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Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer
Smoking is a known lung cancer cause, but no detailed quantitative systematic review exists. We summarize evidence for various indices.
Papers published before 2000 describing epidemiological studies involving 100+ lung cancer cases were obtained from Medline and other sources. Studies were classified as principal, or subsidiary where cases overlapped with principal studies. Data were extracted on design, exposures, histological types and confounder adjustment. RRs/ORs and 95% CIs were extracted for ever, current and ex smoking of cigarettes, pipes and cigars and indices of cigarette type and dose–response. Meta-analyses and meta-regressions investigated how relationships varied by study and RR characteristics, mainly for outcomes exactly or closely equivalent to all lung cancer, squamous cell carcinoma ("squamous") and adenocarcinoma ("adeno").
287 studies (20 subsidiary) were identified. Although RR estimates were markedly heterogeneous, the meta-analyses demonstrated a relationship of smoking with lung cancer risk, clearly seen for ever smoking (random-effects RR 5.50, CI 5.07-5.96) current smoking (8.43, 7.63-9.31), ex smoking (4.30, 3.93-4.71) and pipe/cigar only smoking (2.92, 2.38-3.57). It was stronger for squamous (current smoking RR 16.91, 13.14-21.76) than adeno (4.21, 3.32-5.34), and evident in both sexes (RRs somewhat higher in males), all continents (RRs highest for North America and lowest for Asia, particularly China), and both study types (RRs higher for prospective studies). Relationships were somewhat stronger in later starting and larger studies. RR estimates were similar in cigarette only and mixed smokers, and similar in smokers of pipes/cigars only, pipes only and cigars only. Exceptionally no increase in adeno risk was seen for pipe/cigar only smokers (0.93, 0.62-1.40). RRs were unrelated to mentholation, and higher for non-filter and handrolled cigarettes. RRs increased with amount smoked, duration, earlier starting age, tar level and fraction smoked and decreased with time quit. Relationships were strongest for small and squamous cell, intermediate for large cell and weakest for adenocarcinoma. Covariate-adjustment little affected RR estimates.
The association of lung cancer with smoking is strong, evident for all lung cancer types, dose-related and insensitive to covariate-adjustment. This emphasises the causal nature of the relationship. Our results quantify the relationships more precisely than previously.
It has been known for many years that smoking causes lung cancer. An association was clearly documented in case–control studies conducted in Germany in the 1930s
While some meta-analyses of the evidence have been published in recent years
Because the relationship of smoking to the two major types of lung cancer (squamous cell carcinoma and adenocarcinoma) is known to vary
Full details of the methods used are described in Additional file
Additional file 1
Methods [
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Inclusion and exclusion criteria
Attention was restricted to epidemiological prospective or case–control studies published up to and including 1999, which involved 100 lung cancers or more, and which provided RR estimates for one or more defined major, cigarette-type or dose-related smoking indices. The "major indices" compare ever, current or ex smoking with never or non-current smoking, and refer to smoking of any product, cigarettes, pipes, cigars and combinations, or of specific types of cigarette. The "cigarette type indices" compare smokers of different types of cigarette – filter with plain, manufactured with handrolled and mentholated with non-mentholated. The "dose-related indices" concern amount smoked, age of starting to smoke, duration of smoking, duration of quitting, tar level, butt length or fraction smoked. Pack-years was not considered as it was felt more important to separate effects of extent and duration of exposure. Uncontrolled case studies were not included. There were no further exclusion criteria.
Literature searching
Between 1997 and 2001 potentially relevant papers were sought from Medline and Emtree searches, from British Library monthly bulletins, from files on smoking and health accumulated over many years by P N Lee Statistics and Computing Ltd, and from references cited in papers obtained, until ultimately no paper examined cited a paper of possible relevance not previously examined.
Identification of studies
Relevant papers were allocated to studies, noting multiple papers on the same study, and papers reporting on multiple studies. Each study was given a unique reference code (REF) of up to 6 characters (e.g. COMSTO or LUBIN2), based on the principal author's name and distinguishing multiple studies by the same author.
Some studies were noted as having overlaps with other studies. To minimize problems in meta-analysis arising from double-counting of cases, overlapping studies were divided into two categories, as shown in Additional file
Additional file 2
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Data recorded
Relevant information was entered onto a study database and two linked RR databases. Data entry was carried out in two stages. In 1997–2002, data were entered on the first RR database for the major smoking indices, cigarette type indices, and amount smoked. In 2009–2010, data were entered on the second RR database for the remaining dose-related indices.
The study database contains a record for each study, describing the following aspects: relevant publications; study title; study design; sexes considered; age range, race(s) and other details of the population studied; location; timing and length of follow-up; whether principal or subsidiary, with details of overlaps or links with other studies; number of cases and extent of histological confirmation; number of controls or subjects at risk; types of controls and matching factors used in case–control studies; use of proxy respondents, interview setting and response rates; confounding variables considered; availability of results by histological types; and availability of results for all smoking indices (including those indices not considered here, such as pack-years).
The RR databases hold the detailed results, typically containing multiple records for each study. Each record is linked to the relevant study and refers to a specific RR, recording the comparison made and the results. This record includes the sex, age range, race, lung cancer type, and (for prospective studies) the follow-up period. The smoking exposure of the numerator of the RR is defined by the smoking status (ever, current or ex), smoking product (e.g. any, cigarettes, cigarettes only, pipes only) and cigarette type (e.g. any, mainly hand-rolled cigarettes, filter cigarettes only, mentholated cigarettes). Similar information is recorded about the denominator of the RR. For dose-related indices, the level of exposure is recorded. The source of the RR is also recorded, as are details on adjustment variables. Results recorded include numbers of cases for the numerator and denominator, and, for unadjusted results, numbers of controls, persons at risk or person-years at risk. The RR itself and its lower and upper 95% confidence limits (LCL and UCL) are always recorded. These may be as reported, or derived by various means (see below), with the method of derivation noted.
Identifying which RRs to enter
RRs were entered relating to defined combinations of lung cancer type, smoking index (major, cigarette type or dose-related), confounders adjusted for, and strata, as described below.
Lung cancer type
Results were entered for all lung cancer, for Kreyberg I (as originally presented, or by combining squamous, small and large cell carcinoma) and Kreyberg II (as originally presented, or by combining adenocarcinoma and others not in Kreyberg I), and for squamous, small, and large cell carcinoma and for adenocarcinoma separately. Additionally, the following groups were constructed if not originally presented: all lung cancer or nearest equivalent, but at least squamous cell carcinoma and adenocarcinoma; squamous cell carcinoma or nearest equivalent; adenocarcinoma or nearest equivalent.
Major and cigarette type smoking indices
The intention was to enter RRs comparing current smokers, ever smokers or ex smokers with never or non smokers. Near-equivalent definitions were accepted when stricter definitions were unavailable, so that, for example, never smokers could include occasional smokers (or exceptionally, light smokers), while current smokers could include, and ex-smokers exclude, recent quitters. RRs were to be entered relating to smoking of defined products and, when the product related to cigarette smoking, to defined cigarette types (see also Additional file
Dose-related smoking indices
RRs were entered for seven measures: amount smoked, age of starting, duration of smoking, duration of quitting, tar level, butt length and fraction smoked. RRs were expressed relative to never smokers (or near equivalent), if available, or relative to non smokers otherwise. For duration of quitting, RRs were also expressed relative to current smokers. Except for amount smoked, further RRs were entered, restricted to smokers, and expressed relative to the level expected to have the lowest risk (e.g. shortest duration or latest age started).
Confounders adjusted for
For case–control studies, results were entered adjusted for the greatest number of potential confounding variables for which results were available, and also unadjusted (or adjusted for the smallest number of confounders). For prospective studies, results were entered adjusted for age and the greatest number of confounders, and for age only or age and the smallest number of confounders, with unadjusted results entered only if no age-adjusted results were available. These alternative RRs are subsequently referred to as "most-adjusted" and "least-adjusted". For dose-related RRs restricted to smokers, results with "most adjustment" but without adjustment for other aspects of smoking were also entered if available.
Three strata were considered – sex, age and race. Results were entered for males and females separately when available, with combined sex results only entered when sex-specific results were not available. Results were entered for all ages combined and for individual age groups, and for all races and for individual racial groups.
Derivation of RRs
Adjusted RRs and their 95% CIs were entered as provided, when available. Unadjusted RRs and CIs were calculated from their 2 × 2 table, using standard methods (e.g.
Correction for zero cell
If the 2 × 2 table has a zero cell, 0.5 was added to each cell, and the standard formulae applied.
Combining independent RRs
RRs were combined over ℓ strata (e.g. from a 2 × 2 × ℓ table) using fixed-effect meta-analysis
Combining non-independent RRs
The Hamling et al. method
Estimating CI from crude numbers
If an adjusted RR lacked a CI or p-value but the corresponding 2 × 2 table was available, the CI was estimated assuming that the ratio UCL/LCL was the same as for the equivalent unadjusted RR.
Data entry and checking
Master copies of all the papers in the study file were read closely, with relevant information highlighted to facilitate checking. Where multiple papers are available for a study, a principal publication was identified, although details described only in other publications were also recorded. Preliminary calculations and data entry were carried out by one author and checked by another, and automated checks of completeness and consistency were also conducted. RR/CIs underwent validation checks
Meta-analyses conducted – overview
A pre-planned series of meta-analyses was conducted for various smoking indices for each of the three main outcomes (all lung cancer, squamous cell carcinoma, and adenocarcinoma) and also for some indices for two other outcomes (large cell carcinoma and small cell carcinoma). Nearest equivalent definitions are allowed for the three main outcomes, with the terms "squamous" and "adeno" used subsequently to distinguish these results from those specifically for these cell types. Each meta-analysis was repeated, based on most-adjusted RRs and on least-adjusted RRs. For each meta-analysis conducted, combined estimates were made first for all the RRs selected, then for RRs subdivided by level of various characteristics, testing for heterogeneity between levels.
Selecting RRs for the meta-analyses
All meta-analyses are restricted to records with available RR and CI values. The process of selecting RRs for inclusion in a meta-analysis must try to include all relevant data and to avoid double-counting. For a given analysis (e.g. of current cigarette smoking), several definitions of RR may be acceptable (e.g. cigarette smoking, or cigarette only smoking), so, for studies with multiple RRs, the one to be used is determined by a preference order defined for the meta-analysis. Preference orders may be required for smoking status, smoking product, the unexposed base, and extent of confounder adjustment. As the definitions of RR available may differ by sex (e.g. a study may provide RRs for any product smoking for males, but only for cigarette smoking for females), the RRs chosen for each sex may not necessarily have the same definition. Sexes combined results are only considered where sex-specific results are not available. Similarly RRs from a subsidiary study are only used where eligible RRs are unavailable from the principal study. When multiple preference orders are involved, the sequence of implementation may affect the selection, so preferences for the most important aspects, usually concerning smoking, are implemented first.
Carrying out the meta-analyses
Fixed-effect and random-effects meta-analyses were conducted using the method of Fleiss and Gross
Meta-analyses were conducted in various sets (A to N) corresponding to the sub-sections of the results section of the paper. A full list of the analyses is given in Additional file
The major smoking indices
For the major smoking indices, the first four sets of meta-analyses relate to: A ever smoking, B current smoking, C ever smoking (but with current smoking used if ever smoking not available), referred to subsequently as "ever/current" smoking, and D ex smoking. In what is referred to as the main analysis in each set, smoking of any product is preferred by selecting RRs in the following preference order: 1. smoking of any product vs. never smoked any product; 2. smoking of cigarettes vs. never smoked any product, 3. smoking of cigarettes only vs. never smoked any product; 4. smoking of cigarettes vs. never smoked cigarettes; 5. smoking of cigarettes only vs. never smoked cigarettes; with options 6–10 the same as options 1–5 except that "never smoked" is replaced by "never smoked near equivalent". A variant analysis prefers cigarette smoking (by changing the preference order to 4, 5, 2, 3, 1, 9, 10, 7, 8, 6). In meta-analyses of type C, a further variant analysis reverses the preference so current smoking results are preferred to those for ever smoking, referred to subsequently as "current/ever" smoking. Other variant analyses are based on RRs for specified age ranges.
A further set of meta-analyses, E, concerns smoking of pipes and/or cigars (but not cigarettes), referred to subsequently as smoking of "pipes/cigars only", smokers of pipes only, smokers of cigars only, and smokers of cigarettes and pipes/cigars ("mixed" smokers). Separate meta-analyses were conducted for ever smoking, current smoking, ever/current smoking, current/ever smoking and ex smoking.
The cigarette type indices
Meta-analyses were conducted, in set F, for only filter vs. only plain, ever filter vs. only plain, only filter vs. ever plain, handrolled vs. manufactured, and mentholated vs. non-mentholated. These were only conducted for ever/current smoking, and preferring RRs for cigarettes over RRs for cigarettes only. The analyses with only filter as the numerator used the preference order of filter only, always, mainly, both, equally, and ever, while the analyses with ever filter as the numerator used the reverse preference. Similar preference orders applied to the denominators. The analyses of handrolled vs. manufactured cigarettes used the preference order of any, both, mainly, and only for handrolled, and only ever, only current, any and ever for manufactured.
The dose-related smoking indices
For the dose-related indices, sets of meta-analyses were conducted for: G amount smoked, H age of starting to smoke, I duration of smoking, J duration of quitting compared to never smokers (or long-term ex smokers), K duration of quitting compared to current smokers (or short-term quitters), L tar level, and M butt length or fraction smoked (taking short butt length as being equivalent to a large fraction smoked). For any measure, a study typically provides a set of non-independent RRs for each dose-category, expressed relative to a common base. To avoid double-counting only one was included in any one meta-analysis. Two approaches were adopted. The first involves specifying a scheme with a number of levels of exposure ("key values"), then carrying out meta-analyses for each level in turn, expressed relative to never smokers. For an RR to be allocated to a key value, its dose-category has to include that key-value and no other. Schemes with a few, widely spaced, key values tend to involve more studies, whereas schemes with more key values, closely spaced, involve RRs from fewer studies, but ones with dose categories more closely clustered around the key value. The sets of key values used (with 999 indicating an open-ended category) were 5, 20, 45 and 1, 10, 20, 30, 40, 999 for amount smoked; 26, 18, 14 and 30, 26, 22, 18, 14, 10 for age of starting to smoke; 20, 35, 50 and 5, 20, 30, 40, 50, 999 for duration of smoking; 12, 7, 3 and 20, 12, 3 for duration of quitting vs. never; and 3, 7, 12 and 3, 12, 20 for duration of quitting vs. current. No key value analysis was conducted for tar level, or for butt length/fraction smoked. The second approach (not conducted for amount smoked) involves meta-analysing of RRs for the highest compared with the lowest categories of exposure within smokers available for each study.
Meta-regression analyses
While full multivariable analysis of the data is considered beyond the scope of this report, meta-regression analyses were also carried out using the sets of RRs selected for the main meta-analyses for ever smoking and for current smoking. Following preliminary meta-regressions (not shown), a "fixed model" was fitted to examine the effect on the results of six different categorical variables (sex, location, start year of study, major study type, number of lung cancer cases and number of adjustment factors). Note that the number of lung cancer cases (in the study as a whole), which is referred to subsequently as "number of cases", is used as an indicator of study size. The significance of each of these variables was estimated by an F-test based on the increase in deviance resulting from its exclusion from the basic model. A list of secondary variables was also defined (relating to more detailed aspects of location, outcome, study type and confounder adjustment, national cigarette tobacco type, the product smoked, the denominator used in the RR, use of proxy respondents, whether the study required 100% histological confirmation of lung cancer, whether the population studied worked in risky occupations, the age of the subjects, and the derivation of the RR) with the significance of adding each characteristic to the fixed model estimated by an F-test based on the increase in deviance. Fuller details are given in Additional file
Additional analyses
Additional tests of the relationship of lung cancer risk to various characteristics of interest were based on corresponding pairs of RR and CI estimates within the same study for the same definition of outcome and exposure, and deriving the ratio of the two RRs. Where the pairs involved independent sets of subjects, the variance of the ratio was also derived, and meta-analyses of the ratio were conducted. Where the pairs involved non-independent sets of subjects the numbers of ratios greater and less than 1 were compared using the sign test. Tests of independent pairs related to sex (males vs. females), age (oldest vs. youngest age group) and race (white people vs. non-white or black people). Tests of non-independent pairs related to level of adjustment (most-adjusted vs. least-adjusted), and to comparisons of product smoked (mixed smokers vs. cigarette only smokers, and vs. smokers of pipes/cigars only). Tests were always carried out for all lung cancer and ever/current smoking. For sex, additional analyses were conducted for current and for ever smoking, for squamous and adeno, and also within level of amount smoked. For level of adjustment, two sets of analyses were run. The first, relating to RRs for ever/current smoking were based on the most-adjusted/least-adjusted ratio, while the second, for highest vs. lowest RRs for age of starting to smoke, duration, years quit and tar level, compared RRs that were most- or least-adjusted for other aspects of smoking.
All data entry and most statistical analyses were carried out using ROELEE version 3.1 (available from P.N. Lee Statistics and Computing Ltd, 17 Cedar Road, Sutton, Surrey SM2 5DA, UK). Some analyses were conducted using Quattro Pro 9 or Excel 2003.
Studies identified
A total of 5,993 potentially relevant papers were identified, providing information on 287 eligible studies (Table
Of the 287 studies, 267 are classified as principal, 209 (78.3%) of these being case–control studies, 52 (19.5%) prospective, 5 (1.9%) nested case–control and 1 (0.4%) case-cohort. Note that the last three study designs, where exposure was determined before diagnosis, are combined into one category in Table
Of the 267 principal studies, 158 (59.2%) provide results for both sexes, 90 (33.7%) for males only, and 19 (7.1%) for females only. One hundred and ninety-six (73.4%) of the studies included subjects who are under 30 years old (or allowed their inclusion by having no age restriction), while only 31 (11.6%) were restricted to subjects aged 40 or more. Subjects aged 80 years or more were included by 200 (74.9%), while only 16 (6.0%) were restricted to subjects aged 60 or less. Prospective studies were much more likely than case–control studies to specify age restrictions, e.g. 62.1% vs. 16.7% for age 30 years or more, and 48.3% vs. 18.7% for age less than 80 years. Eighty-nine (33.3%) principal studies were conducted in USA or Canada, with 22 (8.2%) in the UK, 25 (9.4%) in Scandinavia, 43 (16.1%) in other parts of Europe, 37 (13.9%) in China, 18 (6.7%) in Japan, 17 (6.4%) in the rest of Asia and 16 (6.0%) elsewhere – in South or Central America, Africa or Australia. Of the 58 prospective studies, all but 12 were conducted in North America, UK or Scandinavia. Of the principal studies, 42 (15.7%) were conducted in countries where at least 75% of cigarettes smoked are made from Virginia tobacco, with 184 (68.9%) carried out where at least 75% of cigarettes are from blended tobaccos. Forty seven (17.6%) started before 1960. Studies starting after 1979 were predominantly (92.4%) case–control. Thirty-six (13.5%) involved at least 1,000 lung cancer cases. Seven (2.6%) were conducted in miners, with a further 11 (4.1%) conducted in other occupational groups with a known relationship with lung cancer. Proxy respondents were used for some subjects in 74 (27.7%), with full histological confirmation of cases reported to be carried out in 68 (25.5%).
Most study groups (i.e. a principal study or one of its subsidiaries) provide some results for the major indices compared to never smokers, 240 (89.9%) for ever smokers, 134 (50.2%) for current smokers and 127 (47.6%) for ex smokers. Many studies provide results for smoking of any product (162 studies, 60.7%) or for cigarettes (147, 55.1%), but less do so for cigarette only smoking (55, 20.6%), smoking of pipes/cigars only (62, 23.2%), mixed smoking (29, 10.9%), or for the cigarette type indices filter/plain cigarette smoking (38, 14.2%), hand-rolled cigarette smoking (15, 5.6%), or mentholated cigarette smoking (3, 1.1%). Though dose–response data are most commonly available by amount smoked (162, 60.7%), many studies provide data by age of starting to smoke (62, 23.2%), duration (77, 28.8%), and time quit (58, 21.7%). Few studies provide data on tar level (11 studies, 4.1%), fraction smoked (9 studies, 3.4%), or butt length (2 studies, 0.7%).
Relative risks
A total of 16,616 RRs were entered, the number recorded per study varying from 1 to 1,029. Of these, 1,266 relate to subsidiary studies. Table
Of the total of 16,616 RRs, 71.9% relate to case–control studies, and 93.8% are sex-specific. 40.2% come from North American studies, 36.8% from Europe, 16.7% from Asia, and 6.3% from other continents. 60.9% are unadjusted for potential confounding variables and 18.7% are adjusted for sex and/or age only. 70.1% are given directly or are calculated by standard methods, the rest being derived by more complex methods.
Of the total RRs, 5,061 relate to the major smoking indices, where the denominator is never or non smoking, with 3,614 of these relating to smoking of any product or cigarettes (regardless of pipe or cigar smoking), 678 to cigarette only smoking and 769 to pipe, cigar or mixed smoking. Four hundred and forty-eight relate to cigarette type comparisons, most commonly (303 RRs) to the filter vs. plain comparison. All the 25 RRs for the mentholated/non-mentholated comparison come from North American studies, while none of those for the handrolled/manufactured comparison do. There are 10,921 RRs for dose-related indices, based mainly on 3,625 sets, 2,047 vs. never or non smoking, 1,327 vs. the low level, and 251 vs. current smoking. There are most sets for amount smoked (1,145) and least for butt length (5). For amount smoked, age of starting, duration of smoking, years quit (vs. never and vs. current) there are sufficient numbers of dose–response sets to study variation in RR by sex, study type and continent.
None of the RRs included in the meta-analyses and meta-regressions show more than minor failures of the validation tests used, attributable to rounding errors or small imprecisions or uncertainties in estimating the RRs and CIs. Additional file
Additional file 3
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For dose-related indices, Additional file
Additional file 4
Dose-response data, not eligible for inclusion in meta-analysis.
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The meta-analyses and meta-regressions
The main findings are summarized in the following sections, with tables and forest plots. Additional file
Additional file 5
Detailed Analysis Tables (Individual file names as described in Additional file
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Findings are generally presented for three outcomes, referred to as "all lung cancer", "squamous" or "adeno". These outcomes are defined in the Methods section, and also in the footnotes to the tables, and allow the inclusion of results based on alternative similar definitions. (Note that the terms "squamous cell carcinoma" and "adenocarcinoma" are only used when reference is made to results specifically for the particular cell type).
A. Risk from ever smoking
Figure 1
Forest plot of ever smoking of any product and all lung cancer – part 1
Forest plot of ever smoking of any product and all lung cancer – part 1. Table
Figure 2
Forest plot of ever smoking of any product and all lung cancer – part 2
Forest plot of ever smoking of any product and all lung cancer – part 2. This is a continuation of Figure
Figure 3
Forest plot of ever smoking of any product and all lung cancer – part 3
Forest plot of ever smoking of any product and all lung cancer – part 3. This is a continuation of Figure
Figure 4
Forest plot of ever smoking of any product and all lung cancer – part 4
Forest plot of ever smoking of any product and all lung cancer – part 4. This is a continuation of Figure
Figure 5
Forest plot of ever smoking of any product and all lung cancer – part 5
Forest plot of ever smoking of any product and all lung cancer – part 5. This is a continuation of Figure
Figure 6
Forest plot of ever smoking of any product and squamous – part 1
Forest plot of ever smoking of any product and squamous – part 1. Table
Figure 7
Forest plot of ever smoking of any product and squamous – part 2
Forest plot of ever smoking of any product and squamous – part 2. This is a continuation of Figure
Figure 8
Forest plot of ever smoking of any product and adeno – part 1
Forest plot of ever smoking of any product and adeno – part 1. Table
Figure 9
Forest plot of ever smoking of any product and adeno – part 2
Forest plot of ever smoking of any product and adeno – part 2. This is a continuation of Figure
First, the RRs for all three outcomes are markedly heterogeneous. As shown in Table
As shown in Table
Returning to the main meta-analysis (most-adjusted and preferring ever smoking any product), there is a large variation between RRs in the weight they contribute to the analysis. This is very marked for all lung cancer. Here the 328 estimates provided a combined weight of 19,346 (mean 59.0), but the male and female estimates from study LIU4 together contributed a weight of 9,846, 50.9% of the total. Omitting these two estimates substantially reduced the heterogeneity, H falling from 22.84 to 12.54. The next largest weights were 1,550 in study STOCKW (sexes combined), 443 in BROWN2 (males) and 428 in BROWN2 (females). For squamous, the total weight was 1,000 for the 102 RRs (mean 9.8). The largest contributors to this were 164 for BROWN2/males, 90 for BROWN2/females, 52 for LUBIN2/males and 47 for LUBIN2/females, together contributing 35% of the total weight. For adeno, the total weight was 1,514 for the 107 RRs (mean 14.1). Again, BROWN2 and LUBIN2 were the largest contributors, providing, respectively, 24% and 6% of the total weight.
In investigating sources of heterogeneity, variation was studied firstly using a univariable approach, the results for the characteristics considered in Table
For all three outcomes, RRs were always somewhat lower for females than for males or for sexes combined, though the variation by sex was not significant (p ≥ 0.1) for squamous.
For all three outcomes, RRs were lower from studies conducted in Europe and Asia than from studies conducted in North America. While for all lung cancer and adeno RRs were noticeably lower in Asia than in Europe, this difference was not evident for squamous. The difference in RRs by continent was very marked and highly significant (p < 0.001) for all lung cancer and adeno, but less marked, though still significant (p < 0.01) for squamous.
Start year of study
For all lung cancer and squamous, variation by start year was not significant (p ≥ 0.05) although there was some tendency for RRs to be higher in more recent studies. For adeno, the variation was significant (p < 0.01) but there was no clear trend.
Study type
For all three outcomes, RRs were somewhat lower for case–control studies than for prospective studies (or other study designs where the smoking data were collected before lung cancer diagnosis). However, the difference was never statistically significant (p ≥ 0.05).
National cigarette tobacco type
For all three outcomes, there was significant (p < 0.01 or< 0.001) variation. This was mainly due to low estimates in the "other" group, which mainly included results from China. For all lung cancer, RRs for Virginia (6.24, 5.16-7.54, n = 50) and blended (6.30, 5.79-6.87) were quite similar. For squamous and adeno, there were limited results for Virginia, and no clear difference from blended was evident.
Any proxy use
There was some evidence that RRs were higher where proxy respondents were used for squamous (p < 0.05) and adeno (p < 0.1), but not for all lung cancer.
Full histological confirmation
RR estimates were somewhat higher where full histological confirmation of diagnosis was a study requirement, but this was only significant at p < 0.05 for all lung cancer.
Number of cases
Some tendency for RRs to increase with increasing number of cases was evident for all three outcomes, but variation in number of cases was only significant for all lung cancer (p < 0.01).
Smoking product
The analyses in Table
Unexposed base
RRs were somewhat higher where the unexposed base group was never cigarettes than when it was never any product, though this was only significant (p < 0.05) for adeno. This result is somewhat counter-intuitive, as lower RRs might be expected where the base (never cigarettes) includes some smokers (pipe/cigar only), and probably arises from the strong correlation between the definitions of smoking product and unexposed base. Two combinations – any product vs. never any product (n = 203) and cigarettes vs. never cigarettes (n = 90) – form a large proportion of the total RRs (with any product vs never cigarettes not a valid possibility).
Number of adjustment factors
There was no evidence that RR estimates varied by whether they were adjusted for 0, 1 or 2+ potential confounding variables.
The full meta-analysis (see Additional file
For all lung cancer, by far the strongest source of variation was location, with the overall heterogeneity reduced from 22.84 per d.f. to 7.02 per d.f. after including location only into the model. As noted earlier this was mainly due to relatively high RRs in North America and low RRs in Asia. Other clear effects were also associated with start year of study (p < 0.001, higher risks in later studies, much more clearly evident than in the univariable analyses in Table
For squamous, start year of study was the most important factor, on its own reducing the heterogeneity from 5.17 to 4.33 per d.f. (p < 0.001). Other significant characteristics included location (p < 0.001), with RRs high in North America and low in China, and number of cases (p < 0.05), with higher RRs in larger studies. Number of adjustment factors was also significant (p < 0.05), but the pattern was erratic and not the same as for all lung cancer. Though the pattern of results by study type was similar to that for all lung cancer, this characteristic did not contribute significantly to the model. The heterogeneity for the fixed model (Table
For adeno, location was the most important factor, on its own reducing the heterogeneity from 8.78 to 4.36 per d.f. (p < 0.001), with the pattern of results (RRs high in North America and low in Asia) similar to that for all lung cancer. As for all lung cancer, there was variation by start year of study (p < 0.05) and number of cases (p < 0.05), with RRs higher for recent and larger studies. RRs were again higher for prospective studies, but here the difference was not significant (p ≥ 0.05). Here, variation by sex was significant (p < 0.05) with RRs higher for males than females, but number of adjustment factors was not (p ≥ 0.05). The heterogeneity for the fixed model (Table
The fixed model (Table
B. Risk from current smoking
Figure 10
Forest plot of current smoking of any product and all lung cancer – part 1
Forest plot of current smoking of any product and all lung cancer – part 1. Table
Figure 11
Forest plot of current smoking of any product and all lung cancer – part 2
Forest plot of current smoking of any product and all lung cancer – part 2. This is a continuation of Figure
Figure 12
Forest plot of current smoking of any product and all lung cancer – part 3
Forest plot of current smoking of any product and all lung cancer – part 3. This is a continuation of Figure
Figure 13
Forest plot of current smoking of any product and squamous
Forest plot of current smoking of any product and squamous. Table
Figure 14
Forest plot of current smoking of any product and adeno
Forest plot of current smoking of any product and adeno. Table
As for ever smoking, the RRs for all three outcomes are heterogeneous (p < 0.001), with the largest estimates seen being 104.50 for all lung cancer (STUCKE/males), 78.91 for squamous (CPSII/females), and 21.70 for adeno (OSANN/males). The random-effects estimates (all lung cancer 8.43, 95% CI 7.63-9.31, n = 195; squamous 16.91, 13.14-21.76, n = 41; adeno 4.21, 3.32-5.34, n = 44) are all clearly positive, larger than the corresponding estimates for ever smoking, and also show a stronger relationship with squamous than adeno. Similarly to ever smoking, the individual RRs are virtually all above 1.0, though varying substantially. The estimates are again little affected (Table
For the main meta-analysis, the studies contributing most to the total weight for current smoking for all lung cancer were STOCKW/sexes combined (17.8% of the total of 6,750) followed by BROWNS/males (6.0%) and BROWNS/females (5.4%). BROWNS was the major contributor for both squamous and adeno, with the two sex-specific results contributing 36.0% of the total weight of 646 for squamous, and 30.0% of the total weight of 1,017 for adeno. The huge LIU4 study did not provide results for current smoking.
For the characteristics considered in Table
As for ever smoking, meta-regression analyses were conducted to give further insight, the results from the same fixed model including six characteristics being summarized in Table
For all lung cancer, as was the case for ever smoking RRs, by far the strongest source of variation in current smoking RRs was location with relatively high risks in North America and low risks in Asia. The overall heterogeneity reduced from 13.76 per d.f. to 6.73 per d.f. after including location only into the model. Higher risks were also seen in the fixed model in more recent studies (p < 0.001) and for males than females (p < 0.01). There was some evidence (p < 0.1) of higher RRs in larger studies and in prospective studies, but no association was seen with the number of adjustment factors. The heterogeneity for the fixed model shown in Table
For squamous and adeno, numbers of current smoking RRs (41 and 44 respectively) were much lower than those for all lung cancer, with no data for China or the United Kingdom, or for national cigarette type "other". For squamous, only two characteristics in the fixed model (Table
For adeno, three of the characteristics considered in Table
For none of the three outcomes did characteristics associated with detailed location, national cigarette tobacco type, the precise definition of the outcome, adjustment for specific factors, the definitions of smoking product or of the unexposed base, whether the study was conducted in a population working in a risky occupation or whether proxy respondents were used, add significantly to the model.
C. Risk from ever or current smoking
In an attempt to incorporate data from a greater number of studies, additional analyses were carried out for ever/current smoking and for current/ever smoking. The meta-analysis RRs are shown in Table
As many of the RRs are common between the specific ever smoking analyses in Table
D. Risk from ex smoking
Figure 15
Forest plot of ex smoking of any product and all lung cancer – part 1
Forest plot of ex smoking of any product and all lung cancer – part 1. Table
Figure 16
Forest plot of ex smoking of any product and all lung cancer – part 2
Forest plot of ex smoking of any product and all lung cancer – part 2. This is a continuation of Figure
Figure 17
Forest plot of ex smoking of any product and all lung cancer – part 3
Forest plot of ex smoking of any product and all lung cancer – part 3. This is a continuation of Figure
Figure 18
Forest plot of ex smoking of any product and squamous
Forest plot of ex smoking of any product and squamous. Table
Figure 19
Forest plot of ex smoking of any product and adeno
Forest plot of ex smoking of any product and adeno. Table
Again the RRs are markedly heterogeneous (p < 0.001 for all three outcomes), ranging up to 135.69 for all lung cancer (STUCKE/males), 22.90 for squamous (OSANN/males) and 13.10 for adeno (OSANN/males). The random-effects estimates (all lung cancer 4.30, 95% CI 3.93-4.71, n = 182, squamous 8.74, 6.94-11.01, n = 33, and adeno 2.85, 2.20-3.70, n = 34), though all clearly positive, are smaller than the corresponding estimates for current smoking. Individual RRs are only very occasionally below 1.0 and never significantly so. Estimates are little affected by using the more specific definition of each outcome, preferring least-adjusted RRs to most-adjusted RRs, or preferring RRs for ever smoking cigarettes to those for ever smoking any product. RRs for ever smoking cigarettes only were too few for useful analysis for squamous and adeno, but for all lung cancer were similar to those for ever smoking any product. Fuller details are given in the Additional file
For the main meta-analysis of ex smoking, the studies contributing most to the total weight for all lung cancer were STOCKW/sexes combined (22.4% of the total of 4,739), followed by BROWNS/males (8.5%) and BROWNS/females (6.5%). BROWNS was the major contributor for both squamous and adeno, with the two sex-specific results contributing 49.4% of the total weight of 446 for squamous, and 45.2% of the total weight of 619 for adeno.
For the characteristics considered in Table
E. Risk from smoking specific products compared to smoking of any product
Figure 20
Forest plot of ever pipe and/or cigar smoking and all lung cancer
Forest plot of ever pipe and/or cigar smoking and all lung cancer. Table
For ever smoking, current smoking and ex smoking the random-effects RRs are similarly elevated for pipes/cigars, pipes only and cigars only, but to a markedly lesser extent than for cigarettes only. As for cigarette smoking, RRs for pipe and cigar smoking are clearly higher for current smokers than for ex smokers.
Available results for squamous and adeno are limited, and mainly for ever smoking. For pipe and/or cigar smoking, the RR for squamous (3.72, 95% CI 1.95-7.10, n = 8) is somewhat higher than that for all lung cancer (2.92, 2.38-3.57, n = 38), but the RR for adeno is not elevated (0.93, 0.62-1.40, n = 7). The lack of association of adeno with pipe and cigar smoking is also evident in the RRs for pipes only (0.50, 0.23-1.10, n = 4) and for cigars only (0.55, 0.11-2.88, n = 3).
The results for pipe and cigar smoking mainly apply to males, as the few available estimates for females have wide variability. The increased risk in smokers of pipes and cigars is evident in each location studied, though data for Asia are extremely sparse. Unlike for cigarettes, higher RRs are seen for Scandinavia (7.02, 4.72-10.44, n = 6) and for Other Europe (5.17, 2.91-9.19, n = 8) than for North America (2.27, 1.79-2.89, n = 26) or the UK (4.32, 2.73-6.84, n = 11). These results are for ever/current smoking, with the full results given in Additional file
F. Risk by type of cigarette smoked
Figure 21
Forest plot of only filter vs. only plain cigarette smoking and all lung cancer
Forest plot of only filter vs. only plain cigarette smoking and all lung cancer. Table
Figure 22
Forest plot of handrolled vs. manufactured cigarette smoking and all lung cancer
Forest plot of handrolled vs. manufactured cigarette smoking and all lung cancer. Table
Figure 23
Forest plot of mentholated vs. non-mentholated cigarette smoking of any product and adeno
Forest plot of mentholated vs. non-mentholated cigarette smoking of any product and all lung cancer. Table
The random-effects RRs show a reduction in risk for only filter vs. only plain cigarette smoking that is significant for all lung cancer (RR 0.69, 95% CI 0.61-0.78, n = 42), and squamous (0.52, 0.40-0.68, n = 13), though not for adeno (0.84, 0.66-1.08, n = 10). The alternative comparisons for filter and plain, where only a third to a half of the RRs included actually differ, show clear reductions for all lung cancer and squamous associated with filter cigarette smoking, though no difference for adeno (see Table
The risk associated with handrolled smoking is greater than that with manufactured cigarette smoking, with RRs of 1.29 (1.12-1.49, n = 20) for all lung cancer and 1.62 (1.18-2.21, n = 5) for squamous. The RR of 2.09 (0.83-5.25, n = 4) for adeno is based on very heterogeneous estimates, varying from 0.43 to 8.76, and allows no clear conclusion. As results for females are limited, and have wide variability, the conclusions mainly apply to males. The estimated RR for all lung cancer is greater than 1 in all locations studied, though not always statistically significant. However, there are no data from North America.
Data on mentholated cigarette smoking are limited, particularly by histological type. For all lung cancer, the RR of 0.98 (0.80-1.20, n = 6) is consistent with no effect of mentholation on risk, five RR estimates close to or below 1.0, counterbalancing one reported significant increase in males for study KAISER of 1.45 (1.03-2.02). There is some evidence (p < 0.05) of heterogeneity by sex with estimates of 1.15 (0.93-1.43, n = 3) for males, and 0.78 (0.63-0.98, n = 3) for females.
G. Risk by amount smoked
Dose–response by amount smoked was investigated for pipe and cigar smoking, but the number of estimates available was small, and referred only to males. However, there was some evidence of dose–response. Thus for all lung cancer, one can compare RRs for cigar only smoking for the highest (8.21, 4.36-15.49, n = 6) and lowest exposure groups (1.84, 1.22-2.79, n = 5), and can also compare RRs for pipe only smoking for the highest (5.99, 3.57-10.04, n = 9) and lowest exposure groups (3.68, 2.75-4.93, n = 8).
H. Risk by age of starting to smoke
I. Risk by duration of smoking
J. Risk by duration of quitting (vs. never smoking)
K. Risk by duration of quitting (vs. current smoking)
For duration of quitting compared to current smoking the number of data sets available are somewhat less than the corresponding number for duration of quitting compared to never smoking. Results included in the longest vs. shortest analysis shown in Table
L. Risk by tar level
Due to the variety of different methods of quantifying tar levels, only highest vs. lowest analyses have been carried out. No data were available by histological type, and all data relate to cigarette smoking. For all lung cancer and for ever/current smoking of cigarettes the 14 available estimates, from 9 studies, showed some evidence of heterogeneity (H = 2.29, p < 0.01). However, 12 of the estimates showed a higher risk in the higher tar group, and the random-effect estimate (1.42, 1.18-1.71) confirmed the relationship between risk and tar level. The increase was evident for males (1.29, 1.08-1.53, n = 7) and females (1.48, 1.05-2.09, n = 6). There was no evidence of heterogeneity by any specific characteristic, including extent of adjustment, 7 of the 14 estimates being adjusted for one or more of aspects of smoking. These results are based on RRs that are selected as being least adjusted for other aspects of smoking. Alternatively, using RRs selected as most adjusted for other aspects of smoking, the overall estimate was 1.34 (1.16-1.56, n = 14).
M. Risk by butt length and fraction smoked
All the available data relate to cigarette smoking. As the number of available estimates were quite limited, particularly for butt length, they have been combined into a single analysis including RRs for shortest vs. longest butt lengths and for greatest vs. smallest fraction smoked, and including results for ever smoking and current smoking. The combined estimates were 1.43 (1.14-1.79, n = 11) for all lung cancer, 1.39 (1.04-1.86, n = 7) for squamous, and 1.30 (1.07-1.58, n = 6) for adeno. There was some evidence of heterogeneity for all lung cancer (H = 2.29, p < 0.05) and for squamous (H = 2.96, p <0.01), though not for adeno (H = 0.75), but a clear majority (18/24 = 75.0%) of the estimates indicated a higher risk associated with smoking more of the cigarette.
N. Further analyses by histological type
The results so far have been restricted to all lung cancer, squamous or adeno. Table
O. Further analyses based on independent pairs of relative risks
Some studies provide independent RRs for males and females for the same definition of outcome and exposure. Random-effects meta-analysis of the male/female sex ratio confirms the impression already gained from the analyses shown in earlier Tables that RRs tend to be somewhat higher for males, although estimates are heterogeneous. For ever/current smoking, the sex ratio is 1.38 (1.23-1.54) for all lung cancer, based on 93 ratios, 64 higher in males; 1.31 (0.91-1.90) for squamous, based on 30 ratios, 18 higher in males, and 1.43 (1.14-1.78) for adeno, based on 33 ratios, 27 higher in males.
As sex differences may reflect greater cigarette consumption in males, meta-analysis estimates of the sex ratio for ever/current smokers and for all lung cancer were also calculated within levels of amount smoked (as defined in section G). The sex ratio is 1.33 (1.05-1.68) for smokers of about 5 cigs/day, based on 46 ratios, 26 higher in males, 1.59 (1.25-2.01) for smokers of about 20 cigs/day, based on 25 ratios, 20 higher in males, and 1.21 (0.99-1.49) for smokers of about 45 cigs/day, based on 26 ratios, 17 higher in males.
A number of studies provide RR estimates for ever/current smoking separately by age, and random-effects meta-analysis were conducted, based on the ratio of the estimate for the oldest age group for which data were available compared to that for the youngest. Despite only 22 of the 45 (48.9%) of the ratios showing a greater risk in the oldest age group, the meta-analysis showed a significantly higher risk in the oldest age group (ratio 1.17, 95% CI 1.10-1.25), the seven ratios with most weight all being greater than 1.0.
There were also eight studies, all conducted in the US, which provide comparable sex-specific results for ever/current smoking separately for white people and black people (or non-white people). Random-effects meta-analyses of the white/black race ratio showed no difference between the races (1.05, 0.90-1.23, n = 14).
P. Further analyses based on non-independent pairs of relative risks
Some studies also provide separate non-independent least-adjusted and most-adjusted RRs for the same definition of exposure. There is little evidence that adjustment reduces the RR for ever/current smoking. Using the same preferences as in Table
RRs for a dose-related index of smoking may be adjusted for other such indices. For all lung cancer, and for four dose-related indices of smoking, pairs of otherwise similar highest vs lowest RRs were identified in which one of the pair was adjusted for the most available other aspects of smoking, and the other had no such adjustment. Both were also chosen as adjusted for the most possible other variables (although those other variables may differ between the pair). There was a clear tendency for the additional adjustment for other aspects of smoking, typically including amount smoked, to produce lower RR estimates. This was true for 18/22 (81.8%, p < 0.01) of the pairs of estimates for age of starting to smoke, 12/15 (80.0%, p < 0.05) of the pairs for duration of smoking, all 17 (100%, p < 0.001) of those for years quit, and 5/7 (71.4%, NS) of those for tar level.
Based on results for ever/current smoking and for all lung cancer, RRs for mixed smokers were compared with those for smokers of cigarettes only. For 22 of the 34 (64.7%) pairs, the RR was lower for mixed smokers, but this tendency was not significant (p = 0.12). RRs for mixed smokers were also compared with those for smokers of pipes/cigars only. Here 23 of the 24 (95.8%, p < 0.001) pairs showed a lower risk in the smokers of pipes/cigars only.
Q. Publication bias
Some results of Egger's test
Figure 24
Funnel plot for ever smoking and all lung cancer
Funnel plot for ever smoking and all lung cancer. Funnel plot of the 328 relative risk estimates for ever smoking and all lung cancer included in the main meta-analysis in Table
Figure 25
Funnel plot for ever smoking and squamous
Funnel plot for ever smoking and squamous. Funnel plot of the 102 relative risk estimates for ever smoking and squamous included in the main meta-analysis in Table
Figure 26
Funnel plot for ever smoking and adeno
Funnel plot for ever smoking and adeno. Funnel plot of the 107 relative risk estimates for ever smoking and adeno included in the main meta-analysis in Table
Evidence of a relationship
The meta-analyses carried out demonstrate a clear relationship of smoking to overall lung cancer risk. This is evident for ever, current and ex smoking, for pipes and cigars, and for all types of cigarette studied. The increased risk in smokers is evident in both sexes, in younger and older subjects, in all continents studied and in prospective and case–control studies. That this relationship is causal is supported by the evidence of a dose–response, risk increasing with increasing amount smoked, duration of smoking, tar level and fraction smoked, and with earlier age of starting to smoke, and decreasing with duration of quitting. It is also supported by the similarity of results based on most-adjusted and least-adjusted RRs (though adjustment for amount smoked reduces the association with other dose–response indices of smoking). The association is clearly evident with each of the major histological types of lung cancer studied, being stronger for squamous and small cell carcinoma, intermediate for large cell carcinoma, and weakest for adenocarcinoma. Exceptionally, no relationship is seen between adenocarcinoma and pipe or cigar smoking.
The studies are remarkably consistent in reporting an increased risk in ever smokers. Only two of the 328 all lung cancer RRs, none of the 102 squamous RRs, and nine of the 107 adeno RRs considered in Figures
Using univariable and multivariable (meta-regression) methods, we investigated variation in risk by a number of characteristics of the study and the RR for the outcomes all lung cancer, squamous and adeno. While our "fixed" multivariable models involving six characteristics (sex, location, start year of study, study type, number of cases and number of adjustment factors) explained a substantial proportion of the variation (e.g. reducing H from 22.84 to 4.72 for all lung cancer for ever smoking), there was always substantial residual heterogeneity (with H varying from 2.43 to 4.72 in the six analyses in Tables
We also tested for the effect of a number of other characteristics on the estimated RR. A number of relationships were seen in the univariable models that were significant. However, these mainly became non-significant in the multivariable models, presumably due to correlations between the characteristics. Where a characteristic was significant, this tended to be only in one of the six analyses, so not providing convincing evidence of a true effect. It would have been possible, for each of the six combinations of smoking status and outcome we considered, to present analyses of "best" models, based on forward stepwise regression, that each included a different set of predictive characteristics. However we felt that the regressions we presented based on a fixed model were more useful. Sources of variation are discussed further in the following paragraphs.
If possible, sex-specific results are included in the meta-analyses, with combined sex results included only if not. Though variation by sex was not significant in all the main analyses, risk estimates generally tended to be higher for males than females. This is supported by additional analyses comparing RRs within study for the same outcome and exposure definition. Somewhat higher RRs were found in males even in analyses where comparisons were made within the same levels of daily cigarette consumption (about 5, 20 or 45 cigs/day). Even so, the existence of somewhat higher RRs for males does not necessarily indicate any greater susceptibility, as it may reflect their increased exposure to occupational carcinogens, or other differences in smoking history such as greater duration of smoking or increased use of plain and higher tar cigarettes. It should be noted however that in prospective studies where smoking habits were determined at baseline, the greater tendency of males to quit during follow-up may cause bias in the reverse direction. It should also be noted that comparison of smoker/never smoker RRs for men and women does not take account of possible differences in risk between male and female never smokers, the base groups for these comparisons. A detailed overall assessment of this aspect is beyond the scope of this paper, and ideally would involve direct comparison of risk in male and female smokers, with detailed adjustment for age, smoking characteristics and major potential confounding variables. We note that Bain et al.
While it is clear that absolute risk of lung cancer rises markedly with age, both in smokers and never smokers, it is far less clear whether the smoker/never smoker RR also does. Predictions based on the multistage model
Although RRs were entered onto the database, if available, there were few studies that provided such data. For eight studies which provided pairs of comparable RRs for ever/current smoking, there was no indication that RRs for white people differed systematically from those for black people (or non-white people). This, of course, does not rule out the possibility that absolute risks for white people and black people with similar smoking habits may differ. As our concern was only with RRs for smoking, and whether these vary by other characteristics, we have not attempted to collect data comparing absolute risk according to these characteristics, such as white/black RRs within never smokers, or within smokers. Detailed analysis and discussion of racial differences in lung cancer risk between black people and white people is therefore beyond the scope of this paper. Elsewhere Lee
Location and national cigarette tobacco type
A consistent tendency in our meta-analyses was for RRs to be highest in studies in North America, intermediate in Europe and lowest in Asia, particularly in China. There was no very clear evidence of a difference between European countries, or between other countries in Asia, though some of the analyses suggested relatively lower RRs in Greece and Turkey than in the rest of Europe, and higher RRs in India than in the rest of Asia. In an attempt to study a possible explanation for this difference we divided countries into three groups by national cigarette tobacco type. One was the countries (Australia, Canada, India, South Africa, UK and Zimbabwe) which typically use flue-cured Virginia tobacco, another was the countries (all except those in the other two groups) which typically use blended tobacco, and the third included Taiwan and China (countries which used both types quite commonly or where we lacked confirmed information). Including this variable into the meta-analyses did not consistently improve the prediction of our model, a finding which is consistent with the conclusions of other analyses we have conducted based on national data on lung cancer rates and smoking frequency
Study timing
Our meta-regressions generally showed a tendency for RRs to be lower in studies which started earlier. There may be a number of reasons for this, such as changes in the relative use of cigarettes and pipes or cigars, and improvement of study quality, with better standardization of questionnaires and definition of products smoked. However we consider the most plausible reason to be changes in patterns of uptake of smoking, with smokers in earlier born cohorts being less likely to have a lengthy smoking career than smokers in later born cohorts.
Study type
Though this was only clearly significant in the analyses of ever smoking for all lung cancer, there was a consistent tendency for RRs to be somewhat higher from prospective studies than from case–control studies. If this is a true effect, the explanation for it is unclear.
Number of cases
In order to limit the considerable amount of work needed, we limited attention to studies involving at least 100 lung cancer cases. Given that smaller studies would have contributed much less weight to the meta-analyses than would the studies that were included, we consider that this restriction unlikely to have any material effect on our conclusions. The meta-regression analyses did show a consistent tendency for RRs to be higher in larger studies, though this was only significant for ever smoking (all lung cancer p < 0.001), squamous and adeno p < 0.05). This tendency is in the opposite direction to that predicted from publication bias. The explanation is unclear.
Adjustment for other factors
Generally our analyses showed that adjustment for age and other factors had very little effect on the meta-analysis estimates of smoking-related RR, whether one considered the total number of adjustment factors, or the effect of specific factors. This conclusion of a minimal effect of confounding is consistent with that of a detailed analysis of data from the huge CPSII prospective study
Adjustment for other aspects of smoking is, however, important when considering the dose-related variables. Though studies rarely, if ever, present results to allow detailed analysis of the effect of adjustment for one specific aspect of smoking on RRs for another aspect, we have shown that adjustment for other aspects of smoking (which typically includes amount smoked) consistently tends to reduce associations with age of starting to smoke, duration of smoking, years quit and tar level. This is presumably due to the tendency for earlier starters and high tar smokers to smoke more heavily than do later starters and low tar smokers, and for lighter smokers to be more ready to quit smoking. Below, we further discuss the effect of adjustment on results for type of cigarette.
Product smoked
There was consistent evidence that risk of lung cancer was higher for cigarette only smokers than for smokers of any product, and substantially higher than for smokers of pipes only, cigars only or pipes/cigars only. For current smokers, for example, RRs were 9.57 (7.90-11.59) for cigarettes only, as compared to 4.76 (3.44-6.59) for pipes/cigars only. Mixed smokers tended to have similar risks to cigarette only smokers. Interpretation of this finding is difficult as mixed smokers and cigarette only smokers may have a different total exposure to tobacco, as well as a different cigarette consumption. Data on the types of cigars or pipes smoked have not been recorded on the database, but the increased risk is evident in each continent. The results for pipes and cigars mainly apply to males and to RRs for all lung cancer. Though there are only limited results by histological type, it is interesting that there is no indication of an increased risk of adenocarcinoma for pipe and cigar smokers.
Type of cigarette smoked
The conclusions drawn from the results in Table
Comparisons between filter and plain smoking are made more difficult by the variety of ways in which different reports present their results, but based on the index most closely equivalent to only filter vs. only plain, the present report shows a reduction in risk that is significant for all lung cancer (0.69, 95% CI 0.61-0.78) and for squamous (0.52, 0.40-0.68), though not for adeno (0.84, 0.66-1.08). Significant reductions in risk for all lung cancer and squamous, but not for adeno were also evident for the alternative comparisons ever filter vs. only plain, and only filter vs. ever plain. Our analyses were based on most-adjusted RR estimates, with many of the estimates adjusted for other aspects of smoking, such as number of cigarettes smoked. In 2001, a National Cancer Institute monograph
Our conclusions of a higher RR in handrolled vs. manufactured cigarette smokers is consistent with that of the 2001 review
Our review also found no difference in risk between smokers of mentholated and non mentholated cigarette smokers, though based on data from only three studies, only one of which provided results by histological type. Though no more recent studies have reported results by histological type, five further studies have reported results for all lung cancer, and a recently published systematic review
Dose–response relationships
We have investigated the relationship of lung cancer risk to various indices of the dose–response relationship. We did not record data on our database for pack-years, as we wished to investigate the separate roles of daily amount smoked and duration of smoking. Indeed, previous work (e.g.
Derivation of RRs
Almost a third of RRs used in meta-analyses were not directly available from the source or calculated directly from cross-tables of exposure by outcome, and required more complex methods to derive the required RR. It was reassuring that whether or not the RR was derived did not (with one minor exception) add predictive power to the main meta-regression models, suggesting that our extensive use of derived RRs caused no material bias.
Effect of studies with high RRs or large weight
The statistical analyses investigated the role of various characteristics on the estimated risk of all lung cancer, squamous and adeno in relation to ever and current smoking, but generally did not formally test the effect of exclusion of specific studies with extreme RRs or large weights. An exception was the case of study LIU4 for ever smoking and all lung cancer, this study not giving data for current smoking or by histological type. The two sex-specific RRs for this study together contributed 50.9% of the weight for the 328 available RRs from all the studies, and its exclusion increased the overall fixed-effect RR from 4.22 (95% CI 4.16-4.28) to 6.47 (95% 6.34-6.60). However there was little difference in the random-effects estimates, and in the meta-regression analysis the two LIU4 RRs did not produce unusual standardized residuals, suggesting that the relatively low RRs from this study (2.76, 2.69-2.83 for males, and 2.86, 2.77-2.95 for females), were due to the characteristics of the study included in the model (in particular that it was conducted in China) and not due to its unusual results. While there are other large studies, none involved nearly as many lung cancer cases as LIU4, and we feel it unlikely that excluding other specific studies would have had a major effect on our meta-analysis estimates or on our conclusions as to how RRs varied by exposure, outcome and study and RR characteristics.
We did not exclude studies on the basis of the population studied. However, most studies include subjects broadly representative of the general population. A small number of studies were conducted in miners or in other occupations with a known or suspected lung cancer risk, such as welding or foundry working. Risky occupation was considered as a characteristic in the meta-regression models but was never found to be an independent predictor of RRs associated with ever or current smoking.
Publication bias
It is well known that researchers are more likely to wish to publish, and editors more likely to accept for publication, studies finding a statistically significant association between exposure and disease. The published literature may therefore overstate any true association or produce a false-positive relationship. As part of each meta-analysis we have carried out Egger's test of publication bias, though results are generally shown only in the detailed tables. While evidence for such bias generally is mixed, the results for all lung cancer suggest that, where significant bias is seen, it is not in the direction of smaller studies with lower-weight RRs producing higher RRs. Rather it is, as noted above, the larger studies that tend to produce higher RRs. The reason for this finding is unclear. It should also be noted that our analyses are based only on those studies satisfying the inclusion criteria, and that one of these criteria restricted attention to studies with at least 100 lung cancer cases.
We have not attempted to try to correct for publication bias for four reasons. Firstly, we feel that evidence for its existence is not strong. Second, any adjustment for it seems unlikely to affect our main conclusions. Third, any adjustment for it would be complicated by the restriction on study size. Finally, any correction for publication bias would be open to question, as it inevitably involves assumptions that are impossible to verify.
Bias due to misclassification of smoking status
Another source of bias is misclassification of smoking status. Random misclassification would dilute the association, as would any tendency for cases to deny or understate their smoking more than for the general population. Any tendency for current smokers to claim to be ex-smokers, as might happen in a study conducted in a clinical setting or where patients have been advised to stop smoking, would tend to inflate the risk for ex smoking. Adjustment for misclassification would be difficult, as denial rates are likely to vary by aspects of the study design, the way questions are asked, and also by sex, age, location and other demographic variables.
This review has various limitations, many unavoidable. Lack of access to individual subject data limits the ability to carry out meta-analyses using similar exposure indices and confounder adjustment throughout, but obtaining such data was not feasible given many studies were conducted years ago. Obtaining a reliable definition of outcome and exposure is often hindered by incomplete information in the source papers. We do not consider that limiting attention to studies of 100 cases or more is of particular importance as results from smaller studies would contribute little weight to the overall meta-analyses. Limiting attention to studies conducted up to 1999 may be more relevant for some exposures and issues (particularly the trend in RR over time), though we feel that our consideration of data from 287 published studies should give a very reliable overall picture. The problem is that the procedures conducted for this review were extremely time-consuming and it would take some years to update the database and include smaller and more recent studies.
It may also be argued that the analyses presented here do not make full use of all the data collected. This is inevitable, given the extensive amount of information collected and the need to present the findings in a paper of reasonable length. As noted, when discussing dose–response, we do plan further analyses. We would also be willing to make the database available to
After excluding studies involving less than 100 lung cancer cases, we identified 287 epidemiological studies of lung cancer which provided information on risk in relation to one or more of a defined list of smoking indices
Another conclusion is that RR estimates for ever, current or ex smoking of any product (or cigarettes if not available) are clearly elevated for all three outcomes. Individual study RRs virtually all exceed 1.0, and based on random-effects meta-analyses of most-adjusted RRs, increases were seen for ever smoking (all lung cancer 5.50, CI 5.07-5.96, n = 328 RRs; squamous, 10.47, 8.88-12.33, n = 102; adeno 2.84, 2.41-3.35, n = 107), current smoking (all lung cancer 8.43, 7.63-9.31; squamous 16.91, 13.14-21.76; adeno 4.21, 3.32-5.34) and ex smoking (all lung cancer 4.30, 3.93-4.71; squamous 8.74, 6.94-11.01; adeno 2.85, 2.20-3.70). For all lung cancer, RRs were also elevated for cigarettes only smokers (ever smoking 6.36, 5.33-7.59) and mixed smokers of cigarettes and pipes/cigars (7.37, 5.97-9.11), though lower for smokers of pipes/cigars only (2.92, 2.38-3.57), pipes only (3.31, 2.51-4.35) and cigars only (2.95, 1.91-4.56). While pipe and cigar smoking is associated with an increased risk for squamous, there is no increase for adeno. The consistency and strength of the relationships are consistent with a causal relationship (except for pipe and cigar smoking and adenocarcinoma). A causal relationship is also supported by the fact that estimates are generally not materially affected by adjustment for confounding variables, and by the strong evidence of a dose–response relationship, with RRs for all outcomes clearly increasing with amount smoked, duration and earlier starting age, and decreasing with time quit, and for all lung cancer increasing with tar level and fraction smoked. Relationships were also clearly seen between smoking and RRs for the other major histological types, small cell carcinoma and large cell carcinoma.
Our review also provides evidence that risk varied by type of cigarette smoked, with filter cigarette smokers having lower risks than plain cigarette smokers (a conclusion not explained by "over-adjustment" for amount smoked), and that handrolled cigarette smokers have higher risks than manufactured cigarette smokers, though mentholation of cigarettes seems unrelated to risk. It also shows that various characteristics of the study and of the RR affect risk estimates. Thus RRs were generally highest for studies in North America and lowest for Asia, particularly in China, and higher in later starting, larger and prospective studies. RRs were also somewhat higher in males than in females, though this may be related to differences in their detailed smoking habits. There is no clear tendency for the smoking/lung cancer relationship to vary with age.
This comprehensive review provides further insight into the relationship of smoking to lung cancer and its major histological types.
CI: Confidence Interval; d.f: Degrees of Freedom; H: Heterogeneity Statistic (Ratio of deviance to degrees of freedom); LCL: Lower Confidence Limit; n: number of estimates included in meta-analysis; OR: Odds Ratio; REF: 6 character Reference code used to identify a study; RR: Relative Risk (used also to indicate any effect estimate including Odds Ratio and Hazard Ratio); UCL: Upper Confidence Limit.
Competing interests
PNL, founder of P.N.Lee Statistics and Computing Ltd., is an independent consultant in statistics and an advisor in the fields of epidemiology and toxicology to a number of tobacco, pharmaceutical and chemical companies. This includes Philip Morris Products S.A., the sponsor of this study. BAF and KJC are employees of P.N.Lee Statistics and Computing Ltd.
Authors' contributions
BAF and PNL were responsible for planning the study. Literature searches were carried out by KJC with the assistance of PNL and BAF. Data entry was either carried out by KJC and checked by BAF, or carried out by BAF and checked by PNL. Where appropriate, difficulties in interpreting published data or in the appropriate methods for derivation of RRs were discussed by BAF and PNL. The statistical analyses were conducted by BAF along lines discussed and agreed with PNL. PNL and BAF jointly drafted the paper, which was then critically reviewed by KJC. All authors read and approved the final manuscript.
This research was funded by Philip Morris Products S.A. However the opinions and conclusions of the authors are their own, and do not necessarily reflect the position of Philip Morris Products S.A. We thank John Fry for assistance with the statistical analysis. We also thank Pauline Wassell, Diana Morris and Yvonne Cooper for assistance in typing the various drafts of the paper and obtaining the relevant literature.
Tabakmißbrauch und Lungencarcinom
Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. A study of 684 proved cases
A study of the aetiology of carcinoma of the lung
Tobacco smoke carcinogens and lung cancer
Tobacco smoking and cancer: a meta-analysis
Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis
Meta-analysis of disease risk associated with smoking, by gender and intensity of smoking
Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema
Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: a critique
Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category
Simple methods for checking for possible errors in reported odds ratios, relative risks and confidence intervals
Measuring inconsistency in meta-analyses
Bias in meta-analysis detected by a simple, graphical test
Lung cancer rates in men and women with comparable histories of smoking
Systematic review of the epidemiological evidence comparing lung cancer risk in smokers of mentholated and unmentholated cigarettes
Possible effects on smokers of cigarette mentholation: A review of the evidence relating to key research questions
Does use of flue-cured rather than blended cigarettes affect international variation in mortality from lung cancer and COPD?
Smoking vs other risk factors as the cause of smoking-attributable deaths. Confounding in the courtroom
Lung cancer and type of cigarette smoked
Fifty years' experience of reduced-tar cigarettes: what do we know about their health effects?
Does increased cigarette consumption nullify any reduction in lung cancer risk associated with low-tar filter cigarettes?
Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers
Relative risk of pulmonary cancer in cigar and pipe smokers
Lungenkrebs in alpinem ländlichem Gebiet ohne Luftverschmutzung
Prospektív epidemiológiai vizsgálat a tüdőrák rizikócsoportok meghatározására (1975–1994). (Prospective epidemiologic study for the determination of lung cancer risk groups (1975–1994))
Dohányzás és halálozás: longitudinális epidemiológiai vizsgálat (1975–1991). (Smoking and mortality: a longitudinal epidemiological study (1975–1991))
Lung cancer and cigarette smoking in women. A case–control study in Barcelona (Spain)
Analysis of cancer risk related to longitudinal information on smoking habits
Relationship of cigarette smoking and radiation exposure to cancer mortality in Hiroshima and Nagasaki
Passive smoking and lung cancer among Japanese women
Ionizing radiation and lung cancer: a review including preliminary results from a case–control study among A-bomb survivors
Risks of lung cancer, chronic bronchitis, ischaemic heart disease, and stroke in relation to type of cigarette smoked
Silicosis and lung cancer in U.S. metal miners
Does coal mine dust present a risk for lung cancer? A case–control study of U.S. coal miners
Does coal workers' pneumoconiosis predict to lung cancer? Some evidence from a case–control study
Association of family history of cervical, ovarian, and uterine cancer with histological categories of lung cancer: the Iowa Women's Health Study
Association of body mass index and body fat distribution with risk of lung cancer in older women
Association of incident lung cancer with family history of female reproductive cancers: The Iowa women's health study
Vegetables, fruit, and lung cancer in the Iowa Women's Health Study
Respiratory disease mortality among uranium miners
Uranium mining and cigarette smoking effects on man
Lung cancer among uranium miners in the United States
Radiation, smoking and height relationships to lung cancer in uranium miners
Development of carcinoma of the lung as reflected in exfoliated cells
Lung cancer mortality among U.S. uranium miners: a reappraisal
Cigarette smoking and male lung cancer risk with special regard to type of tobacco
A case–control study of lung cancer at a foundry and two engine plants
Retrospective follow-up study of foundry and engine plant workers
Indoor radon exposure and risk of lung cancer: a nested-case–control study in Finland
Re: Indoor radon exposure and risk of lung cancer: a nested case–control study in Finland
Re: Indoor radon exposure and risk of lung cancer: a nested case–control study in Finland
Indoor radon exposure and risk of lung cancer: a nested case–control study in Finland [Erratum letter]
Indoor radon exposure and active and passive smoking in relation to the occurrence of lung cancer
Lung cancer, smoking and diet among Swedish men. International symposium on lifestyle factors and human lung cancer, Guangzhou, China, 12–16 December 1994
Lung cancer, smoking and diet among Swedish men
Dietary factors and lung cancer among men in West Sweden
Pet birds and risk of lung cancer in Sweden: a case–control study
Identification of occupational cancer risks in British Columbia. Part I: methodology, descriptive results, and analysis of cancer risks, by cigarette smoking categories of 15,463 incident cancer cases
Cigarette smoking and histologic type of lung cancer in men
Occupational exposure and lung cancer risk in a coastal area of northeastern Italy
Occupazione e rischio di tumore polmonare nella provincia di Trieste: uno studio caso-controllo. (Occupation and lung cancer risk in the province of Trieste: a case–control study)
Air pollution and lung cancer in Trieste, Italy: spatial analysis of risk as a function of distance from sources
Confronto di metodi di epidemiologia analitica in uno studio caso-controllo su inquinamento atmosferico e tumore polmonare a Trieste. (Comparison of epidemiologic methods in a case–control study of lung cancer and air pollution in Trieste, Italy)
Air pollution and lung cancer in Trieste, Italy
Smoking cessation and nonsmoking intervals: effect of different smoking patterns on lung cancer risk
Occupational and environmental hazards associated with lung cancer
Ergebnisse zur histologie des bronchialkarzinoms aus einer epidemiologischen untersuchung in Nordrhein-Westfalen und Norddeutschland. (Results of the histology of bronchial carcinoma from an epidemiological study in North Rhine-Westphalia and northern Germany)
Lung cancer and use of cigarettes: A French case–control study
Lung cancer risk associated with cigar and pipe smoking
Lung cancer and women: results of a French case–control study
Changes in patterns of cigarette smoking and lung cancer risk: results of a case–control study
Differential effects of tar content, type of tobacco and use of a filter on lung cancer risk in male cigarette smokers
The effect of age at smoking initiation on lung cancer risk [Letter]
What determines mortality risk in male former cigarette smokers?
Cigarettes, lung cancer, and coronary heart disease: the effects of inhalation and tar yield
Inequalities in death - specific explanations of a general pattern?
Carbon monoxide yield of cigarettes and its relation to cardiorespiratory disease
Black (air-cured) and blond (flue-cured) tobacco and cancer risk VI: lung cancer
Statistical analysis of a case control and cohort study of cigarette smoking and lung cancer in the west of Scotland [Abstract]
A Canadian study of mortality in relation to smoking habits - a preliminary report
A Canadian study of smoking and health, second report
Summary of a Canadian study of smoking and health
Investigations on the personality of patients with pulmonary carcinomas compared to a control group
Lung cancer after employment in shipyards during World War II
Occupation and the high risk of lung cancer in Northeast Florida
Lung cancer in motor exhaust-related occupations
Proportion of lung cancers in males, due to occupation, in different areas of the USA
Lung cancer among long-term steel workers
Cigar and pipe smoking and lung cancer risk: a multicenter study from Europe
CYP1A1 genetic polymorphisms, tobacco smoking and lung cancer risk in a French Caucasian population
The Philadelphia Pulmonary Neoplasm Research Project; basic risk factors of lung cancer in older men
Cigarettes, cough, and cancer of the lung
The clinician looks at lung cancer
Risk of lung cancer according to histologic type and cigarette dosage
Occupations and cigarette smoking as factors in lung cancer
Industrial aspects of bronchiogenic neoplasms
Smoking habits of men employed in industry, and mortality
Genotype and phenotype of glutathione S-transferase class μ isoenzymes μ and ψ in lung cancer patients and controls
Risks of lung cancer in smokers who switch to filter cigarettes
Effect of filter cigarettes on the risk of lung cancer
Risk factors for adenocarcinoma of the lung
Gender and histologic type variations in smoking-related risk of lung cancer
Cancer of the lung and Los-Angeles-type air pollution. Prospective study
The causes of lung cancer in Texas
Lung cancer risk associated with cancer in relatives
Lung cancer mortality among women employed in high-risk industries and occupations in Harris County, Texas, 1977–80
Smoking-related risk factors for lung cancer by cell type among women in Texas [Abstract]
Environmental associations with lung cancer in Texas coastal counties
Occupation and lung cancer risk. An analysis by histologic subtypes
Diet and lung cancer risk: findings from the Western New York Diet Study
Polymorphism of glutathione S-transferase M1 and lung cancer risk among African-Americans and Caucasians in Los Angeles County, California
Genetic polymorphism of
Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles County
Lung cancer risk in African-Americans in relation to a race-specific CYP1A1 polymorphism
Alcoholic beverage consumption and lung cancer risk among residents of Los Angeles County
Mentholated cigarette smoking and lung-cancer risk
Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer
Mortality in relation to cigarette and pipe smoking: 16 years' observation of 25,000 Swedish men
Cancer incidence in female smokers: a 26-year follow-up
Are male and female smokers at equal risk of smoking-related cancer: evidence from a Swedish prospective study
Bronchial cancer in Hong Kong 1976–1977
Low plasma cholesterol predicts an increased risk of lung cancer in elderly women
Lung cancer and occupational risk factors in Greece
Epidemiologic characteristics and multiple risk factors of lung cancer in Taiwan
A case–control study of lung cancer death cases in Guangzhou
Combined analysis of case–control studies of smoking and lung cancer in China. International symposium on lifestyle factors and human lung cancer, Guangzhou, China, 12–16 December 1994
A study of lung cancer risks in Zhengzhou
Smoking and lung cancer in China: combined analysis of eight case–control studies
A case–control study of malignant and non-malignant respiratory disease among employees of a fibreglass manufacturing facility
A case–control study of malignant and non-malignant respiratory disease among employees of a fiberglass manufacturing facility. II. Exposure assessment
A case–control study on risk factors in lung cancer
A cohort study of tobacco use, diet, occupation, and lung cancer mortality
Lung cancer: a prospective study of smoking, occupation, and nutrient intake
A prospective study of the attributable risk of cancer due to cigarette smoking
Prospective study of pulmonary function and lung cancer
The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, α-tocopherol, selenium, and total peroxyl radical absorbing capacity
Cancer of the lung in Rhodesian blacks
The causes of lung cancer in Louisiana
Recent case–control studies of lung cancer in the United States
Dietary vitamins A and C and lung cancer risk in Louisiana
Epidemiology of bronchioloalveolar carcinoma
The American Cancer Society cancer prevention study I: 12-year follow-up of 1 million men and women
Disease consequences of cigar smoking
"Tar" and nicotine content of cigarette smoke in relation to death rates
Lung cancer risk is proportional to cigarette tar yield: evidence from a prospective study
Smoking habits and air pollution in relation to lung cancer
Matched groups analysis method
Smoking in relation to the death rates of one million men and women
Smoking and cancer in the United States
Smoking in relation to mortality and morbidity. Findings in first thirty-four months of follow-up in a prospective study started in 1959
Evidence on the effects of giving up cigarette smoking
Air pollution, smoking, and health
Prospective studies on smoking in relation to death rates
Smoking habits and disease in Illinois
Smoking habits… … and health in Kansas and other Central States
Smoking habits and health in Maryland and neighboring states
Smoking habits and disease in Pennsylvania
Smoking habits and disease in New York State
Smoking habits and health in Indiana and neighboring states
Smoking habits and health in Georgia and other southern states
Smoking habits and disease in Ohio
Smoking habits and disease in Missouri
Smoking habits and disease
Excess mortality among cigarette smokers: changes in a 20-year interval
Changes in mortality from smoking in two American Cancer Society prospective studies since 1959
Trends in tobacco smoking and mortality from cigarette use in cancer prevention studies I (1959 through 1965) and II (1982 through 1988)
Cigarette smoking and changes in the histopathology of lung cancer
Age and the exposure-response relationships between cigarette smoking and premature death in Cancer Prevention Study II
Cigar smoking in men and risk of death from tobacco-related cancers [Abstract of the 32nd Annual Society for Epidemiologic Research Meeting, Baltimore, Maryland, June 10–12, 1999]
Particulate air pollution as a predictor of mortality in a prospective study of U.S. adults
Patterns of absolute risk of lung cancer mortality in former smokers
Proportions of cancer deaths attributable to cigarette smoking in women
Smoking and lung cancer in women: findings in a prospective study
Health benefits of smoking cessation
Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States?
Smoking and lung cancer with special regard to type of smoking and type of cancer. A case–control study in northern Sweden
Interaction between underground mining and smoking in the causation of lung cancer: a study of nonuranium miners in northern Sweden
Lung cancer in males and type of dwelling. An epidemiological pilot study
Professional driving, smoking, and lung cancer: a case referent study
Combined effects of mining and smoking in the causation of lung carcinoma: a case–control study in northern Sweden
Underground mining, smoking, and lung cancer: A case–control study in the iron ore municipalities in Northern Sweden
Risk of lung cancer associated with residential radon exposure in south-west England: a case–control study
Lung cancer and tobacco consumption
Smoking and death. Public health measures were taken more than 40 years ago [Letter]
The Nazi war on tobacco: ideology, evidence and possible cancer consequences
Lung cancer and tobacco consumption
Lung cancer among white South Africans: report on a further study
Cigarette smoking as the major cause of lung cancer
Lung cancer and bronchitis in Northern Ireland, 1960–2
Silica, compensated silicosis, and lung cancer in Western Australian goldminers
Mortality in gold and coal miners in Western Australia with special reference to lung cancer
Preliminary study of lung cancer mortality among Western Australian gold miners exposed to silica
Dietary fat and lung cancer: a case–control study in Uruguay
Dietary sugar and lung cancer: a case–control study in Uruguay
Meat consumption and risk of lung cancer; a case–control study from Uruguay
Dietary nitrosodimethylamine and the risk of lung cancer: a case–control study from Uruguay
Occupation and the risk of lung cancer in Uruguay
Fatty foods and the risk of lung cancer: a case–control study from Uruguay
Consumption of tea and coffee and the risk of lung cancer in cigarette-smoking men: a case–control study in Uruguay
Mate drinking and risk of lung cancer in males: a case–control study from Uruguay
Smoking of hand-rolled cigarettes as a risk factor for small cell lung cancer in men: a case–control study from Uruguay
The effect of alcohol on the risk of lung cancer in Uruguay
Type of tobacco and risk of lung cancer: a case–control study from Uruguay
An association between air pollution and mortality in six U.S. cities
Effects of sulfur oxides and respirable particles on human health: methodology and demography of populations in study
Smoking and carcinoma of the lung. Preliminary report
Smoking and carcinoma of the lung
Etiology of lung cancer
The significance of cell type in relation to the aetiology of lung cancer
Mortality in relation to smoking: 40 years' observations on male British doctors
The mortality of doctors in relation to their smoking habits. A preliminary report
Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors
Lung cancer and cigarette smoking
Smoking and lung cancer: Report to the sub-committee for the study of the risks of cancer from air pollution and the consumption of tobacco
Mortality in relation to smoking: ten years' observations of British doctors
Mortality in relation to smoking: ten years' observations of British doctors
Mortality in relation to smoking: 20 years' observations on male British doctors
Mortality among doctors in different occupations
Atmospheric pollution and lung cancer
Mortality in relation to smoking: 22 years' observations on female British doctors
Smoking and death: the past 40 years and the next 40
A prospective cohort study on allium vegetable consumption, garlic supplement use, and the risk of lung carcinoma in the Netherlands
Lung cancer: is there an association with socioeconomic status in The Netherlands?
A large-scale prospective cohort study on diet and cancer in the Netherlands
A prospective cohort study on selenium status and the risk of lung cancer
Race and sex differences in associations of vegetables, fruits, and carotenoids with lung cancer risk in New Jersey (United States)
Occupation and lung cancer risk among New Jersey white males
Case–control study of residential radon and lung cancer among New Jersey Women
Variation in smoking-related lung cancer risk among New Jersey women
Carotenoid intake, vegetables, and the risk of lung cancer among white men in New Jersey
Smoking and lung cancer: risk as a function of cigarette tar content
Epidemiologic studies of vitamins and cancer of the lung, esophagus, and cervix
Smoking and cancer mortality among U.S. veterans: a 26-year follow-up
Former cigarette smoking and mortality among U.S. veterans: a 26-year followup, 1954 to 1980
Smoking and causes of death among US Veterans: 16 years of observation
Smoking and mortality among U.S. veterans
Tobacco consumption and mortality from cancer and other diseases
Tobacco consumption and mortality from cancer and other diseases
The Dorn study of smoking and mortality among U.S. veterans: report on eight and one-half years of observation
Survey of histologic types of primary lung cancer in US veterans
Smoking cessation and mortality trends among two United States populations
Tobacco, alcohol use, and risks of laryngeal and lung cancer by subsite and histologic type in Turkey
Occupational risk factors of lung cancer: a hospital based case–control study
An epidemiological study of risk factors for lung cancer in Guangzhou, China. International symposium on lifestyle factors and human lung cancer, Guangzhou, China, 12–16 December 1994
Indoor and outdoor air pollution and lung cancer
Lung cancer mortality experience of men in certain occupations in California
Screening for lung cancer - results from a case–control study
The impact of smoking habits on lung cancer risk: 28 years' observation of 26,000 Norwegian men and women
Dietary habits and lung cancer risk
Occupational exposure and lung cancer risk
Røking som risikofaktor for ulike kreftformer blant 26000 norske menn og kvinner (Smoking as a risk factor for cancer among 26000 Norwegian males and females)
Smoking cessation and mortality trends among 118,000 Californians, 1960–1997
Epidemiologic study on deaths from lung cancer in Omuta City of Japan. An analysis of the risk factors for lung cancer by a case–control study, especially on the aspects of air pollution, occupation and smoking habits
Study of the relation between smoking as a lifestyle factor and lung cancer in Beijing area of China
Lung cancer and smoking in Shanghai
Lung cancer among Chinese women
A case–control study of lung cancer among women in Shanghai
Tobacco smoking and its effect on health in China
A case–control study of lung cancer in Shanghai
A case–control study of lung cancer and pulmonary tuberculosis
Lung cancer and prior tuberculosis infection in Shanghai
Decreased risk of lung cancer in the cotton textile industry of Shanghai
Protective effects of raw vegetables and fruit against lung cancer among smokers and ex-smokers: a case–control study in the Tokai area of Japan
Case–control studies: matched controls or all available controls?
A case–control study of cytochrome P450 1A1, glutathione S-transferase M1, cigarette smoking and lung cancer susceptibility (Massachusetts, United States)
Cytochrome P450 CYP1A1 MspI polymorphism and lung cancer susceptibility
Association of cigarette smoking and asbestos exposure with location and histology of lung cancer
Erratum re 'A case–control study of cytochrome P450 1A1, glutathione S-transferase M1, cigarette smoking and lung cancer susceptibility (Massachusetts, United States)'
The relationship between avian exposure and bronchogenic carcinoma
Avian exposure and bronchogenic carcinoma
A case–control study of lung cancer and diesel exhaust exposure in railroad workers
On the relationship between cigarette smoking and female lung cancer
Risk factors of lung cancer by histological category in Taiwan
Risk factors of lung cancer
Cigarette smoking and male lung cancer in an area of very high incidence. I. Report of a case–control study in the West of Scotland
Cigarette smoking, social factors, and mortality: new estimates from representative national samples Thesis
Cigarette smoking status - June 1966, August 1967, and August 1968
Local variation in the incidence of lung cancer and bronchitis mortality
The effect of dietary cholesterol and fat on the risk of lung cancer in Hawaii
High-fat foods and the risk of lung cancer
Smoking withdrawal in the reduction of risk of lung cancer
Comparison of dietary histories in lung cancer cases and controls with special reference to vitamin A
Klinische Studien zur Aetiologie des Bronchialkarzinoms. (Clinical studies of the aetiology of bronchial cancer)
Cigar and pipe smoking in relation to lung cancer and excess mortality
A case–control study on the relationship between smoking and genetic background and lung cancer
A retrospective study of lung cancer in women
Asbestos exposure, cigarette smoking and death rates
Relation of cigarette smoking to risk of death of asbestos-associated disease among insulation workers in the United States
Recent perspectives in occupational cancer
Asbestos and lung cancer: an analysis of the epidemiological evidence on the asbestos-smoking interaction
Cancer following occupational exposure to asbestos and vinyl chloride
Smoking and death rates - Report of forty-four months of follow-up of 187,783 men II. Death rates by cause
The relationship between human smoking habits and death rates: A follow up-study of 187,766 men
Smoking and death rates - report on forty-four months of follow-up of 187,783 men I. Total mortality
Smoking and death rates - a riddle in cause and effect
Cigarette smoking and disease
Smoking in relation to lung cancer and other causes of death, Chap 22
The effects of smoking
Inhalation of tobacco smoke
Cancer incidence among mild steel and stainless steel welders and other metal workers
Lung cancer mortality in stainless steel and mild steel welders: a nested case-referent study
The effect of age at smoking initiation on lung cancer risk
The effect of age at smoking initiation on lung cancer risk [Abstract]
Lung cancer risk and social class. The Copenhagen Male Study--17-year follow up
Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease
Preliminary report: findings from the aspirin component of the ongoing Physicians' Health Study
Differences in lung cancer risk from smoking among Japanese, Chinese and Hawaiian women in Hawaii
The significance of the smoking factor in the epidemiology of the cancer of the lung
Proportion of cancer attributable to occupation obtained from a cencus, population-based, large cohort study in Japan
Cigarette smoking and cancer mortality risk in Japanese men and women - results from reanalysis of the Six-Prefecture Cohort study data
Strategy for cancer epidemiology
Epidemiology of lung cancer based on population studies
Prospective studies on cancer epidemiology based on census population in Japan
Smoking and cancer: A prospective study on cancer epidemiology based on a census population in Japan
Prospective studies on cancer epidemiology based on census population in Japan
Diet and cancer
Smoking and cancer in Japan. A prospective study on cancer epidemiology based on census population in Japan. Results of 13 years follow up
Operational epidemiology of cancer
Cohort studies on smoking and mortality in Japan
Health effects of active and passive smoking
Lung cancer in Japan: effects of nutrition and passive smoking
Epidemiological study of lung cancer with special reference to the effect of air pollution and smoking habit
Cigarette smoking and male lung cancer in an area of very high incidence. II. Report of a general population cohort study in the West of Scotland
The effect of environmental tobacco smoke in two urban communities in the west of Scotland
Tuberculosis, respiratory and cardiovascular risks of dying in the Renfrew district of Scotland
Passive smoking and cardiorespiratory health in a general population in the west of Scotland
Smoking and health: the association between smoking behaviour, total mortality, and cardiorespiratory disease in west central Scotland
Lung cancer among the Jews
An ecogenetic hypothesis for lung cancer in women
A case–control study of diet and lung cancer in northeast China
Research on causes of lung cancer: case–control study of 523 cases of lung cancer
An analysis of risk factors of lung cancer in Harbin city
A case–control study of dietary factors in patients with lung cancer
Cigarette smoking and lung cancer in 'Hispanic' whites and other whites in New Mexico
Determinants of lung cancer risk in cigarette smokers in New Mexico
Lung cancer risk and vitamin A consumption in New Mexico
Determinants of lung cancer risk in cigarette smokers [Abstract]
Marriage to a smoker and lung cancer risk
Lung cancer at autopsy in A-bomb survivors and controls, Hiroshima and Nagasaki, 1961–1970. II. Smoking, occupation, and A-bomb exposure
Lung cancer at autopsy in A-bomb survivors and controls, Hiroshima and Nagasaki, 1961–70. I. Autopsy findings and relation to radiation
Occupational risk factors for lung cancer: a case–control study in West Germany
The relation between various histological types of lung cancer and the number of years since cessation of smoking
Lung cancer risk and welding - preliminary results from an ongoing case–control study
Occupational life course and lung cancer risk in men. Findings from a socio-epidemiological analysis of job-changing histories in a case–control study
Lung cancer risk and welding: results from a case–control study in Germany
Are female smokers at higher risk for lung cancer than male smokers? A case–control analysis by histologic type
Are female smokers at higher risk for lung cancer than male smokers? [Abstract]
Dietary factors and risk of lung cancer: results from a case–control study, Toronto, 1981–85
Arsenic exposure, smoking, and lung cancer in smelter workers - a case–control study
On the interaction between occupational arsenic exposure and smoking and its relationship to lung cancer
Lung cancer, smoking and smelter work in an occupational cohort
Quantitative importance of asbestos as a cause of lung cancer in a Swedish industrial city: a case-referent study
Effect of tobacco smoking on various histological types of lung cancer
A case–control study of lung cancer with special reference to the effect of air pollution in Poland
Lung cancer, smoking and employment in foundries
Łączny wpływ palenia tytoniu, czynników zawodowych i zanieczyszczeń powietrza atmosferycznego na ryzyko raka oskrzela. Wyniki badań retrospektywnych w Krakowie (Joint influence of the tobacco smoking, occupational factors and atmospheric air pollution on the risk of bronchial cancer. Results of the retrospective investigations in Cracow)
Badania kliniczno-kontrolne nad rakiem płuc. Palenie tytoniu i zatrudnienie w przemyśle metalurgicznym. (A case control study on lung cancer: smoking and employment in foundries)
Wpływ palenia tytoniu na powstawanie różnych typów histologicznych raka płuca. (Effect of smoking on development of different histological types of lung cancer)
A case–control study of 125 lung cancer cases in Nanchang
A case–control study of air pollution and tobacco smoking in lung cancer among women in Athens.
Lung cancer in Greater Bombay: correlations with religion and smoking habits
Smoking and mortality: the Kaiser Permanente experience
A prospective study of cigarette tar yield and lung cancer
Mentholated cigarette use and lung cancer
Epidemiologic evidence of an association between body iron stores and risk of cancer
Forced expiratory volume (1 second) and lung cancer incidence and mortality
The relationship between smoking of Greek cigarettes and the development of lung cancer
Incidence and distribution of lung cancer in Greece
A case–control study of air pollution and tobacco smoking in lung cancer among women in Athens
Tar content of cigarettes in relation to lung cancer
Risk factors for lung cancer among nonsmoking Illinois residents
Effect of cigarette smoking on major histological types of lung cancer in men
Distribution of GSTM1 null genotype in relation to gender, age and smoking status in Japanese lung cancer patients
Lung cancer risk of the GSTM1 null genotype is enhanced in the presence of the GSTP1 mutated genotype in male Japanese smokers
Tea consumption and cancer
A case-referent study of lung cancer, occupational exposures and smoking: I Comparison of title-based and exposure-based occupational information
A case-referent study of lung cancer, occupational exposures and smoking: II Role of asbestos exposure
A case-referent study of lung cancer, occupational exposures and smoking. III Etiologic fraction of occupational exposures
Vitamin E and smoking and the risk of lung cancer
Dietary cholesterol, fatty acids, and the risk of lung cancer among men
Leanness and lung-cancer risk
Dietary flavonoids and the risk of lung cancer and other malignant neoplasms
Dietary antioxidants and the risk of lung cancer
Risk factors for primary lung cancer among non-smoking women in Taiwan
Pet birds as an independent risk factor for lung cancer: case–control study
Is passive smoking an added risk factor for lung cancer in Chinese women?
Passive smoking is a risk factor for lung cancer in never smoking women in Hong Kong
Active and passive smoking among female lung cancer patients and controls in Hong Kong
An analysis of some risk factors for lung cancer in Hong Kong
Do cooking fuels pose a risk for lung cancer? A case–control study of women in Hong Kong
Smoking and pulmonary carcinoma
Risk factors for lung cancer in young adults
The German radon project - feasibility of methods and first results
Occupational risk factors for lung cancer in women: results of a case–control study in Germany
Lung cancer and tobacco smoking in Norway
The significance of histological typing in the study of the epidemiology of primary epithelial lung tumours: A study of 466 cases
A study of tobacco smoking in Norway
The influence of smoking and other etiopathogenetic factors on the incidence of bronchogenic carcinoma and chronic nonspecific respiratory diseases
Screening for lung cancer high-risk groups
Smoking, passive smoking and histological types in lung cancer in Hong Kong Chinese women
A clinical and epidemiological study of carcinoma of lung in Hong Kong Thesis
Clinical features of bronchogenic carcinoma in Hong Kong: review of 480 patients
Relationship of the type of tobacco and inhalation pattern to pulmonary and total mortality
Tobak, lungekraeft og kronisk obstruktiv lungesygdom. Resultater fra Osterbroundersøgelsen. (Tobacco, lung cancer and chronic obstructive lung disease. Results from the Osterbro study)
Ventilatory function and chronic mucus hypersecretion as predictors of death from lung cancer
Mortality in relation to the type of tobacco smoked [Abstract]
Serological evidence of an association between
Predictive value of current cigarette smoking, pack years and tar exposure in the estimation of lung cancer risk [Abstract]
Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers
Zur kombinierten Wirkung von beruflicher Tätigkeit im Uranerzbergbau, Silikoseerkrankung und Tabakrauchen auf das Lungenkrebsrisiko bei Männern. Eine Fall-Kontroll-Studie im Kreis Aue/Sachsen. Vorläufige Ergebnisse. (Combined effects of employment in uranium ore mines, silicosis, and tobacco smoking on the lung cancer risk in men. A case–control study in the county Aue/Saxony. Preliminary results)
Some lifestyle factors in human lung cancer: a case–control study of 792 lung cancer cases. International symposium on lifestyle factors and human lung cancer, Guangzhou, China, 12–16 December 1994
Associations of
Case–control study of residential radon and lung cancer in Winnipeg, Manitoba, Canada
Etiology of lung cancer: present status
Cancer and tobacco smoking. A preliminary report
Smoking and lung cancer: a review
Mortality attributable to cigarette smoking in Taiwan: a 12-year follow-up study
Der Tabakrauch als Ursache des Lungenkrebses. Spezieler Teil IV. Atiologie und Prophylaxe des Lungenkrebses. (Tobacco smoke as a cause of lung cancer. Special section IV.)
The 1891–1920 birth cohort of Quebec chrysotile miners and millers: mortality 1976–88
Methods of cohort analysis: appraisal by application to asbestos mining
Fibre exposure and mortality from pneumoconiosis, respiratory and abdominal malignancies in chrysotile production in Quebec, 1926–75
Dust exposure and lung cancer in Quebec chrysotile miners and millers
Dust exposure and mortality in chrysotile mining, 1910–75
A study on the relation between indoor exhaust and lung cancer
Indoor air pollution and lung cancer in Guangzhou, People's Republic of China
Smoking and other risk factors for lung cancer in Xuanwei, China
A case–control study of lung cancer risk factors in Xuanwei
An epidemiological study of lung cancer in Xuan Wei County, China: Current progress. Case–control study on lung cancer and cooking fuel
Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths
The survey of smoking and 111 lung cancer cases
An epidemiological study of lung cancer among females
An epidemiological study in lung cancer
An epidemiological study of lung cancer
Risk of lung cancer among cigarette and pipe smokers in southern China