The association between tobacco smoking and colorectal cancer: A meta analysis – Nguyen Thi Nga

JMR 116 E3 (7) - 2018 87 JOURNAL OF MEDICAL RESEARCH Corresponding author: Le Tran Ngoan, Hanoi Medical University Email: letngoan@hmu.edu.vn Received: 15/4/2018 Accepted: 22/11/2018 THE ASSOCIATION BETWEEN TOBACCO SMOKING AND COLORECTAL CANCER: A META ANALYSIS 1Nguyen Thi Nga, 2Pham Phuong Lien, 3Khanpaseuth Sengngam, 4,5Le Tran Ngoan 1Vinh Medical University, Vietnam; 2Hanoi University of Public Health, Vietnam; 3National Institute of Public Health, Lao PDR; 4International University of Health and Welfare, Japan; 5Hanoi Medical University, Vietnam Cigarette smoking is recognized as the cause of a number of diseases including cancer, however, previ- ous findings of its relation to colorectal cancer (CRC) are inconsistent. The objective of this study was to conduct a systematic review and analyze the association between tobacco smoking and CRC from published papers during the previous five years. All published cohort studies within the last five years using specific keywords were reviewed. The title and abstract of all available papers were reviewed and considered for eligibility inclusion. The ln(HR) and se(ln(HR)) were estimated from the multivariable adjusted HR and the 95% confidence interval (CI) was derived from published studies. The random pooled multivariable adjusted HR and 95%CI was analyzed using STATA 10. There were 20 studies included for pooled analysis. The test for heterogeneity yielded Q = 128.044 on 22 degrees of freedom (p = 0.000). Moment-based estimate of between studies variance = 0.021. HR = 1.16; CI (1.08 - 1.27), statistically significant, p < 0.01. We observed a significant positive association between tobacco smoking and the risk of colorectal cancer. Key words: CRC, cigarette smoking, cohort study, meta-analysis I. INTRODUCTION Cigarette smoking has been recognized as the cause of a number of diseases including cancer [1]. Annually, while active smoking kills more than five million people, secondhand smoking (SHS) causes the death of over 600,000 people worldwide [2]. If the situation is not controlled, deaths due to tobacco use will reach eight million per year by 2030. The vast majority of these deaths are projected to occur in the developing world, including Vietnam [3]. Tobacco use was also associated with a high burden of diseases from non- communicable diseases such as cardiovascular diseases, cancers, chronic respiratory diseases and diabetes. Despite these negative health effects, the prevalence of tobacco smoking has been increasing globally in recent years, particularly among youth in low and middle income countries [4 - 6]. Colorectal cancer incidence and mortality has been the fifth most common cancer worldwide; approximately 1.4 million new cases and 694,000 deaths were estimated to have occurred in 2012 alone [7]. Although the involvement of cigarette smoking in the development of colorectal cancer has been reported in some studies, evidence of the association between tobacco smoking and colorectal cancer risk is still unclear [8; 9]. To our knowledge, no literature review has been conducted on the association between 88 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH tobacco smoking and colorectal cancer since our earlier review in 2013. We aim to review the association between tobacco smoking and CRC from published papers during the previous five years. II. METHODS To further investigate the controversial relationship between cigarette smoking and CRC, we conducted a review of all published cohort studies within the last five years. The search process was conducted in January through August of 2017 using PubMed with the keywords: (smoke OR cigarette OR tobacco OR smoking) AND (Colon cancer OR Rectum cancer OR colo-rectal cancer OR colorectal cancer OR colorectum cancer OR colon rectum cancer) AND cohort studies). The studies were collected and handled in two stages. In the first stage, the title and abstract of all collected researches were reviewed. Studies not related to cigarette smoking and CRC were excluded. Studies matching the selection criteria were stored as full text and were moved to the second stage. At this stage, we proceeded to read and check the results and methodology of the studies. Studies related to the association of cigarette smoking and CRC published from 2013 until the present were selected. For studies that published data from the same cohort, we chose only the most recent and complete report for analysis. - Patients were prospectively recruited and followed up. - Studies reported relative risk (RR) or hazard ratios (HR) and their corresponding 95% confidence intervals (95% CIs) of CRC or some other factors effecting CRC status by different smoking categories • At least one of the outcomes (colon, rectal, or CRC) was reported. Inclusion criteria - Patients were prospectively recruited and followed up - Studies reported relative risk (RR) or hazard ratios (HR) and their corresponding 95% confidence intervals (95% CIs) of CRC or some other factors effecting CRC status by different smoking categories. - At least one of the outcomes (colon, rectal, or CRC) was reported Exclusion criteria - Case-control design - Studies that included hereditary CRC syndromes, chronic inflammatory bowel disease, history of colorectal cancer, or previous bowel resection. - Full publication not written in English Data of all studies were extracted and arranged into a formation for analyzing and evaluating. The characteristics extracted include: - Basic information: Name of author, conducted year, published year, setting. - Detailed information: Subject, gender, person at risk, type of CRC. - Research results: Incidence or mortality, smoking category, cigarettes per day, smoking duration, pack-year, initiate age, RR, HR adjusted. The primary outcome of this study was the incidence of CRC (International Classification of Disease [ICD] versions 7 - 9: 153 - 154; ICD 10: C18 - 21). Secondary outcomes included incidence of colonic cancer (ICD 7 - 9: 153; ICD 10: C18 - 19) and rectal cancer (ICD 7 - 9: JMR 116 E3 (7) - 2018 89 JOURNAL OF MEDICAL RESEARCH 154; ICD 10: C20 –21). The cancer diagnosis was identified through hospital records, pathology reports, or cancer registry. All studies used were published and data can be used for researching purposes. All the information collected was kept confidential and was only available for research purposes. Data synthesis and analysis The ln(HR) and se(ln(HR)) were estimated from the multivariable adjusted HR, 95% CI derived from published prospective studies. The random pooled multivariable adjusted HR, 95% CI was analyzed using STATA 10. III. RESULTS We identified eligible 400 abstracts from the initial literature search. After screening and excluding duplicate abstracts, 20 articles were considered of interest and full texts were retrieved for detailed evaluation. The present study included 20 cohort studies with data from a total of 6.302.836 participants. Six studies were conducted in American populations, eight in the Asian Pacific populations and six in European populations (Figure 1). All studies were conducted and followed up between 1972 and 2013. Most of the articles were published in regional or world cancer magazines. In 2016 and 2017, only one study was published while four were published in 2014. Six studies were published in 2015 and eight were published in 2013. Sixteen studies included CRC, three studies included colon cancer only and one included only rectal cancer (Table 1). Five studies indicated cases of CRC deaths but only four studies described hazard ratios of colorectal cancer mortality for current smokers (Table 2). In two studies of Ahmadi et al and Tao L et al, current smoking was associated with colorectal cancer-specific mortality [10; 28] whereas two studies were not associated with colorectal cancer specific mortality [10; 15]. In a study of Jang B et al, multivariable-adjusted Cox proportional hazards regression models showed that smoking before diagnosis was associated with colorectal cancer-specific mortality (RR, 2.14; 95% CI, 1.50 to 3.07) and post-diagnosis smoking was associated with colorectal cancer-specific mortality (RR, 1.92; 95% CI, 1.15 to 3.21) [12]. 90 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH Records identified through data- base searching, (n = 643) Id en tif ic at io n Records excluded (n = 362) Sc re en in g In cl u de d El ig ib ili ty Records after duplicates removed (n = 243) Records screened (n = 400) Full-text articles assessed Full-text articles excluded, Studies included in qualita- tive synthesis (n = 20) Studies included in quanti- tative synthesis (Meta- analysis), (n = 18) Figure 1. Flowchart of systematic literature search and review for eligible studies Table 1. The title and author in included studies Number Name of studies and [source] Author 1 Behavioural and Metabolic Risk Factors for Mortality from Colon and Rectum Cancer: Analysis of Data from the Asia- Pacific Cohort Studies Collaboration [10] Morrison DS et al 2 Active smoking and mortality among colorectal cancer survi- vors: the Cancer Prevention Study II nutrition cohort [11] Yang B et al 3 Weight change later in life and colon and rectal cancer risk in participants in the EPIC-PANACEA study [12] Steins Bisschop BN et al JMR 116 E3 (7) - 2018 91 JOURNAL OF MEDICAL RESEARCH Number Name of studies and [source] Author 4 Risk of colorectal cancer associated with active smoking among female teachers [13] Susan Hurley et al 5 Fruit and vegetable intake and the risk of colorectal cancer: Results from the Shanghai Men's Health Study [14] VogtmannE et al 6 Lifestyle factors associated with survival after colorectal can- cer diagnosis [15] Boyle Tat et al 7 Smoking and survival of colorectal cancer patients: population -based study from Germany [16] Walter V et al 8 The Increased Risk of Colon Cancer Due to Cigarette Smok- ing May Be Greater in Women than Men [17] Parajuli R et al 9 Proportion of Colon Cancer Attributable to Lifestyle in a Co- hort of US Women [18] Erdrich J et al 10 Combined impact of healthy lifestyle factors on colorectal can- cer: a large European cohort study [19] Aleksandrova K et al 11 Does active smoking induce hematogenous metastatic spread in colon cancer? [20] Ahmadi A et al 12 Association of body mass index and smoking on outcome of Chinese patients with colorectal cancer [21] Liu D et al 13 Risk factors for Colorectal Cancer in Thailand [22] Poomphakwaen K et al 14 Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women [23] Tillmans LS et al 15 Smoking increases rectal cancer risk to the same extent in women as in men: results from a Norwegian cohort study [24] Parajuli R et al 16 Mortality determinants in colorectal cancer patients at different grades: a prospective, cohort study in Iran [25] Ahmadi A et al 17 Hypertension is an important predictor of recurrent colorectal adenoma after screening colonoscopy with adenoma polypec- tomy [26] Lin CC et al 18 Heterogeneity of colorectal cancer risk by tumour characteris- tics: Large prospective study of UK women [27] BurónPust A et al 19 Impact of postdiagnosis smoking on long-term survival of can- cer patients: the Shanghai cohort study [28] Tao L et al 20 A Prospective Study of Duration of Smoking Cessation and Colorectal Cancer Risk by Epigenetics-related Tumor Classifi- cation[29] Nishihara R et al 92 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH Table 2. Hazard ratio of colorectal cancer mortality for smoking status Reference Smoking status HR (Multivariate Adjusted)* Never smokers = 1 [10] Current smoker 1.08 (0.72 - 1.62) [11] Current smoker - [15] Current smoker 1.31 (0.82 - 2.09) [25] Current smoker 1.55(1.03 - 2.34) [28] Male Current smoker 2.31 (1.40 - 3.81) *HR adjusted by many variables depending on the research including age, BMI, physical activ- ity, height, drink, smoke, cholesterol, diabetes and education were included in the sex and study stratified model. Table 3. HR of Colorectal Cancer Incidence for smoking status Reference Smoking status Adjusted HR [12] Never, current, former - [13] Never, current, former Current smokers: HR = 1.28, (1.00 - 1.63) Former smokers: HR = 1.10, (0.97 - 1.24) [14] Ever smokers, never smokers - [17] Never, former, current, ever Female ever-smokers: HR =1.19, (1.09 - 1.32) Male ever-smoker: HR = 1.08, (0.97 - 1.19) [18] Cigarette smoking pack years [19] Current, never, former [22] Non-smoker, ex-smokers, current smokers Ex-smokers: HR = 1.34(0.52 - 3.46) Current smokers: HR = 0.51(0.18 - 1.38) [23] Never, ever, former, current smokers [24] Never, former, current, Male ever-smoker: HR = 1.27, ( 1.11 - 1.45) Female ever-smokers: HR = 1.28, (1.11 - 1.48) [27] Current, never - [28] Non-smokers, current smokers - [29] Current smokers - JMR 116 E3 (7) - 2018 93 JOURNAL OF MEDICAL RESEARCH There were 12 studies which indicated the incidence of CRC but only 4 studies described HR indicator for different types of smoking status (Table 3). Our study included 20 studies that met the criteria, including 18 studies showing the asso- ciation of smoking and colorectal cancer with HR and RR, although each study presented many different RR and HR indicators. Therefore, the author conducted a selection of the lowest correlation indicators for the combined study. Of the 18 studies, 15 studies included HR for both colorectal cancer in general; one for colon (colon, proximal, distal); one for result of three types of CRC (colon, rectal and CRC) and one for gender (both for Table 4. Combined analyses results of fixed and random methods Method Pooled estimation 95% confidence interval Asymptotic Number of analyses z-value p-value Random 1.16 1.08 1.27 4.131 0.000 23 Test for heterogeneity: Q = 128.044 on 22 degrees of freedom (p = 0.000). Moment-based estimate of between studies variance = 0.021. Although the degree of dispersion was high when selecting 23 indices from 18 studies, the pooled estimation from the Random methods were simi- lar (statistically significant). After a meta-analysis of 23 indicators of 18 studies, it was concluded that smoking increases the risk of colorectal cancer. female and males) such that 23 variables were analyzed together. In these 23 variables, there were two relatively low risk and statistically significant outcomes while there were seven results for no statistically significant relationship. Fourteen results suggested that smoking increases the risk of colorectal cancer. These results were inconsistent and the data was put into the Stata analysis table. This result evaluated the dispersion of data sets and it can be seen that the studies had a high dispersion (p < 0.000) (Figure 2). Specifically, the results of the analysis by the random method was included in pooled estimation, odds ratio (hazard ratio) = 1.16; CI (1.08 - 1.27) and p < 0.000, (Figure 2, Table 4). 94 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH IV. DISCUSSION The research of David Stewart Morrison et al and T Boy et al found no convincing relationship between smoking and colorectal cancer mortality [10] and the remaining three studies found no association between current smoking and survival in colorectal cancer patients [30 - 32]. A recent meta-analysis of Liang et al reported that current smokers had higher colorectal cancer mortality compared with never-smokers, but the absence of any significant association between former smok- ers and colorectal cancer mortality or between smoking and site specific cancer mortality suggested that further research was needed [33]. The research of Baiyu Yang et al is one of the largest studies of smoking and colorec- tal cancer survival and the first study to prospectively collect both pre- and post- diagnosis smoking information. In this cohort study of colorectal cancer survivors, smoking before or after cancer diagnosis was associ- ated with higher risk of mortality resulting from colorectal cancer [34]. According to a recent meta-analysis from Walter et al, smoking is associated with poorer long-term prognosis after colorectal cancer diagnosis. Specifically, the risk of all-cause mortality was higher for current smoking at all time points (HR, 1.26; 95% CI, 1.15 to 1.37) [35]. We found a greater than two-fold risk of all-cause mortality for both pre- and post-diagnosis smoking compared with never smoking and lower though still sta- Figure 2. Combined estimation of 23 studies JMR 116 E3 (7) - 2018 95 JOURNAL OF MEDICAL RESEARCH tistically significant associations with both pre- and post- diagnosis former smoking. This result is similar to the research of Tao L et al [28]. Only six other studies have examined the association between smoking and colorectal cancer–specific mortality[15; 36 - 40]; of these, two studies with sample sizes comparable to ours [37; 38] found current smoking to be as- sociated with significantly higher colorectal cancer–specific mortality, consistent with our results. However, the previous RRs were lower than the RRs in our study, with pre- diagnosis smoking associated with an RR of 1.30 in a study of patients with colorectal can- cer in Washington state and an RR of 1.46 among patients with colon cancer in a large US cohort [37; 38]. Another study found a greater than two-fold higher risk of colorectal cancer–specific mortality comparing current smokers with former or never-smokers com- bined, and the remaining three studies found no association between pre- and post- diagnosis current and ever smoking with colo- rectal cancer–specific mortality; however, these analyses were based on relatively smaller sample sizes [15; 36; 39; 40]. The study of Ali Ahmadi et al illustrated that smok- ing increased the risk of death in these pa- tients, which is consistent with a study in the United States that reported smoking increased the mortality risk after CRC diagnosis [37]. The colorectal cancer risk estimated for smoking status from the study of Hurley et al (HR = 1.28 for current smokers; HR = 1.10 for former smokers) [13] is consistent with find- ings from a number of recently published meta -analysis on this topic in which summary measures of risk have ranged from 1.12 to 1.26 for current smokers and 1.18 to 1.20 for former smokers [41 - 45]. The marginally lower risk estimate for former smokers in the current study is likely a reflection of the fact that nearly half of the former smokers in our study popula- tion quit smoking more than 20 years before joining the cohort, by which time their risk ap- pears to no longer be elevated. Interestingly, the most recent and one of the largest studies conducted to date reported no association between age at smoking initiation and colorec- tal cancer risk among members of the EPIC cohort [46]. In a recent meta-analysis, Liang reported that for each 10-year delay in smok- ing initiation, there was a 4.4% reduction in risk ratios for colorectal cancer [33]. The degree to which smoking-related colo- rectal cancer risks are similar among men and women has been a matter of debate. Initially, the preponderance of data seemed to suggest that the effect of smoking was either limited to, or at least stronger, among men than among women [47]. Explanations offered for this ap- parent difference have included both limita- tions in exposure potential (given the apparent long latency) as well as real sex-related bio- logic differences potentially arising from differ- ential interactions between smoking and pro- tective endogenous estrogens, body mass index, and/or abdominal adiposity [42]. Two recent meta-analyses of prospective cohort studies on this topic reported that risks for cur- rent smoking continued to be higher among men than among women [42; 43], although only one found these differences to be statisti- cally significant at the 0.05 level [42]. In con- trast, a meta-analyses that included both co- hort and case–control studies published during the same time period reported no evidence for differences in risk by sex [41]. More recent findings from the European Prospective Inves- tigation Into Cancer [46]and the Cancer Pre- 96 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH vention Study II [9], both of which reported no differences in risk by sex, were not included in these meta-analyses. Regardless of whether risks are higher in men than in women, there is now convincing evidence that risks are ap- parent in women. Along with the elevated risks found in this study and those reported among the female participants in the EPIC and CPS-II cohorts, elevated risks also have been re- ported among members of the Norwegian Women and Cancer Study [48] and the Women's Health Initiative [49], both large well- conducted prospective cohort studies among women. The Norwegian study, however, only observed an effect for rectal but not colon can- cer, a finding that also was reported among members of the Canadian Breast Screening Study over 10 years ago [50]. The meta-analysis of Botteri et al in 2008 which analyzed one hundred and six observa- tional studies found that cigarette smoking is significantly associated with colorectal cancer incidence and mortality but the association was stronger for cancer of the rectum than of the colon [41]. The meta-analysis of Tsoi et al included 28 prospective cohort studies in 2009 showing that smoking was associated with a signifi- cantly increased risk of CRC. Current smokers had a modestly higher risk of CRC than never smokers and former smokers still carried a higher CRC risk than never smokers. In addi- tion, the associated risk was higher for men and rectal cancers and the increased risk of CRC was related to cigarettes per day, longer years of smoking, or larger pack years [42]. Another meta-analysis including 103 co- hort studies of Huxley et al in 2009 indicated that smoking may be a lifestyle factor associ- ated with a significant increased risk of colo- rectal cancer [44] but the meta-analysis of Constance M. Johnson et al in 2013 indicated that cigarette smoking was associated with moderately increased risk of CR (RR = 1.06, 95% CI: 1.03 - 1.08 for 5 pack- years) [51]. Limitations To our knowledge, no literature review has been conducted on the association between tobacco smoking and colorectal cancer since our earlier review in 2013. The confidence in the effects estimates in review is affected by a number of limitations. Indeed, we only de- scribed the results of the selected studies by using a sensitive search strategy in Pub Med and conducting screening and data extraction independently and in duplicate. Most studies do not give a precise percentage of the num- ber of smokers, and the groupings of smoking status are different and depend on the re- search questions asked by the authors. Some of the studies that produce the HR index have been calibrated but are corrected by different factors so we were not able to conduct a meta-analysis for all outcomes. One reason was the high level of heterogeneity, as was the case for the quality of life outcome. Another reason was that we could not pool several outcomes derived from the same study, different smoking status, duration and type of CRC. The study results do not cover other life style factors and information on mo- lecular subtypes. Additional studies of our find- ings include the need for further research on this topic by conducting more cohort studies to clearly determine the effects of smoking status on the types and stages of colorectal cancer and the factors that can be combined. JMR 116 E3 (7) - 2018 97 JOURNAL OF MEDICAL RESEARCH V. CONCLUSION In conclusion, this meta-analysis demon- strates that smoking shows a statistically sig- nificant risk of CRC. Male smokers and current smokers had a higher colorectal cancer mor- tality compared with never smokers. ACKNOWLEDGMENTS The present work was the part of a mas- ter’s thesis of the course named “One Health” at Hanoi Medical University. The protocol and completed thesis was approved by a scientific committee of the university. REFERENCES 1. World Health Organization (2011). WHO REPORT on the Global Tobacco Epi- demic, 2011 Warning about the dangers of tobacco. 2. 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