The Effects of Dietary Supplements on Asthma and Lung Cancer Risk in Smokers and Non-Smokers: A Review of the Literature

Smoking is one of the major global causes of death. Cigarette smoke and secondhand (passive) smoke have been causally related to asthma and lung cancer. Asthma is a potential risk factor for developing lung cancer in both smokers and non-smokers. Prospective studies and randomized control trials (RCTs) of dietary supplements and lung cancer risk in adult smokers and non-smokers have yielded inconsistent results. A few prospective studies have shown that long-term use of high doses of some supplements, such as retinol, β-carotene, B vitamins, and vitamin E, increase lung cancer risk in current and former smokers. Limited evidence from RCTs suggests that vitamin D supplementation is effective in improving lung function and reducing asthma risk in current/former smokers. The relationship between dietary supplements and lung cancer risk has never before been examined in asthmatic smokers and non-smokers. This short review aims to examine the evidence from existing studies for the effects of dietary supplements on asthma/lung cancer risk and mortality in smokers and non-smokers.


Introduction
Smoking harms several organ systems of the body and is considered a major risk factor for many diseases (e.g., lung and other cancers, coronary heart diseases and stroke, chronic obstructive pulmonary diseases) that are the largest causes of death among adults worldwide [1][2][3]. Tobacco smoke contains thousands of toxic chemicals, of which 60 are identified carcinogens [4]. Smoking caused nearly 12% of global deaths in 2015, with 52% of those deaths taking place in Russia, India, China, and the USA [3]. It is well known that exposure to second-hand smoke (SHS) is associated with deaths from serious diseases (e.g., ischemic heart disease, chronic obstructive pulmonary disease, stroke, lung cancer) in adults [5,6]. Worldwide, more than 600,000 premature deaths were estimated to have been caused by SHS exposure in 2004. Of these, the rate of female non-smokers (47%) was higher than that of children (28%) and men (26%) [7].
Lung cancer is the first ranked among cancers, accounting for 18.4% of global cancer deaths in 2018. By region, the incidence rates were higher in men than in women, with the highest rates in Micronesia/Polynesia (52.2%), Eastern Europe (49.3%), East Asia (47.2%), and Western and Southern Europe (43%) [8].Cigarette smoking is the main risk factor for lung cancer among men and women worldwide [9], with over 76% (aged ≥50 years) and 49% (aged 15-49 years) of lung cancer deaths in men and 37-42% (aged ≥50 years) of lung cancer deaths in women caused by tobacco use in 2017 [10]. There are several longitudinal and case-control studies that clearly link current and ex-smoking of cigarettes with lung cancer [11,12]. The risk of lung cancer was also caused by other forms of tobacco use, in particular, cigars and pipes/waterpipes [13][14][15]. SHS is recognized as a cause of lung cancer. Several case-control and prospective cohort studies have shown that SHS or passive smoking raises the chance of getting lung cancer in non-smokers, particularly in women [12,16].
Asthma is one of the most prevalent chronic diseases in young adults [17]. Globally, the prevalence of current asthma among adults (aged 18-45 years) varies widely, with the highest prevalence seen in Australia [18]. The global burden of disease (GBD) study reported that 400,000 deaths were caused by asthma in 2015, and the rates were higher in males than in females [19]. Cigarette smoke and SHS exposure are the major triggers of asthma exacerbations in adults. Findings from systematic reviews and meta-analysis of prospective and cross-sectional/case-control studies have confirmed that the risk of asthma has increased in adult current and former smokers [12,20]. Exposure to passive smoke also increased the risk of asthma in adult non-smokers [12]. Asthma has been found to be a risk factor for lung cancer. A few systematic reviews and meta-analyses of prospective and case-control studies have shown that asthma is associated with risk of lung small-cell and squamous cell carcinoma, but not with lung adenocarcinoma. Furthermore, the risk of lung cancer was high in asthmatic smokers and non-smokers [21][22][23].
Dietary supplements are commonly used by cancer patients as they hope these supplements might help to fight their cancer. However, it has been proven that these supplements have the potential to be harmful [24]. A number of prospective and RCT studies that examined the effect of dietary supplements on lung cancer risk and mortality in adult smokers/non-smokers have reported inconsistent results. In a few long-term prospective cohort studies, the risk of lung cancer increased with high doses of retinol supplements in former smokers [25], and with B vitamins (B6, B12) and vitamin E supplements in current smokers [26,27]. Only β-carotene supplements increased the risk of lung cancer among male current smokers in a trial of α-tocopherol and β-carotene supplements [28], but none of the supplements had an effect on post-trial lung cancer risk [29]. In a large trial of retinyl palmitate and β-carotene supplements with a post-trial follow-up of lung cancer, the risk remained increased in former smokers, but overall mortality decreased in current and former smokers [30]. In a large cohort study, multivitamins and other dietary supplements (e.g., ginseng/Q10, herbs/plants, single minerals) taken daily or occasionally had a significant effect in reducing mortality from lung cancer in current smokers [31]. In one cohort study, the risk of lung cancer was increased with vitamin E supplements in non-smokers exposed to side-stream smoke at home/work [32], whereas another study detected no significant effect from vitamin D and calcium supplements [33]. Although multivitamins/other supplements are widely used to prevent chronic diseases [34], the efficacy of these supplements in reducing or treating asthma in adult smokers is unclear. In adult current/former smokers, in whom the use of dietary supplements in the treatment of asthma remains the least studied, vitamin D supplementation tends to improve lung function and decrease risk of asthma [35]. To our knowledge, the risk of lung cancer associated with dietary supplements has never before been studied in asthmatic smokers and non-smokers. Given the significant link between asthma and lung cancer, this link could have health implications for smokers and non-smokers in terms of using dietary supplements. This short review aims to examine existing evidence of the effect of dietary supplements on asthma and lung cancer risk and overall mortality in smokers and non-smokers.

Method
The PubMed/MEDLINE database was searched for relevant articles up to January 2019, using the following key words: "Lung cancer" AND "supplements" OR "multivitamins" AND "smokers" OR "non-smokers" AND "asthma". Studies were included if they focused on the effects of supplements and/or vitamin/mineral intake (from both diet and supplements) on asthma and lung cancer risk and total mortality rate, with the overall results stratified by smoking status or groups. Studies with a primary focus on the effects of dietary intake on risk of lung cancer or asthma were not considered. Studies focusing on other allergic/atopic conditions (atopic dermatitis/eczema, allergic rhinitis, hay fever, food allergy) were also not considered, as the extent of the association between these conditions and lung cancer are still questionable, due to inconsistent findings across studies [36][37][38][39][40].

Smoking and Risk of Asthma
The Vitamin D Assessment (ViDA) study was a randomized, double-blind, placebo-controlled trial, designed to examine the effect of vitamin D supplementation on lung function in adults. The assessment used self-administered questionnaires to collect data on demographic variables, use of vitamin D supplements, history and medications for asthma, sun exposure, and smoking. Lung function (FEV1) was measured using a KoKo Trek spirometer. The effect in the vitamin D supplemented group on lung function was greater and significant compared to the placebo group. In particular, a significant improvement in lung function was observed among ever-smokers (current/former), ever-smokers with vitamin D deficiency, and ever-smokers with asthma/chronic obstructive pulmonary disease (COPD). A more significant lung function improvement was also observed among ever-smokers with asthma/COPD than among non-smokers [35].

Smokers
Three prospective cohort studies performed in the US have used the VITamins and Lifestyle (VITAL) study data. The first study examined associations of long-term, high-dose supplementation (lutein, retinol, vitamin A, β-carotene, and lycopene) with lung cancer risk among men and women. The design involved asking the participants to complete a baseline questionnaire, which sought information about multivitamin/supplement use during the last 10 years. Results showed that use of retinol supplementation for ≥4 years was associated with a significant 53% increased risk of total lung cancer and 80% increased risk of non-small cell cancer. Using β-carotene supplementation for ≥4 years was associated with an increased risk of small cell lung cancer. Ten-year average daily intakes of supplemental retinol in high doses (>1200 mcg/day) were associated with an elevated lung cancer risk of 46% among former smokers (quit ≥10 years) [25]. The second study which examined associations between long-term, high-dose supplementation of multivitamins/other supplements and risk of lung cancer, showed that current smokers with a 10-year use of high dose vitamin E supplements (>215 mg/day) had a 59% increased risk [26]. The third study, which examined associations between long-term, high-dose supplementation of B vitamins and lung cancer risk among current smokers, showed that 10-year use of supplemental B6 (>20 mg/day) and B12 (>55 µg/day) in high doses was associated with an increased risk of lung cancer [27].
A large national cohort study of cancer patients examined whether cod liver oil and other dietary supplements used before diagnosis improved patients' survival. Among lung cancer patients prior to their diagnosis, current smokers achieved higher than non-or former smokers. Validated semi-quantitative questionnaires including Food Frequency Questionnaire (FFQ) were used to assess demographic variables and food intake/supplements over the past 12 months. Patients were classified as supplement occasional users, whole year daily users, seasonal daily users, and non-users. Results found that cod liver oil and other dietary supplements improved lung cancer survival. Whole-year daily use of cod liver oil was associated with a 44% decrease in death. Daily and occasional users of other dietary supplements were associated with a 30%and 45% decrease in death, respectively [31]. A large prospective cohort study examined the association of mineral intake from diet/supplements with lung cancer risk, and showed that among current smokers, a high intake of Ca from diet (>1362 mg/day) was associated with a 14% reduction in risk, whereas a high intake of Mg from diet (>449 mg/day) was associated with a 28% increase in risk. Mineral intake from supplements had no effect on lung cancer risk [41]. A study examining associations between multivitamin/mineral use and the risk and mortality from several cancers among men and women reported no association of multivitamin/mineral use with risk and mortality of lung cancer among current or former smokers [42].

Non-Smokers
Two prospective cohort studies carried out on Chinese female non-smokers used the Shanghai Women's Health Study data. The first study examined associations between α-tocopherol (vitamin E) intake from diet/supplements and lung cancer risk. Validated self-administered FFQs were used at baseline and follow-up (every 2-3 years) to measure the frequency of eating food during the month prior or taking vitamin/mineral supplements (multivitamins, calcium, vitamin C, B, E, and A) for more than two months. Women were classified as never exposed or exposed to side-stream smoke at home/work. During the follow-up period, 481 lung cancer cases were identified. Results showed that women who were exposed to side-stream smoke at home/work were twice as likely to develop lung cancer when using vitamin E supplements [32]. In another study examining associations between calcium/vitamin D intake from diet/supplements and lung cancer risk among women exposed to passive smoke at home/work, no association between the use of calcium or vitamin D supplements and risk of lung cancer was observed [33].

Randomized Controlled Trials/Double-Blind, Randomized, Placebo Controlled Trials
Smokers A double-blind, randomized, placebo-controlled trial carried out in 40 centers examined the associations between supplemental vitamin D plus calcium (CAD supplementation) and lung cancer risk, and whether the ratio of baseline Ca:Mg intake modified such associations. Results revealed no significant associations between supplemental CAD and lung cancer risk in both groups. However, the risk of lung cancer decreased by 35% among current smokers with CAD supplementation and a low Ca:Mg intake ratio (≤2.53), but not among those with a high Ca:Mg intake ratio (>2.53) [43]. The goal of the randomized double-blind, placebo-controlled trial, the Nutritional Prevention of Cancer Trial, was to evaluate the effectiveness of selenium supplementation in reducing the incidence of cancer among patients diagnosed with prostate, colorectal, skin, breast, head and neck, lymphoma, and lung cancer. The trial was successful in significantly reducing risk of prostate cancer. The trial also documented a non-significant 26% reduction in lung cancer risk with selenium supplementation among current and former smokers [44].
A systematic review and meta-analysis of four double-blind, randomized, placebo-controlled trials reported a significant 24% increase in lung cancer risk in current smokers receiving a high-dose of β-carotene from supplements [45]. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was a double-blind, randomized, placebo-controlled trial that examined the effect of α-tocopherol and β-carotene supplementation on lung cancer risk. Results revealed no effect of 50 mg/day α-tocopherol (vitamin E) supplement on the risk of lung cancer, but a 25% increased risk associated with 20 mg/day β-carotene supplement was observed among male current smokers (≥20 cigarettes/day) [28]. In the 18 years of post-intervention follow-up for the same study, 2881 cases were diagnosed with lung cancer, and 16% of all deaths were due to lung cancer. Neither α-tocopherol nor β-carotene supplements had an effect on post-intervention lung cancer risk and mortality [29]. A recent study using the ATBC data assessed whether cigarette tar and nicotine levels modified the association between β-carotene supplementation and lung cancer risk. Smokers were classified as ultralight (<7 mg tar), light (8-14 mg tar), regular (15-20 mg tar), non-filtered (>20 mg tar), ventilated filter (≤0.8 µg nicotine), unventilated filter (>0.8 to ≤ 1.3 µg nicotine), and no filter (>1.3 µg nicotine). Results found a significant association between β-carotene supplementation and lung cancer risk, regardless of the nicotine or tar levels. The lung cancer risk increased by 31%, 18%, 15%, and 22% (tar levels), and by 23%, 15%, and 22% (nicotine levels) among men when supplemented with β-carotene [46]. The EUROSCAN study, a randomized intervention trial, examined the effect of supplementation of N-acetylcysteine (an antioxidant in supplement form) and retinyl palmitate (vitamin A) on lung, neck, and head cancer survival among cancer patients who were mainly current or former smokers. Results showed no effect on lung cancer risk after two years' use of N-acetylcysteine and/or retinyl palmitate supplements [47].
The Women's Health Initiative (WHI) was a prospective observational and randomized placebo-controlled trial (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010), aimed at examining the association between vitamin D intake as well as calcium/vitamin D supplementation and lung cancer risk, and whether vitamin A intake modified such associations among postmenopausal women. Vitamin D intake was assessed using validated self-administered FFQs. Results showed that the risk of lung cancer was reduced by 13%, although not statistically significant, among women exposed to the calcium/vitamin D intervention, compared to those in the placebo or not exposed to trial. The risk of lung cancer was higher in current smokers with calcium/vitamin D supplementation and a high total vitamin A intake (≥3000 µg/day retinol activity equivalents (RAE)) than with a low total vitamin A intake (<3000 µg/day RAE) [48]. A case-cohort study within the Carotene and Retinol Efficacy Trial (CARET, 1988(CARET, -2005 was designed to examine the association of estimated vitamin D from food or dietary supplements with lung cancer risk, and whether CARET active intervention (25,000 IU retinyl palmitate plus 30 mg β-carotene/day vs. no intervention) and total vitamin A intake (≥1500 µg/day RAE vs. <1500 µg/day RAE) modified such associations among current and former smokers. A self-administrated FFQ was used to assess total vitamin D and vitamin A intake, whereas an inventory method during clinical visits was used to assess dietary supplements. The study showed a non-significant association between a high intake of vitamin D (≥800 IU/day), a 74% reduction in lung cancer risk among former smokers, and 7% reduction among current smokers. Furthermore, a non-significant 75% reduction in risk was observed among former smokers who had a high intake of vitamin D (≥400 IU/day) and received the CARET active intervention. However, a significant 62% reduction in risk was observed among current smokers who had a high intake of vitamin D (≥400 IU/day) and vitamin A (≥1500 µg/day RAE) [49]. Goodman et al. [30] in the CARET study assessed whether six post-trial years of retinyl palmitate and β-carotene supplementation could reduce lung cancer incidence and total mortality rates after patients stopped taking the supplements, due to an increase in incidence and mortality rate. Intervention patients in the post-trial phase were reassigned to receive a daily dose of 25,000 IU retinyl palmitate and 30 mg β-carotene/day. During the post-trial phase, current smokers had a 20% lower lung cancer risk and a 39% lower mortality rate than those in the trial phase. Compared to former smokers in the trial phase, those in the post-trial phase had a 31% increased risk but a 15% reduced mortality rate.

Non-Smokers
A study using the Women's Health Initiative (WHI) data aimed to examine whether the associations between 25(OH)D concentration and lung cancer risk differed in a calcium/vitamin D trial intervention (intervention group vs. placebo group/non-participants in the trial) among never-smoking postmenopausal women. Two case-control pairs were selected (lung cancer cases vs. control non-smokers). In the group of never-smoking women, an effect for the calcium/vitamin D supplementation (400 IU vitamin D 3 plus 1 g Ca/day) on such associations was observed. Women with high serum 25(OH)D concentrations (≥50 nmol/L) who received the trial supplement were associated with a statistically non-significant 58% reduced lung cancer risk [50]. Nine hundred and forty studies matching these key words were identified. Twenty studies were selected for full review. Details of the selected studies are provided in the following sections and Table 1. Across ever-smoker subgroups, the effect of vitamin D supplementation compared to placebo was significant. Ever-smokers (β = 57 mL, P = 0.03), ever-smokers with vitamin D deficiency (β = 122 mL, P = 0.04), ever-smokers with asthma/COPD (β = 160 mL, P = 0.004). A significant improvement in lung function was observed among ever-smokers with asthma/COPD over non-smokers (P = 0.0005).

Conclusions
This review found contradictory results across studies examining the effects of dietary supplements on lung cancer risk and mortality in adult smokers/non-smokers. This makes it difficult to draw firm conclusions. In adult smokers, long-term use of high doses of retinol, β-carotene, B vitamins, and vitamin E supplements do not appear to have any protective effects against lung cancer risk among current/former smokers in prospective studies. Supplementation with β-carotene appeared to increase lung cancer risk and mortality in the trial phase among male current smokers, but β-carotene and α-tocopherol supplements had no effect in the post-trial phase. β-carotene and retinyl palmitate supplements for several years post-trial resulted in increased lung cancer risk among former smokers, but decreased mortality among current and former smokers. Taking multivitamins and other supplements (ginseng/Q10, herbs/plants) daily or occasionally has been linked to decreased lung cancer mortality among current smokers. Vitamin D/calcium supplementation together with high vitamin A and calcium/magnesium intake resulted in significant increases in lung cancer risk among current smokers. Mineral supplements/multivitamins, N-acetylcysteine and retinyl palmitate had no effect on lung cancer risk among current/former smokers. In female non-smokers, vitamin E supplementation had been linked to increased lung cancer risk, but vitamin D/calcium supplements had no effect on risk. Overall, supplementation with ginseng/Q10, herbs/plants, and β-carotene/retinyl palmitate may decrease the risk of dying from lung cancer. Vitamin E supplementation does not provide any protection among patients with lung cancer who never smoked. The high intake of vitamin A or calcium/magnesium together with vitamin D/calcium supplements is not advocated. Lack of any effect of supplements with multivitamins, N-acetylcysteine, retinyl palmitate, and vitamin D/calcium in prospective studies makes it difficult to recommend that these supplements would be helpful in protecting against lung cancer. This review suggests caution in recommending long-term, high-dose supplements that contain β-carotene, retinyl palmitate, vitamin E, B, vitamins (B6, B12) for patients with lung cancer, especially current and former smokers. To conclude, it is important to evaluate safety and effectiveness of dietary supplement use by adult smokers and non-smokers before, during, and after lung cancer treatment.
This review found limited evidence for the effects of vitamin D supplements on asthma risk in adult smokers. Only one RCT found vitamin D supplementation did significantly improve lung function and reduce asthma risk in current/former smokers. Further investigations will be needed to examine the effects of other supplements on asthma risk/mortality in adult smokers/non-smokers. Clearly, there is still a gap in knowledge with respect to the effects of dietary supplements on lung cancer risk/mortality in asthmatic smokers and non-smokers. Future trials and prospective studies of these supplements are needed to detect their benefits and harms.
Funding: This research received no external funding.