Tobacco smoking and cancer: A meta-analysis

Transcription

1 Int. J. Cancer: 122, (2008) ' 2007 Wiley-Liss, Inc. Tobacco smoking and cancer: A meta-analysis Sara Gandini 1 *, Edoardo Botteri 1, Simona Iodice 1, Mathieu Boniol 2, Albert B. Lowenfels 3,4, Patrick Maisonneuve 1 and Peter Boyle 2 1 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy 2 International Agency for Research on Cancer, Lyon, France 3 Department of Surgery, New York Medical College, Valhalla, NY 4 Department of Community and Preventive Medicine, New York Medical College, Valhalla, NY We conducted a systematic meta-analysis of observational studies on cigarette smoking and cancer from 1961 to The aim was to quantify the risk for 13 cancer sites, recognized to be related to tobacco smoking by the International Agency for Research on Cancer (IARC), and to analyze the risk variation for each site in a systematic manner. We extracted data from 254 reports published between 1961 and 2003 (177 case-control studies, 75 cohorts and 2 nested case-control studies) included in the 2004 IARC Monograph on Tobacco Smoke and Involuntary Smoking. The analyses were carried out on 216 studies with reported estimates for currentõ and/or formerõ smokers. We performed sensitivity analysis, and looked for publication and other types of bias. Lung (RR ; 95% CI: ), laryngeal (RR ; 95% CI: ) and pharyngeal (RR ; 95% CI: ) cancers presented the highest relative risks (RRs) for current smokers, followed by upper digestive tract (RR ; 95% CI: ) and oral (RR ; 95% CI: ) cancers. As expected, pooled RRs for respiratory cancers were greater than the pooled estimates for other sites. The analysis of heterogeneity showed that study type, gender and adjustment for confounding factors significantly influence the RRs estimates and the reliability of the studies. ' 2007 Wiley-Liss, Inc. Key words: tobacco; cancer; meta-analysis Epidemiological evidence of the association between cigarette smoking and cancer began to emerge in the 1920 s, and by the 1950 s the causal relationship with lung cancer was established. 1 4 Since then, evidence of the association between tobacco smoking and cancer of other parts of the respiratory system and of the digestive tract began to accumulate. In 1985, under the auspice of the International Agency for Research on Cancer (IARC) an international Working Group of experts recognized a causal relationship between tobacco smoking and cancer of the lung, oral cavity, pharynx, larynx, pancreas, urinary bladder, renal pelvis and urethra. 5 The association was primarily based on worldwide epidemiological studies. Seventeen years later, in a revised Monograph on Tobacco Smoke and Involuntary Smoking, 6 the IARC added cancers of the nasal cavities and nasal sinuses, the esophagus, stomach, liver, kidney (renal-cell carcinoma), uterine cervix and bone marrow (myeloid leukemia) to the long list of smoking-related cancers. While the IARC Monograph provides summary statements on the association between cigarette smoking and cancer, it does not provide summary measures of the magnitude of the associations. The aim of this study was to provide a statistical evaluation using a meta-analytic approach of the strength of the association between tobacco smoking and these established smoking-related cancers based on the exhaustive set of studies reported in this revised IARC Monograph. In addition, meta-analytic techniques were used to assess whether specific associations depend upon study characteristics such as the population under observation, the level of exposure, the definition of disease used, or other factors. This work provides, in a single document, summary measures of the risk of cancer because of smoking and reasons for variations among studies. Material and methods Data extraction The following information were extracted and coded from the tables of the Monograph: year of publication, type of study, country of the study, features of populations, definition of the exposure and of the cancer sites, adjustments used in the analysis. For lung cancer, when dose-response estimates were provided in the Monograph, we retrieved the study-specific dose response relative risk estimates, and crude data for each level of exposure, directly from the original articles. We used wide inclusion criteria in order to select and retain a large group of homogeneous studies 1. Study reports should contain the minimum information necessary to estimate relative risks and corresponding 95% confidence intervals (i.e. Odds Ratios or Relative Risks and a measure of uncertainty: standard errors, variance, confidence intervals or exact p-value of the significance of the estimates) for the tobacco smoking. 2. The studies should be independent in order to avoid giving double weight to single studies. In case of multiple reports of the same study, we considered only the estimates from the most recent publication. 3. Homogeneous categorizations were chosen for the exposure to tobacco smoking. Relative risks for ever smokers were not considered. When the authors published an estimate for daily smoking, instead of current smoking, the study was included but this decision was investigated in a sensitivity analysis. 4. The populations studied should be homogeneous, and not be affected by a particular disease, which could affect smoking related cancer risk. When results from case-control studies were presented separately for hospital and for population-based controls, we only included results obtained from population-based controls. Definition of the outcome and exposures Only cancer sites with sufficient evidence of carcinogenicity related to tobacco exposure in humans were considered in this meta-analysis: These included cancer of the lung, oral cavity, pharynx, larynx, pancreas, urinary bladder, renal pelvis and ureter, nasal cavity and nasal sinuses, esophagus, stomach, liver, kidney, uterine cervix and bone marrow (myeloid leukemia). 6 As reported in the Monograph, we presented the results separately for cancers of the lower urinary tract (renal pelvis, bladder and ureter), and for cancer of the upper urinary tract. Cancer of the nasal cavity and Grant sponsor: C.D. Smithers Foundation, Italian Association for Cancer Research (AIRC). *Correspondence to: Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Ripamonti 435, Milan, Italy. Fax: sara.gandini@ieo.it Received 21 March 2007; Accepted after revision 21 June 2007 DOI /ijc Published online 24 September 2007 in Wiley InterScience ( wiley.com). Publication of the International Union Against Cancer

2 156 GANDINI ET AL. nasal-sinuses were grouped together with naso-pharyngeal cancer and classified as nasal-sinus-nasopharynx because there were few studies for each of these single anatomically close sites. Heterogeneity analysis was carried out to verify if there was a significant difference by sub-sites. In this study, we investigated only the effect of tobacco smoking and retained risks estimates for former and current smokers because they were the most widely reported categories in the literature, although the definition of these 2 groups could vary within studies. Many studies do not specify a minimum duration of abstinence for individuals classified as former smokers; when specified, the period of abstinence was at least 1 year since quitting smoking. For many studies only estimates for dose categories (cigarettes per day, pack-years and duration) were available and for those studies we could not obtain an estimate for current smokers. Because of the high number of studies on lung cancer presenting only dose-response estimates for current smokers, we calculated the pooled relative risks (RRs) for lung cancer associated with an increased consumption of 1 cigarette per day. Duration of smoking is the strongest determinant of cancer in smokers but reported data were not homogeneous enough to carry out a metaanalysis on duration. Data analysis strategy We used random effects models, with restricted maximum likelihood estimate, to evaluate summary relative risks. Homogeneity of effects across studies was assessed using the v 2 statistic and quantified by I 2, which represents the percentage of total variation across studies that is attributable to heterogeneity rather than chance. 7 p-values, indicating significance of factors investigated, were obtained with analysis of variance using Proc MIXED in SAS. 8 Subgroup analyses and meta-regressions were carried out to investigate between-study heterogeneity focusing on study type, adjustments used in the analysis, exposure definition, publication year, country, ethnicity and gender. We classified countries as westernized (North America, Europe; Australasia and Japan) and not westernized (Africa, Iceland, China, India and South America) and we also identified 3 ethnic groups: Africans, Caucasians (European countries) and Asians (Japan, China, Korea Philippines and India). Heterogeneity analysis was conducted only for cancer sites with 15 estimates available to avoid very small subgroups and unreliable results. Since the v 2 test has limited power, we considered statistically significant heterogeneity at the p level of association. Sensitivity analysis was carried out in order to evaluate whether results were influenced by a single study. We ignored the distinction among various measures of relative risk (i.e. odds ratio, rate ratio, risk ratio) on the assumption that tobacco related cancers are sufficiently rare. Every measure of association, adjusted for the maximum number of confounding variables, and the corresponding confidence interval, was translated into log relative risk and corresponding variance with the formula proposed by Greenland. 9 When several measures of RR were given for a single study, we used random effects models, even in absence of heterogeneity, including the 2 sources of variation (within and between studies), to take into account correlation within study. 10 Current and former smokings are the exposure categories of main interest of our meta-analysis. Dose-response RRs were analyzed only for lung cancer, the most associated cancer site. For some cancer sites, the number of studies providing risk estimates for current and former smoking differed as risk estimates for current smokers were reported only by level of cigarette consumption. Therefore, the comparison of the pooled estimates for current and for former-smoking was based on different sets of studies. This situation was particularly prominent for pancreatic cancer and for esophageal cancer, for which we had a high percentage of excluded studies (44% for pancreas and 27% per esophagus). For these 2 cancer sites, we had a sufficient (15) number of estimates to be able to compare the pooled estimates for former-smokers based on studies for which estimates for current-smokers were reported and based on studies for which only dose response-estimates were reported. For these cancer sites, we also carried out a subgroup analysis on current smoking estimates based on the subset of studies that presented both current and former smoking estimates. Lung cancer was the cancer site with the highest percentages of studies excluded and for this reason we have carried out a dose-response analysis. In the main analysis, we did not include colorectal cancer because smoking was not considered as an established risk factor for colorectal cancer in However, a quite recent meta-analysis on all risk factors for colorectal cancer in China, based on 5 published studies, reported a significant risk for cigarette smoking in China (RR , 95% CI: ). 11 Thus in the sensitivity analysis we decided to evaluate the estimates for colorectal cancer. Evaluation of dose response We used a linear model, within each study, to estimate the relative risk associated with an increase of 1 cigarette per day. The model was fitted according to the method proposed by Greenland and Longnecker, 12 which requires the estimates and the number of subjects at each level of cigarettes consumption. This doseresponse model takes into account the fact that the estimates for separate levels depend on the same reference group. When number of subjects at each level was not available from the papers, coefficients were calculated ignoring the correlation between the estimates of risk in the separate exposure levels. Doses expressed in quantity of tobacco per unit of time (grams per day or kilograms per month) were converted into number of cigarettes smoked per day. Estimates for pack-year were not included in the analysis because they were not comparable with estimates expressed for cigarettes per day. We assigned to each class the number of cigarettes smoked corresponding to the midpoint of the range. For the highest categories a fix value of 60 cigarettes per day was set as the maximum. The summary RR were obtained pooling the study-specific estimates by the classical random effects models, adjusting for study design and for the possibility to take into account the correlation between the estimates of risk in the separate exposure levels. Results Data from 254 papers published between 1961 and 2003 (177 case-control studies, 75 cohort and 2 nested case-control studies) were extracted from the IARC Monograph and considered for the analysis. Studies were conducted in many countries (8 from Africa, 4 from Australia or New Zealand, 39 from China, 28 from Japan, 8 from India, 13 from South America, 80 from USA or Canada and 74 from Europe). Two hundred and sixteen studies reported separate estimates for currentõ or formerõ smokers. Figures 1 4 present the forest plots for current smokers by cancer sites. In order to respect the inclusion criteria, we eliminated 3 studies from the liver cancer analysis because they were based on series of patients with pre-existing medical conditions (mainly cirrhosis), not representative of the general population Pooled RRs indicated a significant association between tobacco smoking and various cancer types (Table I). For most sites, the pooled estimates for current smoking were greater that the ones for former smoking. Overall, the pooled risk estimates for current smoking presented a high degree of between-study heterogeneity, while risk estimates for former smoking presented generally a lower degree of heterogeneity. Table II presents the pooled RRs for current smokers stratified for selected heterogeneity factors. Results for former smokers, which were similar, were not reported.

3 TOBACCO SMOKING AND CANCER: A META-ANALYSIS 157 FIGURE 1 Forest plots for current smokers by cancer sites: C10-15; C10; C11, C30-31; C14. When available, fully adjusted RRs were retrieved. M: male, F: female; Upper digestive tract a: white, b: black; Oral Cavity a: tongue; Nasal-sinuses Nasopharynx a: nasal cavity and sinuses, b: adenocarcinoma of nasal cavity and accessory sinuses, c: squamous-cell carcinoma of nasal cavity, and accessory sinuses, d: nasopharyngeal cancer.

4 FIGURE 2 Forest plots for current smokers by cancer sites: C15; C16; C22; C25. When available, fully adjusted RRs were retrieved. M: male, F: female; Esophagus a: high-risk area, b: low-risk area, c: adenocarcinoma, d: squamous-cell carcinoma, e: squamous-cell carcinoma/ black, f: squamous-cell carcinoma/white; Stomach a: white, b: black, c: aged 67 years, d: aged > 67 years, e: single, f: multiple, g: gastric cardia, h: other subsites. Liver a: cohort I, b: cohort II; Pancreas a: never-drinkers of coffee, b: more than 2 cups of coffee per day.

5 TOBACCO SMOKING AND CANCER: A META-ANALYSIS 159 FIGURE 3 Forest plots for current smokers by cancer sites: C32; C34; C53; C64. When available, fully adjusted RRs were retrieved. M: male, F: female; Lung a: Mestre, b: Venice, c: aged <35 years, d: aged years, e: aged years, f: heavy smoker, g: light smoker, h: black, i: white; Cervix: a: Columbia, b: Spain, c: invasive cervical cancer, d: carcinoma in situ, e: adenocarcinoma, f: squamous-cell carcinoma.

6 160 GANDINI ET AL. FIGURE 4 Forest plots for current smokers by cancer sites: C65 67; C92. When available, fully adjusted RRs were retrieved. M: male, F: female; Lower Urinary Tract a: light smoker, b: moderate smoker, c: heavy smoker, d: renal pelvis, e: ureter. The highest pooled RR for current smokers was observed for lung cancer (RR ; 95% CI: ), which was significantly greater in case-control studies (RR ; 95% CI: ) than in cohort studies (RR ; 95% CI: ) (p < 0.001). For lung cancer, dose-response estimates were available in 44 studies: 19 with estimates only for men, 11 with estimates only for women and 14 with separate estimates for men and for women. Overall, the risk of lung cancer increases by 7% for each additional cigarette smoked per day (RR , 95% CI: ). This increased risk appears to be slightly higher in women (RR ; 95% CI: ) than in men (RR , 95% CI: ) (p-value < 0.001; adjusting for study type). Separate pooled risk estimates for men and for women for 3 broad smoking categories (1 9 cigarettes per day, cig/day and >20 cig/day) are given in Table III. Following lung cancer, the highest RRs for current smoking were observed for cancer of the larynx (RR ; 95% CI: ), pharynx (RR ; 95% CI: ), combined upper digestive tract (RR ; 95% CI: ) and more specifically cancer of the oral cavity (RR ; 95% CI: ). For all these cancer sites, the pooled RRs for former smokers were much lower than those observed for current-smokers (Table I). For stomach cancer, the pooled RRs for current smokers (RR ; 95% CI: ) and former smokers (RR ; 95% CI: ) support a significant association. Three studies with peculiar characteristics were eliminated in a sensitivity analysis (2 studies in which the control group included patients with other diseases 16,17 and a large retrospective mortality study 18 which had a huge weight in the pooled analysis and with scarce information available). After exclusion of these 3 studies, the pooled RR for current smokers remained unchanged (RR ; 95% CI: ). For pancreas cancer, we observed a significant association both for current smokers (pooled RR ; 95% CI: ) and for former smokers (RR ; 95% CI: ). In a sensitivity analysis, we excluded a Japanese cohort study 19 because the authors presented an estimate only for daily smokers. After excluding this study, there was no change in the pooled RR for current smokers: (RR ; 95% CI: ). A peculiar significant protective effect of cigarette smoking (RR 5 0.3; 95% CI: ) on pancreatic cancer mortality in men was reported in a Chinese cohort, 20 based on 15 deaths (the weight of the study was however very small, w ). After exclusion of this study, the pooled RR remained identical (RR ; 95% CI: ) and the heterogeneity disappeared (p ).

7 TOBACCO SMOKING AND CANCER: A META-ANALYSIS 161 TABLE I POOLED RRs BY CANCER SITE AND TYPE OF EXPOSURE TO CIGARETTE SMOKING Cancer site ICD 10 Smoking status RR* (95% CI) No. of studies p-value Heterogeneity I 2 % Upper Digestive Tract C10-15 Current 3.57 (2.63, 4.84) Former 1.18 (0.73, 1.91) 14 < Oral cavity C10 Current 3.43 (2.37, 4.94) Former 1.40 (0.99, 2.00) Pharynx C14 Current 6.76 (2.86, 16.0) 7 < Former 2.28 (0.95, 5.50) Esophagus C15 Current 2.50 (2.00, 3.13) 22 < Former 2.03 (1.77, 2.33) Stomach C16 Current 1.64 (1.37, 1.95) 32 < Former 1.31 (1.17, 1.46) 33 < Liver C22 Current 1.56 (1.29, 1.87) 24 < Former 1.49 (1.06, 2.10) Pancreas C25 Current 1.70 (1.51, 1.91) Former 1.18 (1.04, 1.33) Nasal-sinuses, C11 Current 1.95 (1.31, 2.91) 10 < Nasopharynx, C30-31 Former 1.39 (1.08, 1.79) Larynx C32 Current 6.98 (3.14, 15.5) 10 < Former 4.65 (3.35, 6.45) Lung C34 Current 8.96 (6.73, 12.1) 21 < Former 3.85 (2.77, 5.34) 20 < Cervix C53 Current 1.83 (1.51, 2.21) 23 < Former 1.26 (1.11, 1.42) Kidney C64 Current 1.52 (1.33, 1.74) Former 1.25 (1.14, 1.37) Lower Urinary Tract C65-67 Current 2.77 (2.17, 3.54) 21 < Former 1.72 (1.46, 2.04) 15 < Myeloid Leukemia C92 Current 1.09 (0.70, 1.70) Former 1.27 (0.28, 5.83) *References category Never smokers ; I 2 represents the percentage of total variation across studies that is attributable to heterogeneity rather than to chance. The pooled risk estimates for the other cancer sites considered, excluding myeloid leukemia (RR ; 95% CI: for current smokers, and RR ; 95% CI: for former smokers), demonstrated significant association for both current and former smokers (Table I). The pooled risk estimates for current smokers were, respectively, RR (95% CI: ) for cancer of the nasal cavity, RR (95% CI: ) for lower urinary tract cancer, RR (95% CI: ) for kidney cancer, RR (95% CI: ) for cancer of the cervix uteri and RR (95% CI: ) for liver cancer. Similarly, the pooled risk estimates for former smokers were RR (95% CI: ) for cancer of the nasal cavity, RR (95% CI: ) for lower urinary tract cancer, RR (95% CI: ) for kidney cancer, RR (95% CI: ) for cancer of the cervix uteri and RR (95% CI: ) for liver cancer. Heterogeneity analysis In Table II, we can see that gender explained some heterogeneity (p < 0.001) of the risk estimates for stomach cancer, with greater estimates for men (RR ; 95% CI: ) than for women (RR ; 95% CI: ). Country was a borderline significant factor (p ) for variability of the estimates for pancreatic cancer: (RR ; 95% CI: for westernized countries and RR , 95% CI: for not westernized countries). When possible, we evaluated the differences in cancer risk among 3 ethnic groups: African-Americans, Caucasians and Asians. We found a borderline-significant heterogeneity between ethnic groups for esophagus cancer (p ) with higher risk in African-Americans (RR ; 95% CI: ) and Caucasians (RR ; 95% CI: ) than Asians (RR ; 95% CI: ). A similar risk pattern was observed for lung cancer although heterogeneity between groups did not reached statistical significance (p ) (Table II). Study design was important for lung cancer (p < 0.001) with greater pooled estimate obtained for case-control (RR , 95% CI: ) than for cohort studies (RR ; 95% CI: ). Adjustment for confounders was significant (p ) for upper digestive tract cancer with greater pooled RR for studies reporting estimates adjusted for alcohol (RR , 95% CI: ) than for those unadjusted (RR , 95% CI: ); for stomach (p ) with greater pooled RR for studies reporting estimates adjusted for diet (RR , 95% CI: ) than for those unadjusted (RR , 95% CI: ) and for lung cancer (p ) with greater pooled RR for studies reporting estimates with any adjustment (RR , 95% CI: ) than for those unadjusted (RR , 95% CI: ). For cervical cancer the adjustment for HPV did not result significant in the heterogeneity analysis, however it is important to notice that only a few studies adjusted for HPV, which is an established and essential risk factor for cervical cancer. For esophageal and pancreatic cancers, we compared the pooled estimates for former-smoking, based on studies for which estimates for current-smokers were reported and based on studies for which only dose response-estimates were reported, and found no sign of heterogeneity (p-value and p respectively). We also calculated the pooled estimates for current smoking in the subset of studies that presented both, current and former smoking estimates: the summary RR estimate for esophageal cancer, based on 16 studies, slightly increased (3.13; 95%CI: 2.63, 3.68) with highly significant heterogeneity between studies (p < and I %). For pancreas cancer, the summary RR estimate, based on 12 studies, did not changed (1.77; 95%CI: 1.54, 2.04) and the heterogeneity between studies decreased (p and I %). We also studied separately cancers of the nasal-sinuses and of the naso-pharynx which share different etiological factors: the pooled RR for nasal-sinus cavity among current smokers was lower (1.49; 95%CI: 0.59, 3.96; evaluated on 3 studies and I 2 5 0) than for nasopharynx (2.23; 95%CI: 1.13, 4.42; evaluated on 7 studies and I %) even if the difference was not statistically significant p For colorectal cancer, we retrieved 38 studies that reported data for current smokers and 31 studies for former smokers. The pooled

8 162 GANDINI ET AL. TABLE II POOLED RRs BY TYPE OF FACTORS THAT COULD INDUCE HETEROGENEITY Cancer site (ICD 10) Factor Strata Up. Digest. Tract C10-15 Esophagus C15 Stomach C16 RR (95% CI) p # RR (95% CI) p # RR (95% CI) P # Sex Men 3.52 (1.94, 6.37) (1.81, 3.52) (1.46, 2.07) < Women 3.80 (1.97, 7.33) (1.51, 3.44) (1.20, 1.75) 19 Alcohol Adj (3.11, 5.23) (2.18, 4.12) Not adj (1.13, 3.65) (1.52, 2.88) 11 Study type CC 4.14 (3.07, 5.57) (1.94, 3.36) (1.29, 1.95) Cohort 2.36 (1.42, 3.93) (1.34, 3.95) (1.24, 2.35) 10 Ethnic African (1.49, 8.20) group Americans Asians 2.33 (0.17, 31.6) (1.14, 2.31) (1.20, 2.89) 8 Caucasians 4.42 (0.97, 20.1) (1.89, 5.92) (0.85, 1.96) 12 Country West (2.23, 4.17) (1.27, 1.89) Not West (1.52, 2.83) (1.31, 2.61) 8 Diet Adj (1.65, 2.99) Not Adj (1.21, 1.74) 24 Liver C22 Pancreas C25 Lung C34 Sex Men 1.85 (1.21, 2.83) (1.32, 2.03) (6.85, 14.24) Women 1.49 (1.12, 1.98) (1.31, 2.30) (5.36, 10.73) 10 Alcohol Adj (1.06, 2.20) Not Adj (1.17, 2.05) 14 Study type CC 1.54 (1.16, 2.05) (1.33, 1.98) (9.64, 20.4) < Cohort 1.54 (1.10, 2.17) (1.44, 2.22) (4.49, 8.82) 11 Ethnic African (0.78, 4.69) (3.03, 34.49) group Americans Asians 1.54 (1.17, 2.02) (1.21, 1.79) (2.83, 10.78) 5 Caucasians 0.93 (0.45, 1.93) (0.99, 2.04) (5.92, 16.67) 9 Country West (0.98, 2.25) (1.58, 2.19) (6.50, 14.6) Not West (1.21, 2.03) (1.16, 1.79) (3.76, 10.58) 7 HBV/HCV Adj (0.90, 1.75) Not Adj (1.34, 2.29) 15 Any adj. Any 1.82 (1.56, 2.13) (7.87, 15.5) None 1.39 (1.06, 1.82) (3.65, 9.70) 7 Cervix C53 Kidney C64 Low. Ur. Tract C65-67 Sex Men 1.59 ( 1.32, 1.91) (2.01, 3.92) Women 1.35 (1.05, 1.73) (1.82, 4.10) 14 Study type CC 1.64 (1.02, 2.65) (1.30, 1.87) (2.26, 3.97) Cohort 2.24 (1.14, 4.39) (1.19, 1.83) (1.19, 3.55) 5 Ethnic African (0.01, 926) N.A (0.35, 15.89) group Americans Caucasians 1.56 (1.08, 2.24) (1.23, 9.33) 7 Country West (0.51, 6.94) (0.79, 3.26) Not West (0.15, 17.1) (2.30, 3.82) 16 No. partners Adj (1.10, 2.86) Not Adj (0.93, 4.18) 7 HPV Adj (0.56, 3.89) Not Adj (1.22, 2.94) 19 BMI Adj (1.42, 2.00) Not Adj (1.09, 1.63) 9 CC: case-controls studies; Cohort: cohort studies. Ethnic group: Caucasians includes European countries; Asians includes Japan, China, Korea, Philippines and India. West.: Westernized countries (North America, Europe and Australasia); Not west.: not westernized countries (Africa, China, India, Japan and South America). Adj.: adjustment of the relative risk estimates (When possible, each stratified estimate is fully adjusted for all the other confounders considered by the authors). HPV: human papillomavirus (HPV) infection adjustment. HBV/ HCV: estimates adjusted also for infection with hepatitis B or C virus. No. partners: adjustment also for number of sexual partners. N.A. not applicable. p-value from mixed models for difference between groups. Estimates by subgroup were not reported when one of the groups has no study. RRs associated with current and former smoking were, respectively: 1.08 (95% CI: ) and 1.16 (95% CI: ). The association for current smoking was significantly (p ) stronger for cohort studies (RR 5 1.2; 95% CI: ), than for case-control studies (RR 5 1.0; 95% CI: ). As alcohol has recently been associated with an increased risk of both colon and rectal cancer and is also strongly correlated with cigarette smoking, we performed a separate analysis considering only studies providing estimates adjusted for alcohol and found significant pooled RRs (RR 5 1.2; 95% CI: ). 21 A similar analysis restricted to studies adjusted for body mass index also showed an elevated risk of colorectal cancer (RR 5 1.2; 95% CI: ). We also evaluated the pooled RRs estimates separately for colon and for rectal cancer, but found no significant difference in risk (p ) between colon (RR ; 95%CI: 0.94, 1.16) based on 25 studies (I ) and rectum cancer (RR ; 95% CI: 0.99, 1.25) based on 21 studies (I ). Thus, the list of cancer sites for which smoking is an established risk factor may be incomplete, suggesting a need for further research. However, looking at the ratios between ORs for current and former smokers, we can observe greater estimates for former than current smokers only for colon-rectum and myeloid leukemia. This could suggest that these estimates should be considered with caution.

9 TOBACCO SMOKING AND CANCER: A META-ANALYSIS 163 TABLE III DOSE-RESPONSE RR ESTIMATES FOR LUNG CANCER Cigarette consumption Men (33 studies) Women (25 studies) RR (95% CI) RR (95% CI) 1 9 cig/day 1.39 (1.28, 1.50) 1.49 (1.37, 1.61) cig/day 2.67 (2.11, 3.37) 3.30 (2.59, 4.20) 20 cig/day (7.40, 25.50) (12.70, 45.90) Heterogeneity for gender is tested by meta-regression: p-value <0.001 The estimates refer to the median values of each interval of exposure and the references category correspond to 0 cigarette per day. The Pooled RRs are adjusted for study design and when possible take into account the fact that the estimates for separate smoking exposure levels depends on the same reference group. Publication bias We have indication of publication bias for oral cancer, kidney cancer and hepatocellular carcinoma (p-values from weighted Egger s test for funnel plot are 0.04, 0.03 and <0.01, respectively). With the sensitivity analysis proposed by Copas and Shi, 22 adding 20 possible unpublished papers for oral cancer the p-value becomes 0.1 and the pooled RR for current smoking does not change considerably: RR ; 95% CI: Adding 14 papers for kidney cancer the p-value for the funnel plot is not any more significant and we have an adjusted RR for current smoking still statistically significant: 2.59 (95% CI: ). If we add 5 papers for hepatocellular carcinoma the p-values is not any more significant and Copas and Shi methods suggests an adjusted estimate still statistically significant: 1.50 (95% CI: ). Discussion While smoking is an established risk factor for many forms of cancer, the magnitude of the risk varies between studies and to date an overall picture with summary risk estimates of all established cancer sites is not available. Therefore, we conducted a systematic meta-analysis, based on information reported in a recent IARC Monograph on Tobacco Smoke and Involuntary Smoking, which represents an up-to-date, authoritative, and comprehensive reference source. We used wide inclusion criteria in order to investigate possible sources of variations and inconsistencies, heterogeneity analysis being one of the primary issues to take into consideration. Overall, we found an important heterogeneity of the single studies estimates for all cancer sites. The heterogeneity was greater for the current-smoking estimates than for the former-smoking estimates, probably because the time from exposure mitigates and smoothes out the estimates. One of the points not addressed in the IARC Monograph regards the differential susceptibility for smoking related cancers in various ethnic groups. Some evidence 23,24 suggests the African-Americans are more susceptible to the effects of tobacco smoke compared to Caucasians and Caucasians are more susceptible than Asians. This pattern was verified in our analysis for many cancer sites. The pooled RR for current smokers for lung cancer is the highest among all cancer sites. However, caution should be taken with the very high-risk estimates reported in some case-control studies (Table II). In fact we found a significant heterogeneity of the pooled estimates according to study type, with greater RRs in case-control studies than in cohort studies (p < 0.001). We also found a significantly heterogeneity considering the type of adjustment performed in the original studies, with greater pooled estimates based on adjusted RRs (p ). We found a slightly higher pooled estimate for current smoking in males than in females, along with marked heterogeneity of the dose-response estimates between men and women. On the other hand, we observed significantly higher risk estimates associated with increased cig/day consumption in women. However, there is currently inconsistent and inadequate epidemiological evidence to support that women are more susceptible than men to develop tobacco-related lung cancer. 25 An influence of the study design is unlikely since the proportion of estimates deriving from cohort studies was similar in men (29%) and in women (32%) and since pooled estimates were adjusted for study type. The association between gender, smoking and lung cancer has been previously investigated in a meta-analysis 26 of 15 case-control studies from China and in a pooled analysis 27 of 10 case-control studies from Europe. Again, in both reports the estimates for current smoking were greater for men than for women, like in our meta-analysis, but in contrast with our results Simonato et al. 27 found greater dose-response estimates using pack-years for men than for women. Previous results from the Nurses Health Study and the Health Professionals Follow-up Study of men did not support a different susceptibility, given equal smoking exposure. 28 Similar results were obtained in a large European case-control study where the authors evaluated variation of risk estimates by histological types and time since quitting. 29 In contrast, a recent North American prospective study suggested that women appear to have increased susceptibility to tobacco carcinogens but a lower rate of fatal outcome of lung cancer compared to men: the prevalence odds ratio comparing women with men was 1.9 (95% CI; ) but the hazard ratio of fatal outcome of lung cancer comparing women with men was HR (95% CI; ). 25 For upper digestive tract cancer, we found heterogeneity of the pooled estimates based on studies with or without adjustment for alcohol consumption. The pooled estimate was significantly higher when considering only studies reporting alcohol adjusted risk estimates. This could be the result of the strong multiplicative effect between tobacco and alcohol in the etiology of these cancers. It has been estimated that tobacco smoking and alcohol drinking account for about 3 quarters of all oral and pharyngeal cancers. 30 Estimates for cancer of the esophagus, were homogeneous across gender and countries, and did not vary across study type or type of adjustment. However, estimates for gastric cancer varied significantly across gender. As salted, smoked, pickled, and preserved foods (rich in salt, nitrite, and preformed N-nitroso compounds) have been associated with an increased risk of gastric cancer, we studied variation of the estimates according to adjustment for diet. We found significantly (p ) greater pooled estimates for current smoking in studies that published diet adjusted estimates. Although, Helicobacter pylori represent major etiological factor for gastric cancer, only 1 study included in the meta-analysis adjusted for H. pylori. 31 In that study the RR was higher in H. pylori/infected men and this result suggests that smoking may increase the carcinogenic effect of H. pylori. So far, only 1 single pooled analysis of 2 prospective studies in Japan 32 have provided summary estimates of the risk of gastric cancer in association with smoking. The authors found marginally higher effect for current smoking (RR , 95% CI: ) and former smoking (RR , 95% CI: ) compared to the results found in our study. Estimates for cancer of the liver, were homogeneous across gender and countries, and did not vary across study type or type of adjustment, this after exclusion of 3 studies based on series of patients with preexisting medical conditions. In fact, the presence of liver cirrhosis, whether related to alcohol abuse, or infection with hepatitis B or C virus, could have hampered the evaluation of the association with smoking. Smoking is the major etiological factor that has been linked to pancreas cancer. In our analysis, the risk was slightly higher in westernized countries, probably reflecting a differential smoking pattern in these countries. Despite an overwhelming role of the human papillomavirus (HPV) infection in the etiology of cervical cancer, cigarette smoking has been identified as an additional risk factor or risk modifier. Until recently, scientists were unable to decide whether the relationship was causal or due to confounding factors such as the

10 164 GANDINI ET AL. number of sexual partners. In our study, the pooled-estimates for current smoking was statistically significant with no evident sign of heterogeneity according to the various factors studied and comparable to the summary risk estimate of a pooled analysis of 10 case-control studies conducted in HPV-positive women (RR , 95% CI: for current and RR , 95% CI: for former). 33 Estimates for urinary tract cancer (kidney and bladder) were homogeneous across gender and countries. As expected, the pooled risk for current smokers among men was greater for cancer of the bladder (RR ; 95% CI ) than for cancer of the kidney (RR ; 95% CI ). For kidney cancer, estimates based on studies adjusted for body mass index, a major contributing cause of this type of cancer, were marginally greater than estimates based on unadjusted results. For bladder cancer, our pooled estimate is slightly lower than that of a recent pooled-analysis 34 of 14 case-controls studies (RR for current smokers , 95% CI: for men and RR , 95% CI: for women), but similar to that of a previous meta-analysis of 23 case-control and cohort studies (RR ; 95% CI: , for men and women combined). 35 This comprehensive meta-analysis quantifies much of the existing evidence linking smoking with well-known anatomic cancer sites such as the respiratory tract, upper digestive tract, urinary tract, and reviews likely sources of heterogeneity which could explain different risk estimates obtained in different reports. It provides a single source for reliable estimates of tobacco-related carcinogenesis that could serve as monitoring the cancer burden with the calculation of attributable fractions. In addition, the review suggests additional organs, such as the colon, where the link between smoking and cancer needs additional study. 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