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Tobacco smoking and cancer: A meta-analysis

Sara Gandini1*, Edoardo Botteri

1, Simona Iodice

1, Mathieu Boniol

2, Albert B. Lowenfels

3,4,

Patrick Maisonneuve1 and Peter Boyle2

1Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy2International Agency for Research on Cancer, Lyon, France3Department of Surgery, New York Medical College, Valhalla, NY4Department of Community and Preventive Medicine, New York Medical College, Valhalla, NY

We conducted a systematic meta-analysis of observational studieson cigarette smoking and cancer from 1961 to 2003. The aim wasto quantify the risk for 13 cancer sites, recognized to be related totobacco smoking by the International Agency for Research onCancer (IARC), and to analyze the risk variation for each site in asystematic manner. We extracted data from 254 reports publishedbetween 1961 and 2003 (177 case-control studies, 75 cohorts and 2nested case-control studies) included in the 2004 IARC Mono-graph on Tobacco Smoke and Involuntary Smoking. The analyseswere carried out on 216 studies with reported estimates for ‘cur-rent� and/or ‘former� smokers. We performed sensitivity analysis,and looked for publication and other types of bias. Lung (RR 58.96; 95% CI: 6.73–12.11), laryngeal (RR 5 6.98; 95% CI: 3.14–15.52) and pharyngeal (RR 5 6.76; 95% CI: 2.86–15.98) cancerspresented the highest relative risks (RRs) for current smokers, fol-lowed by upper digestive tract (RR 5 3.57; 95% CI: 2.63–4.84)and oral (RR 5 3.43; 95% CI: 2.37–4.94) cancers. As expected,pooled RRs for respiratory cancers were greater than the pooledestimates for other sites. The analysis of heterogeneity showedthat study type, gender and adjustment for confounding factorssignificantly influence the RRs estimates and the reliability of thestudies.' 2007 Wiley-Liss, Inc.

Key words: tobacco; cancer; meta-analysis

Epidemiological evidence of the association between cigarettesmoking and cancer began to emerge in the 1920’s, and by the1950’s the causal relationship with lung cancer was established.1–4

Since then, evidence of the association between tobacco smokingand cancer of other parts of the respiratory system and of the di-gestive tract began to accumulate. In 1985, under the auspice ofthe International Agency for Research on Cancer (IARC) an inter-national Working Group of experts recognized a causal relation-ship between tobacco smoking and cancer of the lung, oral cavity,pharynx, larynx, pancreas, urinary bladder, renal pelvis and ure-thra.5 The association was primarily based on worldwide epidemi-ological studies. Seventeen years later, in a revised Monograph onTobacco Smoke and Involuntary Smoking,6 the IARC added can-cers of the nasal cavities and nasal sinuses, the esophagus, stom-ach, liver, kidney (renal-cell carcinoma), uterine cervix and bonemarrow (myeloid leukemia) to the long list of smoking-relatedcancers.

While the IARC Monograph provides summary statements onthe association between cigarette smoking and cancer, it does notprovide summary measures of the magnitude of the associations.The aim of this study was to provide a statistical evaluation usinga meta-analytic approach of the strength of the associationbetween tobacco smoking and these established smoking-relatedcancers based on the exhaustive set of studies reported in this re-vised IARC Monograph. In addition, meta-analytic techniqueswere used to assess whether specific associations depend uponstudy characteristics such as the population under observation, thelevel of exposure, the definition of disease used, or other factors.This work provides, in a single document, summary measures ofthe risk of cancer because of smoking and reasons for variationsamong studies.

Material and methods

Data extraction

The following information were extracted and coded from thetables of the Monograph: year of publication, type of study, coun-try of the study, features of populations, definition of the exposureand of the cancer sites, adjustments used in the analysis. For lungcancer, when dose-response estimates were provided in the Mono-graph, we retrieved the study-specific dose response relative riskestimates, and crude data for each level of exposure, directly fromthe original articles.

We used wide inclusion criteria in order to select and retain alarge group of homogeneous studies

1. Study reports should contain the minimum informationnecessary to estimate relative risks and corresponding 95%confidence intervals (i.e. Odds Ratios or Relative Risks anda measure of uncertainty: standard errors, variance, confi-dence intervals or exact p-value of the significance of theestimates) for the tobacco smoking.

2. The studies should be independent in order to avoid givingdouble weight to single studies. In case of multiple reports ofthe same study, we considered only the estimates from themost recent publication.

3. Homogeneous categorizations were chosen for the exposureto tobacco smoking. Relative risks for ‘‘ever’’ smokers werenot considered. When the authors published an estimate for‘‘daily’’ smoking, instead of ‘‘current’’ smoking, the studywas included but this decision was investigated in a sensitiv-ity analysis.

4. The populations studied should be homogeneous, and not beaffected by a particular disease, which could affect smokingrelated cancer risk.

When results from case-control studies were presented sepa-rately for hospital and for population-based controls, we onlyincluded results obtained from population-based controls.

Definition of the outcome and exposures

Only cancer sites with sufficient evidence of carcinogenicityrelated to tobacco exposure in humans were considered in thismeta-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 reportedin the Monograph, we presented the results separately for cancersof the lower urinary tract (renal pelvis, bladder and ureter), and forcancer of the upper urinary tract. Cancer of the nasal cavity and

Grant sponsor: C.D. Smithers Foundation, Italian Association for CancerResearch (AIRC).*Correspondence to: Division of Epidemiology and Biostatistics, Euro-

pean Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.Fax:139-02-57489813. E-mail: [email protected] 21 March 2007; Accepted after revision 21 June 2007DOI 10.1002/ijc.23033Published online 24September 2007 inWiley InterScience (www.interscience.

wiley.com).

Int. J. Cancer: 122, 155–164 (2008)' 2007 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

nasal-sinuses were grouped together with naso-pharyngeal cancerand classified as nasal-sinus-nasopharynx because there were fewstudies for each of these single anatomically close sites. Heteroge-neity analysis was carried out to verify if there was a significantdifference by sub-sites.

In this study, we investigated only the effect of tobacco smok-ing and retained risks estimates for ‘‘former’’ and ‘‘current’’ smok-ers because they were the most widely reported categories in theliterature, although the definition of these 2 groups could varywithin studies. Many studies do not specify a minimum durationof abstinence for individuals classified as former smokers; whenspecified, the period of abstinence was at least 1 year since quit-ting smoking. For many studies only estimates for dose categories(cigarettes per day, pack-years and duration) were available andfor those studies we could not obtain an estimate for current smok-ers. Because of the high number of studies on lung cancer present-ing only dose-response estimates for current smokers, we calcu-lated the pooled relative risks (RRs) for lung cancer associatedwith an increased consumption of 1 cigarette per day. Duration ofsmoking is the strongest determinant of cancer in smokers butreported data were not homogeneous enough to carry out a meta-analysis on duration.

Data analysis strategy

We used random effects models, with restricted maximum like-lihood estimate, to evaluate summary relative risks. Homogeneityof effects across studies was assessed using the v2 statistic andquantified by I2, which represents the percentage of total variationacross studies that is attributable to heterogeneity rather thanchance.7 p-values, indicating significance of factors investigated,were obtained with analysis of variance using Proc MIXED inSAS.8 Subgroup analyses and meta-regressions were carried out toinvestigate between-study heterogeneity focusing on study type,adjustments used in the analysis, exposure definition, publicationyear, country, ethnicity and gender. We classified countries as‘‘westernized’’ (North America, Europe; Australasia and Japan)and ‘‘not westernized’’ (Africa, Iceland, China, India and SouthAmerica) and we also identified 3 ethnic groups: Africans, Cauca-sians (European countries) and Asians (Japan, China, Korea Phil-ippines and India). Heterogeneity analysis was conducted only forcancer sites with �15 estimates available to avoid very small sub-groups and unreliable results. Since the v2 test has limited power,we considered statistically significant heterogeneity at the p 50.10 level of association. Sensitivity analysis was carried out inorder to evaluate whether results were influenced by a singlestudy.

We ignored the distinction among various measures of relativerisk (i.e. odds ratio, rate ratio, risk ratio) on the assumption thattobacco related cancers are sufficiently rare. Every measure ofassociation, adjusted for the maximum number of confoundingvariables, and the corresponding confidence interval, was trans-lated into log relative risk and corresponding variance with theformula proposed by Greenland.9 When several measures of RRwere given for a single study, we used random effects models,even in absence of heterogeneity, including the 2 sources of varia-tion (within and between studies), to take into account correlationwithin study.10

Current and former smokings are the exposure categories ofmain interest of our meta-analysis. Dose-response RRs were ana-lyzed only for lung cancer, the most associated cancer site.

For some cancer sites, the number of studies providing risk esti-mates for current and former smoking differed as risk estimatesfor current smokers were reported only by level of cigarette con-sumption. Therefore, the comparison of the pooled estimates forcurrent and for former-smoking was based on different sets ofstudies. This situation was particularly prominent for pancreaticcancer and for esophageal cancer, for which we had a high per-centage of excluded studies (44% for pancreas and 27% peresophagus). For these 2 cancer sites, we had a sufficient (�15)

number of estimates to be able to compare the pooled estimatesfor former-smokers based on studies for which estimates for cur-rent-smokers were reported and based on studies for which onlydose response-estimates were reported. For these cancer sites, wealso carried out a subgroup analysis on current smoking estimatesbased on the subset of studies that presented both current and for-mer smoking estimates. Lung cancer was the cancer site with thehighest percentages of studies excluded and for this reason wehave carried out a dose-response analysis.

In the main analysis, we did not include colorectal cancerbecause smoking was not considered as an established risk factorfor colorectal cancer in 2004. However, a quite recent meta-analy-sis on all risk factors for colorectal cancer in China, based on 5published studies, reported a significant risk for cigarette smokingin China (RR 5 1.40, 95% CI: 1.10–1.77).11 Thus in the sensitiv-ity analysis we decided to evaluate the estimates for colorectalcancer.

Evaluation of dose response

We used a linear model, within each study, to estimate the rela-tive risk associated with an increase of 1 cigarette per day. Themodel was fitted according to the method proposed by Greenlandand Longnecker,12 which requires the estimates and the number ofsubjects at each level of cigarettes consumption. This dose-response model takes into account the fact that the estimates forseparate levels depend on the same reference group. When numberof subjects at each level was not available from the papers, coeffi-cients were calculated ignoring the correlation between the esti-mates of risk in the separate exposure levels. Doses expressed inquantity of tobacco per unit of time (grams per day or kilogramsper month) were converted into number of cigarettes smoked perday. Estimates for pack-year were not included in the analysisbecause they were not comparable with estimates expressed forcigarettes per day.

We assigned to each class the number of cigarettes smoked cor-responding to the midpoint of the range. For the highest categoriesa fix value of 60 cigarettes per day was set as the maximum. Thesummary RR were obtained pooling the study-specific estimatesby the classical random effects models, adjusting for study designand for the possibility to take into account the correlation betweenthe estimates of risk in the separate exposure levels.

Results

Data from 254 papers published between 1961 and 2003 (177case-control studies, 75 cohort and 2 nested case-control studies)were extracted from the IARC Monograph and considered for theanalysis. Studies were conducted in many countries (8 fromAfrica, 4 from Australia or New Zealand, 39 from China, 28 fromJapan, 8 from India, 13 from South America, 80 from USA orCanada and 74 from Europe). Two hundred and sixteen studiesreported separate estimates for ‘current� or ‘former� smokers. Fig-ures 1–4 present the forest plots for current smokers by cancersites.

In order to respect the inclusion criteria, we eliminated 3 studiesfrom the liver cancer analysis because they were based on seriesof patients with pre-existing medical conditions (mainly cirrhosis),not representative of the general population.13–15

Pooled RRs indicated a significant association between tobaccosmoking and various cancer types (Table I). For most sites, thepooled estimates for current smoking were greater that the onesfor former smoking. Overall, the pooled risk estimates for currentsmoking presented a high degree of between-study heterogeneity,while risk estimates for former smoking presented generally alower degree of heterogeneity.

Table II presents the pooled RRs for current smokers stratifiedfor selected heterogeneity factors. Results for former smokers,which were similar, were not reported.

156 GANDINI ET AL.

FIGURE 1 – Forest plots for current smokers by cancer sites: C10-15; C10; C11, C30-31; C14. When available, fully adjusted RRs wereretrieved. M: male, F: female; Upper digestive tract a: white, b: black; Oral Cavity a: tongue; Nasal-sinuses Nasopharynx a: nasal cavity andsinuses, b: adenocarcinoma of nasal cavity and accessory sinuses, c: squamous-cell carcinoma of nasal cavity, and accessory sinuses, d: nasopha-ryngeal cancer.

157TOBACCO SMOKING AND CANCER: A META-ANALYSIS

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: gastriccardia, 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.

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 35–39 years, e: aged 40–44 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.


The highest pooled RR for current smokers was observed forlung cancer (RR 5 8.96; 95% CI: 6.73–12.11), which was signifi-cantly greater in case-control studies (RR 5 14.02; 95% CI: 9.64–20.40) than in cohort studies (RR 5 6.29; 95% CI: 4.49–8.82) (p< 0.001). For lung cancer, dose-response estimates were availablein 44 studies: 19 with estimates only for men, 11 with estimatesonly for women and 14 with separate estimates for men and forwomen. Overall, the risk of lung cancer increases by 7% for eachadditional cigarette smoked per day (RR 5 1.07, 95% CI: 1.06–1.08). This increased risk appears to be slightly higher in women(RR 5 1.08; 95% CI: 1.07–1.10) than in men (RR 5 1.07, 95%CI: 1.05–1.08) (p-value < 0.001; adjusting for study type). Sepa-rate pooled risk estimates for men and for women for 3 broadsmoking categories (1–9 cigarettes per day, 10–19 cig/day and>20 cig/day) are given in Table III.

Following lung cancer, the highest RRs for current smoking wereobserved for cancer of the larynx (RR5 6.98; 95% CI: 3.14–15.52),pharynx (RR 5 6.76; 95% CI: 2.86–15.98), combined upper diges-tive tract (RR5 3.57; 95%CI: 2.63–4.84) and more specifically can-cer of the oral cavity (RR 5 3.43; 95% CI: 2.37–4.94). For all thesecancer sites, the pooled RRs for former smokers were much lowerthan those observed for current-smokers (Table I).

For stomach cancer, the pooled RRs for current smokers (RR 51.64; 95% CI: 1.37–1.95) and former smokers (RR5 1.31; 95% CI:1.17–1.46) support a significant association. Three studies with pecu-liar characteristics were eliminated in a sensitivity analysis (2 studiesin which the control group included patients with other diseases16,17

and a large retrospective mortality study18 which had a huge weightin the pooled analysis and with scarce information available). Afterexclusion of these 3 studies, the pooled RR for current smokersremained unchanged (RR5 1.68; 95%CI: 1.43–1.98).

For pancreas cancer, we observed a significant association bothfor current smokers (pooled RR 5 1.70; 95% CI: 1.51–1.91) andfor former smokers (RR5 1.18; 95% CI: 1.04–1.33). In a sensitiv-ity analysis, we excluded a Japanese cohort study19 because theauthors presented an estimate only for ‘‘daily smokers.’’ Afterexcluding this study, there was no change in the pooled RR forcurrent smokers: (RR 5 1.72; 95% CI: 1.50–1.98). A peculiar sig-nificant protective effect of cigarette smoking (RR 5 0.3; 95% CI:0.1–0.9) on pancreatic cancer mortality in men was reported in aChinese cohort,20 based on 15 deaths (the weight of the study washowever very small, w 5 3.18). After exclusion of this study, thepooled RR remained identical (RR 5 1.71; 95% CI: 1.59–1.84)and the heterogeneity disappeared (p5 0.22).

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.

160 GANDINI ET AL.

The pooled risk estimates for the other cancer sites considered,excluding myeloid leukemia (RR 5 1.09; 95% CI: 0.70–1.70 forcurrent smokers, and RR 5 1.27; 95% CI: 0.28–5.83 for formersmokers), demonstrated significant association for both currentand former smokers (Table I). The pooled risk estimates for cur-rent smokers were, respectively, RR 5 1.95 (95% CI: 1.31–2.91)for cancer of the nasal cavity, RR 5 2.77 (95% CI: 2.17–3.54) forlower urinary tract cancer, RR 5 1.52 (95% CI: 1.33–1.74) forkidney cancer, RR 5 1.83 (95% CI: 1.51–2.21) for cancer of thecervix uteri and RR 5 1.56 (95% CI: 1.29–1.87) for liver cancer.Similarly, the pooled risk estimates for former smokers wereRR 5 1.39 (95% CI: 1.08–1.79) for cancer of the nasal cavity, RR5 1.72 (95% CI: 1.46–2.04) for lower urinary tract cancer, RR 51.25 (95% CI: 1.14–1.37) for kidney cancer, RR 5 1.26 (95% CI:1.11–1.42) for cancer of the cervix uteri and RR 5 1.49 (95% CI:1.06–2.10) for liver cancer.

Heterogeneity analysis

In Table II, we can see that gender explained some heterogene-ity (p < 0.001) of the risk estimates for stomach cancer, withgreater estimates for men (RR 5 1.74; 95% CI: 1.46–2.07) thanfor women (RR 5 1.45; 95% CI: 1.20–1.75). Country was a bor-derline significant factor (p 5 0.06) for variability of the estimatesfor pancreatic cancer: (RR 5 1.86; 95% CI: 1.58–2.19 for wester-nized countries and RR 5 1.44, 95% CI: 1.16–1.79 for not wester-nized countries). When possible, we evaluated the differences incancer risk among 3 ethnic groups: African-Americans, Cauca-sians and Asians. We found a borderline-significant heterogeneitybetween ethnic groups for esophagus cancer (p 5 0.06) withhigher risk in African-Americans (RR5 3.49; 95% CI: 1.49–8.20)and Caucasians (RR 5 3.35; 95% CI: 1.89–5.92) than Asians (RR5 1.62; 95% CI: 1.14–2.31). A similar risk pattern was observedfor lung cancer although heterogeneity between groups did notreached statistical significance (p5 0.30) (Table II).

Study design was important for lung cancer (p < 0.001) withgreater pooled estimate obtained for case-control (RR 5 14.02,95% CI: 9.64–20.40) than for cohort studies (RR 5 6.29; 95%

CI: 4.49–8.82). Adjustment for confounders was significant (p 50.04) for upper digestive tract cancer with greater pooled RR forstudies reporting estimates adjusted for alcohol (RR 5 4.03, 95%CI: 3.11–5.23) than for those unadjusted (RR 5 2.03, 95% CI:1.13–3.65); for stomach (p 5 0.02) with greater pooled RR forstudies reporting estimates adjusted for diet (RR 5 2.22, 95%CI: 1.65–2.99) than for those unadjusted (RR 5 1.45, 95% CI:1.21–1.74) and for lung cancer (p 5 0.04) with greater pooledRR for studies reporting estimates with any adjustment (RR 511.06, 95% CI: 7.87–15.53) than for those unadjusted (RR 55.95, 95% CI: 3.65–9.70). For cervical cancer the adjustment forHPV did not result significant in the heterogeneity analysis, how-ever it is important to notice that only a few studies adjusted forHPV, which is an established and essential risk factor for cervi-cal cancer.

For esophageal and pancreatic cancers, we compared the pooledestimates for former-smoking, based on studies for which esti-mates for current-smokers were reported and based on studies forwhich only dose response-estimates were reported, and found nosign of heterogeneity (p-value 5 0.28 and p 5 0.84 respectively).We also calculated the pooled estimates for current smoking in thesubset of studies that presented both, current and former smokingestimates: the summary RR estimate for esophageal cancer, basedon 16 studies, slightly increased (3.13; 95%CI: 2.63, 3.68) withhighly significant heterogeneity between studies (p < 0.001 and I2

5 66%). For pancreas cancer, the summary RR estimate, based on12 studies, did not changed (1.77; 95%CI: 1.54, 2.04) and the het-erogeneity between studies decreased (p5 0.22 and I2 5 20%).

We also studied separately cancers of the nasal-sinuses and ofthe naso-pharynx which share different etiological factors: thepooled RR for nasal-sinus cavity among current smokers waslower (1.49; 95%CI: 0.59, 3.96; evaluated on 3 studies and I2 5 0)than for nasopharynx (2.23; 95%CI: 1.13, 4.42; evaluated on 7studies and I2 5 77%) even if the difference was not statisticallysignificant p 5 0.36.

For colorectal cancer, we retrieved 38 studies that reported datafor current smokers and 31 studies for former smokers. The pooled

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 I2 %

Upper Digestive Tract C10-15 Current 3.57 (2.63, 4.84) 11 0.010 53Former 1.18 (0.73, 1.91) 14 <0.001 84

Oral cavity C10 Current 3.43 (2.37, 4.94) 12 0.001 65Former 1.40 (0.99, 2.00) 9 0.098 40

Pharynx C14 Current 6.76 (2.86, 16.0) 7 <0.001 85Former 2.28 (0.95, 5.50) 3 0.034 71

Esophagus C15 Current 2.50 (2.00, 3.13) 22 <0.001 81Former 2.03 (1.77, 2.33) 21 0.175 20

Stomach C16 Current 1.64 (1.37, 1.95) 32 <0.001 75Former 1.31 (1.17, 1.46) 33 <0.001 51

Liver C22 Current 1.56 (1.29, 1.87) 24 <0.001 69Former 1.49 (1.06, 2.10) 12 0.009 53

Pancreas C25 Current 1.70 (1.51, 1.91) 18 0.038 37Former 1.18 (1.04, 1.33) 22 0.172 24

Nasal-sinuses, C11Nasopharynx, C30-31

Current 1.95 (1.31, 2.91) 10 <0.001 68Former 1.39 (1.08, 1.79) 6 0.830 0

Larynx C32 Current 6.98 (3.14, 15.5) 10 <0.001 89Former 4.65 (3.35, 6.45) 3 0.550 0

Lung C34 Current 8.96 (6.73, 12.1) 21 <0.001 75Former 3.85 (2.77, 5.34) 20 <0.001 51

Cervix C53 Current 1.83 (1.51, 2.21) 23 <0.001 77Former 1.26 (1.11, 1.42) 22 0.645 0

Kidney C64 Current 1.52 (1.33, 1.74) 14 0.031 39Former 1.25 (1.14, 1.37) 12 0.001 59

Lower Urinary Tract C65-67 Current 2.77 (2.17, 3.54) 21 <0.001 76Former 1.72 (1.46, 2.04) 15 <0.001 63

Myeloid Leukemia C92 Current 1.09 (0.70, 1.70) 4 0.183 36Former 1.27 (0.28, 5.83) 3 0.030 66

*References category ‘‘Never smokers’’; I2 represents the percentage of total variation across studies that is attributable to heterogeneity ratherthan to chance.


RRs associated with current and former smoking were, respec-tively: 1.08 (95% CI: 0.99–1.18) and 1.16 (95% CI: 1.08–1.24).The association for current smoking was significantly (p 5 0.02)stronger for cohort studies (RR 5 1.2; 95% CI: 1.1–1.3), than forcase-control studies (RR 5 1.0; 95% CI: 0.9–1.1). As alcohol hasrecently been associated with an increased risk of both colon andrectal cancer and is also strongly correlated with cigarette smok-ing, we performed a separate analysis considering only studiesproviding estimates adjusted for alcohol and found significantpooled RRs (RR 5 1.2; 95% CI: 1.0–1.4).21 A similar analysis re-stricted to studies adjusted for body mass index also showed anelevated risk of colorectal cancer (RR 5 1.2; 95% CI: 1.0–1.4).

We also evaluated the pooled RRs estimates separately for colonand for rectal cancer, but found no significant difference in risk(p 5 0.14) between colon (RR 5 1.05; 95%CI: 0.94, 1.16) basedon 25 studies (I2 5 71) and rectum cancer (RR 5 1.11; 95% CI:0.99, 1.25) based on 21 studies (I2 5 74).

Thus, the list of cancer sites for which smoking is an establishedrisk factor may be incomplete, suggesting a need for furtherresearch. However, looking at the ratios between ORs for currentand former smokers, we can observe greater estimates for formerthan current smokers only for colon-rectum and myeloid leuke-mia. This could suggest that these estimates should be consideredwith caution.

TABLE II – POOLED RRs BY TYPE OF FACTORS THAT COULD INDUCE HETEROGENEITY

Cancer site (ICD 10)

Up. Digest. Tract C10-15 Esophagus C15 Stomach C16Factor Strata

RR (95% CI) p # RR (95% CI) p # RR (95% CI) P #

Sex Men 3.52 (1.94, 6.37) 0.66 7 2.52 (1.81, 3.52) 0.52 7 1.74 (1.46, 2.07) <.001 8Women 3.80 (1.97, 7.33) 5 2.28 (1.51, 3.44) 14 1.45 (1.20, 1.75) 19

Alcohol Adj. 4.03 (3.11, 5.23) 0.04 9 3.00 (2.18, 4.12) 0.11 11Not adj. 2.03 (1.13, 3.65) 2 2.10 (1.52, 2.88) 11

Study type CC 4.14 (3.07, 5.57) 0.06 7 2.55 (1.94, 3.36) 0.72 17 1.59 (1.29, 1.95) 0.68 22Cohort 2.36 (1.42, 3.93) 4 2.30 (1.34, 3.95) 5 1.71 (1.24, 2.35) 10

Ethnicgroup

African-Americans

– 0.46 – 3.49 (1.49, 8.20) 0.06 1 – 0.19 –

Asians 2.33 (0.17, 31.6) 2 1.62 (1.14, 2.31) 6 1.86 (1.20, 2.89) 8Caucasians 4.42 (0.97, 20.1) 5 3.35 (1.89, 5.92) 5 1.29 (0.85, 1.96) 12

Country West. 3.05 (2.23, 4.17) 0.08 11 1.55 (1.27, 1.89) 0.36 24Not West. 2.08 (1.52, 2.83) 11 1.85 (1.31, 2.61) 8

Diet Adj. 2.22 (1.65, 2.99) 0.02 8Not Adj. 1.45 (1.21, 1.74) 24

Liver C22 Pancreas C25 Lung C34

Sex Men 1.85 (1.21, 2.83) 0.28 10 1.63 (1.32, 2.03) 0.63 6 9.87 (6.85, 14.24) 0.36 14Women 1.49 (1.12, 1.98) 16 1.73 (1.31, 2.30) 8 7.58 (5.36, 10.73) 10

Alcohol Adj. 1.53 (1.06, 2.20) 0.94 10Not Adj. 1.55 (1.17, 2.05) 14

Study type CC 1.54 (1.16, 2.05) 1.00 11 1.63 (1.33, 1.98) 0.45 11 14.02 (9.64, 20.4) <.001 10Cohort 1.54 (1.10, 2.17) 13 1.79 (1.44, 2.22) 7 6.29 (4.49, 8.82) 11

Ethnicgroup

African-Americans

1.91 (0.78, 4.69) 0.30 2 – 0.84 – 10.2 (3.03, 34.49) 0.30 2

Asians 1.54 (1.17, 2.02) 14 1.47 (1.21, 1.79) 8 5.52 (2.83, 10.78) 5Caucasians 0.93 (0.45, 1.93) 3 1.42 (0.99, 2.04) 2 9.94 (5.92, 16.67) 9

Country West. 1.48 (0.98, 2.25) 0.80 7 1.86 (1.58, 2.19) 0.06 11 10.10 (6.50, 14.6) 0.13 13Not West. 1.57 (1.21, 2.03) 17 1.44 (1.16, 1.79) 7 6.30 (3.76, 10.58) 7

HBV/HCV Adj. 1.25 (0.90, 1.75) 0.11 9Not Adj. 1.75 (1.34, 2.29) 15

Any adj. Any 1.82 (1.56, 2.13) 0.08 12 11.06 (7.87, 15.5) 0.04 14None 1.39 (1.06, 1.82) 6 5.95 (3.65, 9.70) 7

Cervix C53 Kidney C64 Low. Ur. Tract C65-67

Sex Men 1.59 ( 1.32, 1.91) 0.19 12 2.80 (2.01, 3.92) 0.87 9Women 1.35 (1.05, 1.73) 10 2.73 (1.82, 4.10) 14

Study type CC 1.64 (1.02, 2.65) 0.3 14 1.56 (1.30, 1.87) 0.65 9 3.00 (2.26, 3.97) 0.21 15Cohort 2.24 (1.14, 4.39) 9 1.47 (1.19, 1.83) 5 2.05 (1.19, 3.55) 5

Ethnicgroup

African-Americans

3.54 (0.01, 926) N.A. 2 2.34 (0.35, 15.89) 0.54 2

Caucasians 1.56 (1.08, 2.24) 8 3.39 (1.23, 9.33) 7Country West. 1.87 (0.51, 6.94) 0.62 18 1.61 (0.79, 3.26) 0.10 3

Not West. 1.62 (0.15, 17.1) 6 2.96 (2.30, 3.82) 16No. partners Adj. 1.77 (1.10, 2.86) 0.66 16

Not Adj. 1.97 (0.93, 4.18) 7HPV Adj. 1.48 (0.56, 3.89) 0.42 4

Not Adj. 1.90 (1.22, 2.94) 19BMI Adj. 1.69 (1.42, 2.00) 0.08 5

Not Adj. 1.34 (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 fullyadjusted for all the other confounders considered by the authors). HPV: human papillomavirus (HPV) infection adjustment. HBV/ HCV: esti-mates 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.

162 GANDINI ET AL.

Publication bias

We have indication of publication bias for oral cancer, kidneycancer and hepatocellular carcinoma (p-values from weightedEgger’s test for funnel plot are 0.04, 0.03 and <0.01, respec-tively). With the sensitivity analysis proposed by Copas and Shi,22

adding 20 possible unpublished papers for oral cancer the p-valuebecomes 0.1 and the pooled RR for current smoking does notchange considerably: RR 5 2.28; 95% CI: 1.55–3.36. Adding 14papers for kidney cancer the p-value for the funnel plot is not anymore significant and we have an adjusted RR for current smokingstill statistically significant: 2.59 (95% CI: 1.93–3.47). If we add 5papers for hepatocellular carcinoma the p-values is not any moresignificant and Copas and Shi methods suggests an adjusted esti-mate still statistically significant: 1.50 (95% CI: 1.21–1.73).

Discussion

While smoking is an established risk factor for many forms ofcancer, the magnitude of the risk varies between studies and todate an overall picture with summary risk estimates of all estab-lished cancer sites is not available. Therefore, we conducted a sys-tematic meta-analysis, based on information reported in a recentIARC Monograph on ‘‘Tobacco Smoke and Involuntary Smok-ing,’’ which represents an up-to-date, authoritative, and compre-hensive reference source. We used wide inclusion criteria in orderto investigate possible sources of variations and inconsistencies,heterogeneity analysis being one of the primary issues to take intoconsideration.

Overall, we found an important heterogeneity of the single stud-ies estimates for all cancer sites. The heterogeneity was greater forthe current-smoking estimates than for the former-smoking esti-mates, probably because the time from exposure mitigates andsmoothes out the estimates.

One of the points not addressed in the IARC Monograph regardsthe differential susceptibility for smoking related cancers in variousethnic groups. Some evidence23,24 suggests the African-Americansare more susceptible to the effects of tobacco smoke compared toCaucasians and Caucasians are more susceptible than Asians. Thispattern was verified in our analysis for many cancer sites.

The pooled RR for current smokers for lung cancer is the high-est among all cancer sites. However, caution should be taken withthe very high-risk estimates reported in some case-control studies(Table II). In fact we found a significant heterogeneity of thepooled estimates according to study type, with greater RRs incase-control studies than in cohort studies (p < 0.001). We alsofound a significantly heterogeneity considering the type of adjust-ment performed in the original studies, with greater pooled esti-mates based on adjusted RRs (p 5 0.04). We found a slightlyhigher pooled estimate for current smoking in males than infemales, along with marked heterogeneity of the dose-responseestimates between men and women. On the other hand, weobserved significantly higher risk estimates associated withincreased cig/day consumption in women. However, there is cur-rently inconsistent and inadequate epidemiological evidence to

support that women are more susceptible than men to developtobacco-related lung cancer.25 An influence of the study design isunlikely since the proportion of estimates deriving from cohortstudies was similar in men (29%) and in women (32%) and sincepooled estimates were adjusted for study type. The associationbetween gender, smoking and lung cancer has been previouslyinvestigated in a meta-analysis26 of 15 case-control studies fromChina and in a pooled analysis27 of 10 case-control studies fromEurope. Again, in both reports the estimates for current smokingwere greater for men than for women, like in our meta-analysis,but in contrast with our results Simonato et al.27 found greaterdose-response estimates using pack-years for men than forwomen. Previous results from the Nurses’ Health Study and theHealth Professionals Follow-up Study of men did not support adifferent susceptibility, given equal smoking exposure.28 Similarresults were obtained in a large European case-control studywhere the authors evaluated variation of risk estimates by histo-logical types and time since quitting.29 In contrast, a recent NorthAmerican prospective study suggested that women appear to haveincreased susceptibility to tobacco carcinogens but a lower rate offatal outcome of lung cancer compared to men: the prevalenceodds ratio comparing women with men was 1.9 (95% CI; 1.5–2.5)but the hazard ratio of fatal outcome of lung cancer comparingwomen with men was HR 5 0.48 (95% CI; 0.25–0.89).25

For upper digestive tract cancer, we found heterogeneity of thepooled estimates based on studies with or without adjustment foralcohol consumption. The pooled estimate was significantlyhigher when considering only studies reporting alcohol adjustedrisk estimates. This could be the result of the strong multiplicativeeffect between tobacco and alcohol in the etiology of these can-cers. It has been estimated that tobacco smoking and alcoholdrinking account for about 3 quarters of all oral and pharyngealcancers.30

Estimates for cancer of the esophagus, were homogeneousacross gender and countries, and did not vary across study type ortype of adjustment. However, estimates for gastric cancer variedsignificantly across gender. As salted, smoked, pickled, and pre-served foods (rich in salt, nitrite, and preformed N-nitroso com-pounds) have been associated with an increased risk of gastriccancer, we studied variation of the estimates according to adjust-ment for diet. We found significantly (p 5 0.02) greater pooledestimates for current smoking in studies that published dietadjusted estimates. Although, Helicobacter pylori represent majoretiological factor for gastric cancer, only 1 study included in themeta-analysis adjusted for H. pylori.31 In that study the RR washigher in H. pylori/infected men and this result suggests thatsmoking may increase the carcinogenic effect of H. pylori. So far,only 1 single pooled analysis of 2 prospective studies in Japan32

have provided summary estimates of the risk of gastric cancer inassociation with smoking. The authors found marginally highereffect for current smoking (RR 5 1.84, 95% CI: 1.39–2.43) andformer smoking (RR 5 1.77, 95% CI: 1.29–2.43) compared to theresults found in our study.

Estimates for cancer of the liver, were homogeneous acrossgender and countries, and did not vary across study type or type ofadjustment, this after exclusion of 3 studies13–15 based on series ofpatients with preexisting medical conditions. In fact, the presenceof liver cirrhosis, whether related to alcohol abuse, or infectionwith hepatitis B or C virus, could have hampered the evaluation ofthe association with smoking.

Smoking is the major etiological factor that has been linked topancreas cancer. In our analysis, the risk was slightly higher inwesternized countries, probably reflecting a differential smokingpattern in these countries.

Despite an overwhelming role of the human papillomavirus(HPV) infection in the etiology of cervical cancer, cigarette smok-ing has been identified as an additional risk factor or risk modifier.Until recently, scientists were unable to decide whether the rela-tionship was causal or due to confounding factors such as the

TABLE III – DOSE-RESPONSE RR ESTIMATES FOR LUNG CANCER

Men (33 studies) Women (25 studies)Cigarette consumption

RR (95% CI) RR (95% CI)

1–9 cig/day 1.39 (1.28, 1.50) 1.49 (1.37, 1.61)10–19 cig/day 2.67 (2.11, 3.37) 3.30 (2.59, 4.20)�20 cig/day 13.70 (7.40, 25.50) 24.10 (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 expo-sure and the references category correspond to 0 cigarette per day.

The Pooled RRs are adjusted for study design and when possibletake into account the fact that the estimates for separate smoking expo-sure levels depends on the same reference group.


number of sexual partners. In our study, the pooled-estimates forcurrent smoking was statistically significant with no evident signof heterogeneity according to the various factors studied and com-parable to the summary risk estimate of a pooled analysis of 10case-control studies conducted in HPV-positive women (RR 52.03, 95% CI: 1.31–4.04 for current and RR 5 1.80, 95% CI:0.95–3.44 for former).33

Estimates for urinary tract cancer (kidney and bladder) were ho-mogeneous across gender and countries. As expected, the pooledrisk for current smokers among men was greater for cancer of thebladder (RR 5 2.80; 95% CI 2.01–3.92) than for cancer of thekidney (RR 5 1.59; 95% CI 1.32–1.91). For kidney cancer, esti-mates based on studies adjusted for body mass index, a major con-tributing cause of this type of cancer, were marginally greater thanestimates based on unadjusted results.

For bladder cancer, our pooled estimate is slightly lower thanthat of a recent pooled-analysis34 of 14 case-controls studies (RRfor current smokers 5 3.89, 95% CI: 3.53–4.29 for men and RR

5 3.55, 95% CI: 3.06–4.10 for women), but similar to that of aprevious meta-analysis of 23 case-control and cohort studies (RR5 2.57; 95% CI: 2.20–3.00, for men and women combined).35

This comprehensive meta-analysis quantifies much of the exist-ing evidence linking smoking with well-known anatomic cancersites such as the respiratory tract, upper digestive tract, urinarytract, and reviews likely sources of heterogeneity which couldexplain different risk estimates obtained in different reports. Itprovides a single source for reliable estimates of tobacco-relatedcarcinogenesis that could serve as monitoring the cancer burdenwith the calculation of attributable fractions. In addition, thereview suggests additional organs, such as the colon, where thelink between smoking and cancer needs additional study.

Acknowledgements

We thank Dr. Giorgia Rosanna Bollani and Dr. William Russel-Edu for their assistance in preparing this manuscript.

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