPPLEMENTARY MATERIALS

Supplementary materials can be found via https://doi.org/10.15430/JCP.25.009.