Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer

BMC Cancer201212:385

DOI: 10.1186/1471-2407-12-385

Received: 4 January 2012

Accepted: 18 July 2012

Published: 3 September 2012

Abstract

Background

Smoking is a known lung cancer cause, but no detailed quantitative systematic review exists. We summarize evidence for various indices.

Methods

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”).

Results

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.

Conclusions

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.

Background

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 [1], and in the United States and Great Britain [2, 3] in the 1950s, and was strengthened by surveys of large cohorts. This led the US Surgeon General to conclude in 1964 [4] that “cigarette smoking is a cause of lung cancer in men, and a suspected cause of lung cancer in women”. Further reports [5, 6] have defined the relationship in more detail, and it has been estimated that, in the United States, 90% of male lung cancer deaths and 75%-80% of female lung cancer deaths are caused by smoking [7].

While some meta-analyses of the evidence have been published in recent years [810] none consider more than a relatively small fraction of the published evidence. We attempt to rectify this omission, though the sheer extent of the available data, and resources available, has meant limiting attention to papers published in the last century and studies involving over 100 lung cancer cases. As will be seen, this still gives us an extensive database involving almost 300 studies.

Because the relationship of smoking to the two major types of lung cancer (squamous cell carcinoma and adenocarcinoma) is known to vary [5, 6], we present detailed results relating, not only to total lung cancer risk, but also to these two histological types of lung cancer. We also present some more limited results for other lung cancer types. To provide a broad description of the relationship of smoking to lung cancer, we do not concentrate on a single primary analysis, but quantify the relationships to each of a range of indices of smoking, investigating how these relationships vary according to characteristics such as sex, age, location, study design, period considered, definition of exposure and extent of confounder adjustment. The style of this systematic review is similar to one we have recently published for smoking and COPD, chronic bronchitis and emphysema [11].

Methods

Full details of the methods used are described in Additional file 1: Methods, and are summarized below. Throughout this paper, we use the term relative risk (RR) to include its various estimators, including the odds ratio and the hazard ratio.

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 2: Studies. The first category involved minor overlap, which could not be disentangled, and which it was decided to ignore. The second category contains sets of studies which probably or definitely overlap. Here the set member containing the most comprehensive data (e.g. largest number of cases or longest follow-up) was called the ‘principal study’, other members being ‘subsidiary studies’ only considered in meta-analyses where the required RR was unavailable from the principal study.

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 1: Methods). If available, results (for each of current, ex and ever smoking) were entered for five comparisons: any product vs. never any product, cigarettes vs. never any product, cigarettes only vs. never any product, cigarettes vs. never cigarettes, and cigarettes only vs. never cigarettes (and also for five equivalent comparisons for current vs non smoking). Here “cigarettes” ignores whether other products (i.e. pipes and cigars) are also smoked, while “cigarettes only” excludes mixed smokers. Additionally, when the numerator related to the smoking of filter, handrolled or mentholated cigarettes, RRs were entered with the denominator defined as relating to plain, manufactured or non-mentholated smokers respectively.

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.

Strata

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. [12]), noting any discrepancies between calculated values and those provided by the author. Sometimes the 2 × 2 table was constructed by summing over groups (e.g. adding current and ex smokers to obtain ever smokers) or from a percentage distribution. Various other methods were used as required to provide estimates of the RR and CI. Some more commonly used methods are summarized below, fuller details being given in Additional file 1: Methods.

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 [13], giving an estimate adjusted for the stratifying variable.

Combining non-independent RRs

The Hamling et al. method [14] was used (e.g. to derive an adjusted RR for ever smokers from available adjusted RRs for current and ex smokers, each relative to never smokers, or to combine adjusted RRs for several histological types, each relative to a single control group).

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 [15].

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 [13], with heterogeneity quantified by H, the ratio of the heterogeneity chisquared to its degrees of freedom, which is directly related to the statistic I2 [16] by the formula I2 = 100 (H-1)/H. For all meta-analyses, Egger’s test of publication bias [17] was also included.

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 1: Methods.

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 1: Methods.

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.

Software

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.

Results

Studies identified

A total of 5,993 potentially relevant papers were identified, providing information on 287 eligible studies (Table 1).
Table 1

Literature searching and study identification

 

N

(%)

Papers

  

Identified as potentially relevant

5993

100%

Not obtainable

244

4.1%

Obtained

5749

95.9%

Did not provide relevant data at all

4901

81.8%

Satisfied inclusion criteria except less than 100 lung cancer cases

175

2.9%

Satisfied all inclusion criteria

673

11.2%

Studies

  

Identified

287

100.0%

Principal

267

93.0%

Subsidiary

20

7.0%

Table 2 presents selected details of the 287 studies while Table 3 gives the distribution of their major characteristics. Additional file 2: Studies gives fuller descriptions of the studies.
Table 2

Selected details of the 287 studies of lung cancer

Study REF

Main ref

Other refs

Brief study descriptiona

Outcome(s)b

Casesc

Full Histd

Princ REFe

ABELIN

[29]

[30]

Switzerland rural CC 1941-64

All

118

No

 

ABRAHA

[31]

[32]

Hungary Budapest cohort 1975-94

All,Sq,Ad

571

No

 

AGUDO

[33]

 

Spain Barcelona area CC 1989-92

All

103

No

 

AKIBA

[34]

[3537]

Japan atomic bomb survivors cohort 1963-87

All

610

No

 

ALDERSf

[38]

[39, 40]

UK CC 1977-82

All,Sq,Ad

1448

No

 

AMANDU

[41]

 

US metal miner cohort 1959-75

All

132

No

 

AMES

[42]

[43]

US 4 NIOSH coal miner cohorts nested CC 1959-75

All

317

No

 

ANDERS

[44]

[4547]

US Iowa Women's Health cohort 1986-94

All,Sq,Ad

343

No

 

ARCHER

[48]

[4953]

US uranium miners cohort 1950-74

All

146

No

 

ARMADA

[54]

 

Spain CC 1986-90

All

325

Yes

 

AUSTIN

[55]

[56]

US Ohio foundry workers CC 1970-86

All

166

No

 

AUVINE

[57]

[5860]

Finland radon CC 1986-92

All

517

No

 

AXELSO

[61]

 

Sweden radon CC 1960-81

All

152

No

 

AXELSS

[62]

[6365]

Sweden 26 municipality CC 1989-93

All

436

No

 

BAND

[66]

 

Canada occupational CC 1983-90

All,Sq,Ad

2831

Yes

 

BARBON

[67]

[6872]

Italy Trieste CC 1979-86

All,Sq,Ad

755

Yes

 

BECHER

[73]

[74, 75]

Germany pilot for BIPS CC 1985-86

All,Sq,Ad

194

Yes

 

BENHAM

[76]

[7781]

France CC 1976-80

All,Sq,Ad

1625

Yes

LUBIN2

BENSHL

[82]

[8385]

UK Whitehall civil servants cohort 1967-87

All

486

No

 

BERRIN

[86]

[87]

Italy CC 1977-80

All

1101

Yes

LUBIN2

BEST

[88]

[8991]

Canada war veteran pensioners cohort 1955-62

All

381

No

 

BLOHMK

[92]

 

Germany Heidelberg personality CC

All

888

Yes

 

BLOT1

[93]

 

US Georgia CC 1970-76

All

458

No

 

BLOT3

[94]

[95, 96]

US Florida CC 1976-79

All

321

No

 

BLOT4

[97]

[96]

US Pennsylvania CC 1974-77

All

335

No

 

BOFFET

[98]

 

West Europe pipe and cigar CC 1988-94

All

5621

No

 

BOUCHA

[99]

 

France Paris CC 1988-92

Sq

150

Yes

 

BOUCOT

[100]

[101103]

US Philadelphia LC Research cohort 1951-65

All,Sq,Ad

121

No

 

BRESLO

[104]

[105]

US California CC 1949-52

All,Sq,Ad

518

Yes

 

BRETT

[106]

 

UK X-ray volunteers cohort 1960-63

All

150

No

 

BROCKM

[107]

 

Germany Berlin CC study 1990-92

All

117

Yes

 

BROSS

[108]

[109]

US Roswell Park Memorial CC study 1960-66

All

974

No

 

BROWN1

[110]

 

US Colorado adenocarcinoma CC 1979-82

Ad

102

Yes

 

BROWN2

[111]

 

US Missouri CC 1984-90

All,Sq,Ad

14596

Yes

 

BUELL

[112]

 

US California American Legion cohort 1957-62

All

304

No

 

BUFFLE

[113]

[114118]

US Texas 6 counties CC 1976-80

All,Sq,Ad

943

No

 

BYERS1

[119]

 

US Roswell Park Memorial CC 1957-65

Sq,Ad

1002

No

BROSS, GRAHAM

BYERS2

[120]

 

US Western New York Diet CC 1980-84

All

448

Yes

 

CARPEN

[121]

[122126]

US California Genetics CC 1991-94

All

356

No

 

CASCO2

[127]

 

Germany Berlin NAT2 Genotyping CC 1991-94

All

155

No

 

CASCOR

[127]

 

Germany Berlin NAT2 Phenotyping CC

All

389

Yes

 

CEDERL

[128]

[129131]

Sweden cohort 1963-89

All

491

No

 

CHAN

[132]

 

Hong Kong 5 hospital CC 1976-77

All,Sq,Ad

397

No

 

CHANG

[133]

 

US California cholesterol cohort 1972-91

All

136

No

 

CHATZI

[134]

 

Greece Athens CC 1987-88

All

282

Yes

 

CHEN

[135]

 

Taiwan Taipai CC

Sq,Ad

323

Yes

 

CHEN2

[136]

[137]

China Guangzhou CC

All

193

No

 

CHEN3

[137]

[138, 139]

China Zhengzhou CC

All

254

No

 

CHIAZZ

[140]

[141]

US Owens-Corning Fiberglass Newark CC 1940-82

All

144

No

 

CHOI

[142]

 

South Korea Cancer Centre CC 1985-88

All,Sq,Ad

375

No

 

CHOW

[143]

 

US Lutheran Brotherhood Ins. cohort 1966-86

All

219

No

 

CHYOU

[144]

[145, 146]

US Hawaii Oahu Japanese cohort 1965-90

All,Sq,Ad

227

Yes

 

COMSTO

[147]

 

US Washington Co Serum Bank nested CC 1975-93

All,Sq,Ad

258

No

 

COOKSO

[148]

 

Zimbabwe-Rhodesia Harare CC 1961-72

All

234

Yes

 

CORREA

[149]

[95, 96, 150152]

US Louisiana CC 1979-82

All,Sq,Ad

1359

No

 

CPSIg

[153]

[154178]

US ACS million person CPSI cohort 1959-72

All,Sq,Ad

5138

No

 

CPSII

[179]

[6, 175178, 180188]

US 2nd ACS cancer prevention cohort 1982-94

All,Sq,Ad

3229

No

 

DAMBER

[189]

[190196]

Sweden North CC 1972-77

All,Sq,Ad

579

No

 

DARBY

[197]

 

UK SW England radon CC 1988-93

All

982

No

 

DAVEYS

[198]

[198201]

Germany Thuringia (Schairer&Schoniger) CC 1930-41

All

109

No

 

DEAN

[202]

[203]

South Africa CC 1947-56

All

603

No

 

DEAN2

[204]

[205]

UK/N Ireland CC 1960-62

All

954

No

 

DEAN3h

[206]

[207]

UK Cleveland Co CC 1969-73

All

766

No

 

DEKLER

[208]

[209, 210]

Australia Kalgoorlie miners cohort 1961-93

All

138

No

 

DESTE2

[211]

[211217]

Uruguay Montevideo CC 1993-96

All,Sq,Ad

463

No

 

DESTEF

[218]

[219221]

Uruguay Montevideo CC 1988-94

All,Sq,Ad

497

Yes

 

DOCKER

[222]

[223]

US Harvard six cities cohort 1974-91

All

120

No

 

DOLL

[3]

[224227]

UK original Doll and Hill CC 1948-52

All,Sq,Ad

1465

No

 

DOLL2i

[228]

[229239]

UK British Doctors cohort 1951-91

All

920

No

 

DORANT

[240]

[241243]

Netherlands case-cohort 1986-89

All

550

Yes

 

DORGAN

[244]

[95, 96, 245250]

US New Jersey CC 1980-83

All,Sq,Ad

2026

Yes

 

DORN

[251]

[252260]

US Veterans cohort 1954-80

All,Sq,Ad

5097

No

 

DOSEME

[261]

 

Turkey Istanbul CC 1979-84

All,Sq,Ad

1210

No

 

DROSTE

[262]

 

Belgium Antwerp CC 1995-97

All

478

Yes

 

DU

[263]

[264]

China Guangzhou CC 1985

All

849

No

 

DUNN

[265]

 

US California 9 occupations cohort 1954-58

All

139

No

 

EBELIN

[266]

 

Germany Berlin (Lichtenberg) CC 1980-85

All

130

No

 

ENGELA

[267]

[268270]

Norway cohort 1964-93

All,Sq,Ad

435

No

 

ENSTRO

[271]

 

US California CPSI cohort 1959-97

All

2879

No

 

ESAKI

[272]

 

Japan Omuta and Arao CC 1961-71

All

245

No

 

FAN

[273]

 

China Sino-MONICA-Beijing Project CC 1990-91

All,Sq,Ad

403

No

 

GAO

[274]

[137, 139, 275281]

China Shanghai CC 1984-86

All,Sq,Ad

1405

No

 

GAO2

[282]

[283]

Japan Tokai diet CC 1988-91

All

282

No

 

GARCIA

[284]

[285287]

US Boston genetics CC 1992-96

All

416

Yes

 

GARDIN

[288]

[289]

UK/Scotland Airdrie avian CC 1988-92

All

143

No

 

GARSHI

[290]

 

US railroad workers diesel CC 1981-82

All

1081

No

 

GENG

[291]

[292]

China Tianjin CC

All

292

No

 

GER

[293]

[294]

Taiwan Tri-Service General Hospital 1990-91

All,Sq,Ad

141

No

 

GILLIS

[295]

[87]

UK/Scotland West CC 1977-81

All,Sq,Ad

656

No

LUBIN2

GODLEY

[296]

[297]

US 1966–68 NMFS & 1967 current pop survey CC

All

1986

No

 

GOLLED

[298]

[299]

UK Teeside CC 1952-62

All

443

No

 

GOODMA

[300]

[301]

US Hawaii CC 1983-85

All

326

Yes

 

GRAHAM

[302]

 

US Roswell Park Memorial CC 1956-60

All

685

No

 

GREGOR

[303]

 

UK Brompton Hospital vitamin A CC 1976-77

All

104

Yes

 

GSELL

[304]

[305]

Switzerland St Gallen CC 1937-54

All

150

Yes

 

GUO

[306]

 

China Quanshan county Jiangsu CC 1984-86

All

196

No

 

HAENSZ

[307]

 

US Multiple hospital CC 1955-57

All,Sq,Ad

158

Yes

 

HAMMO2

[308]

[309312]

US & Canada asbestos workers cohort 1967-76

All

450

No

 

HAMMON

[313]

[314320]

US 9 state cohort 1952-55

All,Sq,Ad

448

No

 

HANSEN

[321]

[322]

Denmark welding companies cohort 1968-86

All

105

No

 

HEGMAN

[323]

[324]

US Utah radon CC 1989-91

All,Sq,Ad

282

Yes

 

HEIN

[325]

 

Denmark Copenhagen Male cohort 1970-88

All

144

No

 

HENNEK

[326]

[327]

US doctors betacarotene trial cohort 1982-95

All

169

No

 

HINDS

[328]

 

US Hawaii CC 1968-78

All,Sq,Ad

292

No

 

HIRAY2

[329]

[330]

Japan Tokyo CC 1950-52

All

145

No

 

HIRAYAj

[331]

[330, 332345]

Japan 6 prefecture cohort 1965-82

All

1917

No

 

HITOSU

[346]

 

Japan Amagaski and Nishinomiya CC 1960-66

All

216

No

 

HOLEk

[347]

[348351]

UK/Scotland Renfrew & Paisley cohort 1972-85

All

225

No

 

HOROWI

[352]

 

Canada Montreal CC 1956-67

All

236

No

 

HORWIT

[353]

 

US Yale/New Haven CC 1977-82

All

112

No

 

HU

[354]

 

China Heilongjiang 5 hospital CC study 1985-87

All

227

Yes

 

HU2

[355]

[137, 139, 356]

China Harbin CC study 1977-79

All

523

No

 

HUANG

[357]

 

China Sichuan CC 1990-91

All

135

No

 

HUMBLE

[358]

[359362]

US New Mexico statewide CC 1980-82

All

521

No

 

ISHIMA

[363]

[364]

Japan A bomb survivors CC 1961-70

All,Sq,Ad

180

Yes

AKIBA

JAHN

[365]

[366369]

Germany BIPS CC 1988-93

All,Sq,Ad

1004

No

BOFFET

JAIN

[370]

[371, 372]

Canada Ontario CC 1981-85

All,Sq,Ad

845

No

 

JARUP

[373]

[374, 375]

Sweden smelter workers CC 1928-81

All

102

No

 

JARVHO

[376]

 

Sweden Goteborg asbestos CC 1983-84

All

147

No

 

JEDRYC

[377]

[378382]

Poland CC 1980-87

All,Sq,Ad

1630

No

 

JIANG

[383]

[137, 139]

China Nanchang CC 1984

All,Sq,Ad

125

No

 

JOLY

[384]

 

Cuba Havana CC 1978-80

All,Sq,Ad

826

No

 

JUSSAW

[385]

 

India Greater Bombay CC 1964-73

All,Sq,Ad

792

No

 

KAISE2

[386]

[387, 388]

US California Kaiser cohort 1979-91

All

318

No

 

KAISER

[389]

[390]

US California Kaiser cohort 1964-80

All

714

No

 

KANELL

[391]

[391, 392]

Greece Hellenic Anticancer Inst CC 1950-62

All

862

No

 

KATSOU

[393]

 

Greece Athens CC 1987-89

All,Sq,Ad

101

No

 

KAUFMA

[394]

 

US & Canada tar level CC 1981-86

All

881

No

 

KELLER

[395]

 

US Illinois CC 1985-87

All

15038

No

 

KHUDER

[396]

 

US Philadelphia 15 hospital CC 1985-87

All,Sq,Ad

482

Yes

 

KIHARA

[397]

[398]

Japan Kanagawa genetic CC 1991-98

All,Sq,Ad

440

No

 

KINLEN

[399]

 

UK tea drinking cohort 1967-86

All

718

No

 

KJUUS

[400]

[401, 402]

Norway Telemark and Vestfold CC 1979-83

All

176

No

 

KNEKT

[403]

[404407]

Finland Mobile Clinic Health cohort 1966-91

All

515

No

 

KO

[408]

 

Taiwan Kaohsiung CC 1992-93

All

117

Yes

 

KOHLME

[409]

 

Germany Berlin pet birds CC 1990

All

239

No

 

KOO

[410]

[411414]

Hong Kong 8 hospital CC 1981-83

All,Sq,Ad

200

No

 

KOULUM

[415]

 

Finland Helsinki CC 1936-52

All

812

No

 

KREUZE

[416]

[417, 418]

Germany radon CC 1990-96

All

2260

No

BOFFET

KREYBE

[419]

[420, 421]

Norway CC 1948-53

All,Sq,Ad

300

Yes

 

KUBIK

[422]

[423]

Czechoslovakia Kolin district cohort 1965-71

All

108

No

 

LAMTH

[424]

[411]

Hong Kong 8 hospital CC 1983-86

All,Sq,Ad

445

No

 

LAMWK

[425]

[411]

Hong Kong Queen Mary Hospital CC 1981-84

All,Sq,Ad

163

No

 

LAMWK2

[426]

[132, 413]

Hong Kong Queen Mary Hospital CC 1976-80

All,Sq,Ad

480

No

 

LANGE

[427]

[428430]

Denmark Copenhagen City Heart cohort 1976-89

All

268

No

 

LAURIL

[431]

[432, 433]

Finland ATBC nested CC 1988-93

All

230

No

 

LAUSSM

[434]

 

Germany Aue/Saxony uranium miners CC 1982-89

All

432

No

 

LEI

[435]

 

China Guangzhou CC 1986

All

792

No

 

LEMARC

[436]

 

US Hawaii Oahu genotyping CC 1992-97

All

341

Yes

 

LETOUR

[437]

 

Canada Winnipeg radon CC 1983-90

All

738

Yes

 

LEVIN

[438]

[302, 439, 440]

US Roswell Park Memorial CC 1938-52

All

475

No

 

LIAW

[441]

 

Taiwan 12 township cohort 1982-94

All

127

No

 

LICKIN

[442]

[443, 444]

Germany West CC

All

224

No

 

LIDDEL

[445]

[446449]

Canada Quebec chrysotile mine cohort 1970-88

All

304

No

 

LIU

[450]

 

China Shun Yi CC 1980-86

All

229

No

 

LIU2

[451]

 

China Guangzhou CC 1983-84

All

316

No

 

LIU3

[452]

[137, 453, 454]

China Xuanwei farmers CC 1985-86

All

110

No

 

LIU4

[455]

 

China million deaths 1986-88

All

100000

No

 

LIU5

[456]

[137]

China Wuhan CC 1978-79

All

111

No

 

LOMBA2

[457]

[458]

US Boston CC 1960-67

All,Sq,Ad

225

No

 

LOMBAR

[458]

[457, 459]

US Boston CC 1951-64

All

1040

No

 

LUBIN

[460]

[460462]

China Yunnan tin miners CC 1984-88

All,Sq,Ad

427

No

XIANGZ

LUBIN2

[463]

[464469]

West Europe CC 1976-80

All,Sq,Ad

7804

Yes

 

LUO

[470]

 

China Fuzhou CC 1990-91

All,Sq,Ad

102

Yes

 

MACLEN

[471]

 

Singapore CC 1972-73

All

233

No

 

MAGNUS

[472]

[473]

Norway nickel workers cohort 1953-93

All

203

No

 

MARSH

[474]

 

US Arizona 6 smelter town CC 1979-90

All

150

No

 

MARSH2

[475]

 

US Arizona 4 smelter town CC 1979-90

All

114

No

 

MARTIS

[476]

 

UK Tyneside asbestos CC 1972-73

All

201

No

 

MASTRA

[477]

 

Italy silica CC 1973-80

All

309

No

 

MATOS

[478]

 

Argentina Buenos Aires CC 1994-96

All,Sq,Ad

200

No

 

MATSUD

[479]

[330]

Japan Osaka CC 1965

All,Sq,Ad

179

No

 

MCCONN

[480]

 

UK Liverpool CC 1946-49

All

100

Yes

 

MCDUFF

[481]

 

Canada Saskatchewan CC 1979-83

All

165

No

 

MCLAUG

[482]

 

China 5 region silica workers CC 1972-89

All

316

No

 

MIGRAN

[483]

[484, 485]

UK British part of migrant cohort 1964-77

All

259

No

 

MILLER

[486]

 

US Erie County CC 1972-84

All

168

No

 

MILLS

[487]

 

US Ohio CC 1940-47

All

444

No

 

MOLLO

[488]

 

Italy Turin CC 1982-92

All,Sq,Ad

145

Yes

 

MRFIT

[489]

[490]

US MRFIT initial screening cohort 1973-82

All

2004

No

 

MRFITR

[489]

[490492]

US MRFIT randomized subjects cohort 1973-85

All

119

No

MRFIT

MURATA

[493]

 

Japan Chiba gastric screen nested CC 1984-93

All

107

No

 

MZILEN

[494]

 

South Africa Northern Province black people CC

All

374

No

 

NAM

[495]

 

US National Mortality Followback 1986

All

1199

No

 

NOTAN2

[496]

[497]

India Tata Memorial Hospital CC 1963-71

All

683

No

 

NOTANI

[498]

 

India Tata Memorial Hospital CC 1986-90

All

246

No

 

NOU

[499]

 

Sweden Uppsala CC 1971-76

All,Sq,Ad

273

No

 

ODRISC

[500]

[501]

UK Salford Bronchoscopy Database CC

All

446

No

 

ORMOS

[502]

 

Hungary Szeged CC 1947-59

All,Sq,Ad

119

Yes

 

OSANN

[503]

 

US Orange Co. Cancer Surveillance CC 1984-86

All,Sq,Ad

1986

No

 

OSANN2

[504]

[505]

US California Kaiser nested CC 1969-77

All,Sq,Ad

217

Yes

KAISER

PARKIN

[506]

 

Zimbabwe-Rhodesia Bulawayo CC 1963-77

All

877

No

 

PASTOR

[507]

 

Italy Lombardy CC 1976-79

All

204

No

 

PAWLEG

[508]

 

Poland Cracow CC 1992-94

All

176

Yes

 

PERNU

[509]

 

Finland CC 1944-58

All

1606

No

 

PERSH2

[510]

 

Sweden 109 municipality CC 1980-84

All

1022

No

 

PETO

[511]

 

UK FEV cohort 1954-81

All

103

No

 

PEZZO2

[512]

 

Argentina Rosario CC 1992-98

All

367

Yes

 

PEZZOT

[513]

 

Argentina Rosario CC 1987-91

All,Sq,Ad

215

Yes

 

PIKE

[514]

 

US California LA County air poll. CC 1972-75

All

731

No

 

PISANI

[515]

[87]

Italy Lombardy diet CC 1980-81

All

417

No

LUBIN2

POFFIJ

[516]

[517]

West Europe Ardennes-Eifel radon CC 1990-95

All

971

No

 

POLEDN

[518]

 

US Toxic waste dumpsite CC 1978-81

All

209

No

 

PRESCO

[519]

[520]

Denmark 3 Copenhagen cohort studies pooled 1964-93

All,Sq,Ad

867

No

HEIN, LANGE

QIAO

[521]

[522, 523]

China Yunnan tin miners CC 1985

All

107

No

XIANGZ

QIAO2

[524]

 

China Yunnan tin miners cohort 1992-95

All

241

No

 

RACHTA

[525]

 

Poland Cracow CC 1991-94

All

118

Yes

 

RADZIK

[526]

 

Poland lung cancer relatives CC 1986-87

All

189

No

 

RANDIG

[527]

 

Germany Berlin CC 1951-54

All

448

No

 

REN

[137]

 

China CC

All

244

No

 

RESTRE

[528]

 

Colombia CC 1978-80

All

102

No

 

RIMING

[529]

 

UK Mass radiography cohort 1970-76

All

104

No

 

RONCO

[530]

 

Italy Turin CC 1976-80

All

126

No

 

ROOTS

[531]

 

Germany Berlin debrisoquine CC

All

270

Yes

CASCOR

ROTHSC

[532]

 

US Southern Louisiana CC 1971-77

All

284

No

 

SAARIK

[533]

 

Finland genetics CC 1988-96

All,Sq,Ad

205

Yes

 

SADOWS

[534]

 

US National Cancer Institute CC 1938-43

All

477

No

 

SANKAR

[535]

 

India Trivandrum diet CC 1990

All

281

No

 

SCHWAR

[536]

[537]

US Michigan CC 1984-87

All,Sq,Ad

5588

Yes

 

SEGI

[538]

 

Japan nationwide CC 1948-52

All

159

No

 

SEGI2

[539]

 

Japan Tokyo and Sendai CC 1962-70

All,Sq,Ad

378

No

 

SEOW

[540]

 

Singapore NAT2 CC 1997-98

All,Sq,Ad

153

Yes

 

SHAW

[541]

 

US & Canada Bethesda/Quebec debrisoquine CC 1988-92

All

335

Yes

 

SHIMIZ

[542]

 

Japan Sendai Kosei Hospital CC 1977-82

All,Sq,Ad

751

No

 

SIEMIA

[543]

[544547]

Canada Montreal occupational CC 1979-85

All,Sq,Ad

857

Yes

 

SIMARA

[548]

 

Thailand Chiang Mai CC 1971-72

All

115

No

 

SITAS

[549]

 

South Africa Johannesburg black people CC −1997

All

*

No

 

SOBUE

[550]

[551, 552]

Japan Osaka CC 1986-88

All,Sq,Ad

1376

Yes

 

SOBUE2

[553]

 

Japan Osaka CC 1965-83

All,Sq,Ad

2083

No

 

SPEIZE

[554]

[555]

US Nurses' Health cohort 1976-92

All

593

Yes

 

SPITZ

[556]

[557566]

US Texas University Genetics

All

177

Yes

 

STASZE

[567]

 

Poland Gliwice CC 1954-58

All,Sq,Ad

281

Yes

 

STAYNE

[568]

[569]

US Third National Cancer Survey CC 1969-71

All,Sq,Ad

420

No

 

STOCKS

[570]

[571, 572]

UK British Empire Cancer Campaign CC 1952-55

All

2932

No

 

STOCKW

[573]

 

US Florida phosphate mining area CC 1981-83

All

22161

No

 

STUCKE

[574]

 

France GSTM1 CC 1989-92

All

247

Yes

 

SUN

[575]

 

China Liaoning genetics CC 1992-94

All

207

Yes

 

SUZUK2

[576]

[577]

Brazil Rio de Janeiro CC 1991-92

All,Sq,Ad

123

Yes

 

SUZUKI

[578]

 

Japan Osaka CC 1978-86

Ad

238

Yes

 

SVENSS

[579]

[580, 581]

Sweden Stockholm County CC 1983-86

All,Sq,Ad

210

No

 

TANG

[582]

[583]

US Columbia Presbyterian genetics CC

All

119

Yes

 

TANG2

[584]

 

UK 4 cohort studies pooled 1967-90

All

836

No

BENSHL, HOLE, WALD

TAO

[585]

 

China Shanghai CC 1988-90

All

723

No

 

TENKAN

[586]

[587591]

Finland part Finland/Norway cohort 1962-87

All

242

No

 

TIZZAN

[592]

 

Italy CC 1959-61

All,Sq,Ad

1358

No

 

TOKARS

[593]

[594597]

Russia Nuclear Workers nested CC 1966-91

All,Sq,Ad

162

Yes

 

TOUSEY

[598]

 

US Duval County CC 1993-96

All

507

Yes

 

TSUGAN

[599]

 

Japan National Cancer Centre CC 1976-85

All,Sq,Ad

134

Yes

 

TULINI

[600]

 

Iceland Rejkjavik cohort 1967-95

All

472

No

 

TVERDA

[601]

 

Norway cohort 1972-88

All

238

No

 

ULMER

[602]

 

Germany Bochum CC 1971-75

All

726

No

 

VEIERO

[603]

 

Norway Health Screening cohort 1977-91

All

153

No

TVERDA

VUTUC

[604]

[604620]

Austria CC 1976-80

All,Sq,Ad

1877

No

LUBIN2

WAKAI

[621]

 

Japan Okinawa CC 1988-91

All,Sq,Ad

333

Yes

 

WALD

[622]

 

UK BUPA cohort 1975-93

All

102

No

 

WANG

[623]

 

China Guangdong CC 1990-93

All,Sq,Ad

390

Yes

 

WANG2

[624]

[137, 139]

China Tai Yuan CC 1980-82

All

103

No

 

WANG3

[137]

[139, 625]

China Nanjing CC

All

293

No

 

WANG4

[626]

 

China Xuanwei farmers cohort 1976-96

All

1170

No

 

WARSIN

[442]

 

Netherlands CC

All

134

No

 

WATSON

[627]

[628]

US New York Memorial Hospital CC 1950-52

All

301

Yes

 

WICKLU

[629]

 

US Washington County orchardists CC 1968-80

All

155

No

 

WIGLE

[630]

 

Canada Alberta CC 1971-73

All

728

No

 

WILKIN

[631]

 

UK London Chest Hospital CC 1992-93

All

271

No

 

WU

[632]

 

US California LA County CC 1981-82

All,Sq,Ad

220

Yes

 

WU2

[633]

 

US California LA County CC 1983-86

Ad

336

Yes

 

WUNSCH

[634]

[635]

Brazil Sao Paulo CC study 1990-91

All

398

No

 

WUWILL

[636]

[137, 139, 637640]

China Shenyang and Harbin CC study 1985-87

All,Sq,Ad

965

No

 

WYNDE2

[641]

[642644]

US New York CC study 1962-64

All,Sq,Ad

404

Yes

 

WYNDE3

[645]

 

US New York Memorial CC study 1966-69

All,Sq,Ad

350

Yes

 

WYNDE4

[2]

[646]

US 8 state CC study 1948-50

All,Sq,Ad

684

No

 

WYNDE5

[647]

[648]

US 4 city CC study 1969-76

All,Sq,Ad

1365

Yes

WYNDE6

WYNDE6l

[649]

[644, 650677]

US 4 city CC study 1969-96

All,Sq,Ad

4423

Yes

 

WYNDE7

[676]

 

US 6 city CC study 1977-84

All,Sq,Ad

2085

Yes

WYNDE6

WYNDE8

[677]

 

US 4 city CC study 1985-90

All,Sq,Ad

1044

Yes

WYNDE6

WYNDER

[678]

 

Cuba Havana CC study 1956-57

All

120

No

 

XIANGZ

[679]

 

China Yunnan tin miners cohort study 1976-87

All

983

No

 

XU

[637]

[137, 139, 638, 639]

China Shenyang CC study 1985-87

All,Sq,Ad

729

No

 

XU2

[680]

[639]

China Anshan Iron-Steel workers CC study 1987-93

All

610

No

 

XU3

[681]

[137]

China Tianjin CC study 1981

All, Sq, Ad

135

No

 

XU4

[137]

[682]

China 26 city air pollution CC study

All

206

No

 

YAMAGU

[683]

 

Japan occupational CC study 1989-90

All

144

Yes

 

YONG

[684]

[260]

US NHANES I - NHEFS cohort study 1971-92

All

216

No

 

YUAN

[685]

 

China Shanghai cohort study 1986-93

All

142

No

 

ZHANG

[686]

[137]

China Jinzhou CC study 1988-89

All

100

No

 

ZHENG

[687]

[137, 139, 688]

China Shanghai CC study 1982-84

All,Sq,Ad

540

Yes

 

ZHOU

[689]

 

China Medical Univ CC study 1978-94

All,Sq,Ad

1360

No

 

a CC = case–control, date range for cohort study is from start at baseline interview to end of follow-up.

b Indicates whether the study provided data for all lung cancer (All), squamous cell carcinoma (Sq) or adenocarcinoma (Ad), or a near equivalent definition (see Methods).

c Number of lung cancer cases.

d Whether or not full histological confirmation of cases was carried out.

e For subsidiary studies, this column shows the relevant principal study.

f Additional sources were two unpublished reports made available by personal communication from P N Lee.

g Additional sources were two unpublished reports made available by personal communication from Dr E C Hammond.

h An additional source was an unpublished report made available by personal communication from Dr G Dean.

i An additional source was an unpublished report made available by personal communication from Dr J Peto.

j An additional source was an unpublished report made available by personal communication from Dr T Hirayama.

k An additional source was an unpublished report made available by personal communication from Dr V Hawthorne.

l An additional source was an unpublished report made available by personal communication from Dr G C Kabat.

Table 3

Distribution of the main characteristics of the 287 studies of lung cancer

Characteristic

Level

Principal studies

Subsidiary studies

All studies

  

Outcomea

Study typeb

Total

Total

  

All

Squamous

Adeno

CC

prosp

Total

  

Study status

Principal

262

84

86

209

58

267

-

267

 

Subsidiary

(19)

(12)

(12)

(15)

(5)

(20)

20

20

Study type

Case–control

204

73

75

209

-

209

15

224

 

Prospective

52

9

9

-

52

52

4

56

 

Other

6

2

2

-

6

6

1

7

Study sex

Both

154

53

54

133

25

158

11

169

 

Male

90

19

19

59

31

90

8

98

 

Female

18

12

13

17

2

19

1

20

Lowest agec

<20 or unlimited

177

56

57

165

16

181

13

194

 

20-29

15

3

3

9

6

15

2

17

 

30-39

39

15

16

26

14

40

5

45

 

40+

31

10

10

9

22

31

0

31

Highest age

<60

16

2

2

10

6

16

3

19

 

60-69

21

6

6

6

15

21

1

22

 

70-79

29

11

12

23

7

30

3

33

 

80+ or unlimited

196

65

66

170

30

200

13

213

Location

North America

87

29

31

63

26

89

6

95

 

United Kingdom

22

2

2

13

9

22

2

24

 

Scandinavia

25

6

6

14

11

25

2

27

 

Other Europe

42

13

12

39

4

43

7

50

 

China

37

10

10

34

3

37

2

39

 

Japan

17

8

9

15

3

18

1

19

 

Other Asia

16

10

10

16

1

17

0

17

 

Other

16

6

6

15

1

16

0

16

Start year of study

<1960

47

12

12

33

14

47

1

48

 

1960-69

40

13

13

21

19

40

6

46

 

1970-79

59

17

19

45

16

61

7

68

 

1980-89

83

33

33

78

8

86

5

91

 

1990+

33

9

9

32

1

33

1

34

Number of casesd

100-249

109

25

26

84

28

112

5

117

 

250-499

70

25

26

57

15

72

3

75

 

500-999

47

14

14

38

9

47

3

50

 

1000+

36

20

20

30

6

36

9

45

Risky occupational population

No

244

83

85

203

46

249

18

267

 

Mining

7

0

0

0

7

7

2

9

 

Other risky

11

1

1

6

5

11

0

11

National cigarette tobacco type

Virginia

42

6

6

30

12

42

2

44

 

Blended

180

66

68

142

42

184

16

200

 

Othere

40

12

12

37

4

41

2

43

Any proxy use

None/unknown

189

66

67

137

56

193

17

210

 

Yes

73

18

19

72

2

74

3

77

Full histological confirmation

No

199

49

49

145

54

199

12

211

 

Yes

63

35

37

64

4

68

8

76

Main outcome(s)a

All

262

82

82

204

58

262

19

281

 

Squamous

82

84

83

73

11

84

12

96

 

Adeno

82

83

86

75

11

86

12

98

 

All only

180

-

-

133

47

180

8

188

 

Squamous only

-

1

-

1

0

1

0

1

 

Adeno only

-

-

3

3

0

3

0

3

 

more than one

82

83

83

72

11

83

12

95

a Indicates whether the study provided data for all lung cancer, squamous cell carcinoma or adenocarcinoma, or their near equivalent definitions (see Methods). For squamous, the near equivalent definitions included are: Kreyberg I; squamous cell or small carcinoma; squamous cell or undifferentiated carcinoma; and not adenocarcinoma. For adeno, the near equivalent definitions included are: Kreyberg II; adenocarcinoma or large cell carcinoma; adenocarcinoma, alveolar or bronchioloalveolar carcinoma; not squamous cell or small cell carcinoma; and not squamous cell or undifferentiated carcinoma.

b CC = case–control, prosp = prospective.

c At start of study.

d In study as a whole.

e Indicates China and Taiwan.

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 3 (and the text below based on it). The other 20 studies are classified as subsidiary. Of the principal studies, 262 provide data for all lung cancer, 84 for squamous and 86 for adeno. Only rarely did these studies provide data only for squamous (1 study) or adeno (3 studies). The data come less often from case–control designs for all lung cancer (77.9%) than for squamous (86.9%) and adeno (87.2%).

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 4 summarizes the distribution of various characteristics of the RRs by outcome, sex, study type and location.
Table 4

Distribution of the main characteristics of the relative risks a

Smoking indexb

Dose response RRsb,c

Total

Principald

By lung cancer typea

By sex

    

All

Squamous

Adeno

Combined

Male

Female

All

 

16616

15350

11316

2268

1698

1031

11202

4383

Any product or cigarettes vs. never/non

 

3614

3366

2359

488

432

342

2065

1207

Cig only smoking vs. never/non

 

678

621

535

72

56

18

513

147

Pipe/Cigar/Mixed vs. never/non

 

769

678

644

61

53

22

717

30

Handrolled vs. manufactured

 

120

104

74

22

14

8

93

19

Filter vs. Plain

 

303

264

167

74

37

9

182

112

Menthol vs. non-menthol

 

25

16

20

2

1

5

10

10

Amount smoked

All RRs

3627

3509

2708

412

310

198

2459

970

 

Sets vs. never/non

1145

1104

858

123

100

64

741

340

Age of starting

All RRs

1442

1344

1052

167

128

67

970

405

 

Sets vs. never/non

256

242

188

29

24

13

159

84

 

Sets vs. low

301

285

197

44

35

14

196

91

 

Non-categorical RRs

14

14

6

2

2

2

7

5

Duration of smoking

All RRs

2337

2129

1544

342

240

202

1470

665

 

Sets vs. never/non

374

337

248

54

40

37

221

116

 

Sets vs. low

434

384

261

75

56

38

260

136

 

Non-categorical RRs

72

70

32

19

20

1

39

32

Years quit (vs. never)

All RRs

1665

1504

991

276

198

64

1241

360

 

Sets vs. never/non

207

194

124

35

26

11

146

50

 

Sets vs. low

255

234

157

39

27

8

190

57

 

Non-categorical RRs

3

3

3

0

0

2

1

0

Years quit (vs. current)

All RRs

1421

1248

867

221

145

55

1076

290

 

Sets vs. current

251

231

155

38

25

11

183

57

 

Sets vs. low

244

223

158

33

23

10

177

57

 

Non-categorical RRs

0

0

0

0

0

0

0

0

Tar

All RRs

222

198

156

33

33

18

127

77

 

Sets vs. never/non

22

18

16

3

3

4

13

5

 

Sets vs. low

41

36

33

4

4

3

24

14

 

Non-categorical RRs

55

55

19

18

18

0

27

28

Butt length

All RRs

15

15

15

0

0

0

6

9

 

Sets vs. never/non

3

3

3

0

0

0

1

2

 

Sets vs. low

2

2

2

0

0

0

1

1

 

Non-categorical RRs

2

2

2

0

0

0

1

1

Fraction smoked

All RRs

192

192

42

70

40

5

140

47

 

Sets vs. never/non

40

40

10

14

8

1

29

10

 

Sets vs. low

50

50

12

18

10

1

34

15

 

Non-categorical RRs

0

0

0

0

0

0

0

0

Lung cancer type (near equivalent definitions)a

All

11316

10553

11316

0

0

760

7700

2856

 

Squamous

2268

2038

0

2268

0

113

1538

617

 

Adeno

1698

1532

0

0

1698

68

1098

532

Lung cancer type (exact definitions)

All lung cancer

10980

10247

10980

0

0

671

7571

2738

 

Squamous cell carcinoma

1064

1004

0

1064

0

66

710

288

 

Adenocarcinoma

1172

1112

0

0

1172

64

726

382

 

Large cell carcinoma

393

392

0

0

0

13

266

114

 

Small cell carcinoma

718

662

0

0

0

29

497

192

 

Other

223

173

0

0

0

48

103

72

Adjustment

None

10113

9266

6740

1362

1086

651

6613

2849

 

Sex and/or age only

3099

3053

2423

264

234

132

2307

660

 

Other (but not sex or age)

701

686

442

142

63

51

418

232

 

Sex and/or age plus other

2703

2345

1711

365

315

197

1864

642

Derivation

Original

1853

1705

1088

261

254

163

1157

533

 

Standard calculations

9803

8983

6701

1371

996

663

6376

2764

 

Other methods

4960

4662

3527

638

448

205

3669

1086

   

Continent

   

Study type

  
  

Total

North America

Europe

Asia

Other

Case–control

Other

 

All

 

16616

6676

6122

2770

1048

11945

4671

 

Any product or cigarettes vs. never/non

 

3614

1493

1163

771

187

2716

898

 

Cigarette only smoking vs. never/non

 

678

284

340

27

27

345

333

 

Pipe/Cigar/Mixed vs. never/non

 

769

380

327

39

23

428

341

 

Handrolled vs. manufactured

 

120

0

68

30

22

90

30

 

Filter vs. Plain

 

303

74

178

27

24

268

35

 

Menthol vs. non-menthol

 

25

25

0

0

0

13

12

 

Amount smoked

All RRs

3627

1601

1288

612

126

2240

1387

 
 

Sets vs. never/non

1145

507

404

189

45

712

433

 

Age of starting

All RRs

1442

496

512

301

133

1017

425

 
 

Sets vs. never/non

256

82

93

58

23

186

70

 
 

Sets vs. low

301

93

105

71

32

224

77

 
 

Non-categorical RRs

14

10

1

3

0

14

0

 

Duration of smoking

All RRs

2337

939

706

462

230

1816

521

 
 

Sets vs. never/non

374

148

111

80

35

287

87

 
 

Sets vs. low

434

154

141

94

45

353

81

 
 

Non-categorical RRs

72

60

9

3

0

70

2

 

Years quit (vs. never)

All RRs

1665

668

657

196

144

1339

326

 
 

Sets vs. never/non

207

89

75

23

20

170

37

 
 

Sets vs. low

255

86

111

33

25

208

47

 
 

Non-categorical RRs

3

3

0

0

0

3

0

 

Years quit (vs. current)

All RRs

1421

457

674

177

113

1155

266

 
 

Sets vs. current

251

76

112

36

27

213

38

 
 

Sets vs. low

244

84

102

31

27

198

46

 
 

Non-categorical RRs

0

0

0

0

0

0

0

 

Tar

All RRs

222

158

64

0

0

182

40

 
 

Sets vs. never/non

22

16

6

0

0

19

3

 
 

Sets vs. low

41

25

16

0

0

26

15

 
 

Non-categorical RRs

55

55

0

0

0

54

1

 

Butt length

All RRs

15

0

13

0

2

15

0

 
 

Sets vs. never/non

3

0

3

0

0

3

0

 
 

Sets vs. low

2

0

2

0

0

2

0

 
 

Non-categorical RRs

2

0

0

0

2

2

0

 

Fraction smoked

All RRs

192

32

56

99

5

190

2

 
 

Sets vs. never/non

40

10

8

21

1

40

0

 
 

Sets vs. low

50

12

16

21

1

48

2

 
 

Non-categorical RRs

0

0

0

0

0

0

0

 

Lung cancer type (near equivalent)a

All

11316

4879

3955

1765

717

6942

4374

 
 

Squamous

2268

773

931

445

119

2131

137

 
 

Adeno

1698

615

618

346

119

1601

97

 

Lung cancer type (exact definitions)

All lung cancer

10980

4654

3923

1686

717

6608

4372

 
 

Squamous carcinoma

1064

205

433

307

119

1008

56

 
 

Adenocarcinoma

1172

308

435

310

119

1097

75

 
 

Large cell carcinoma

393

208

94

88

3

379

14

 
 

Small cell carcinoma

718

148

427

108

35

669

49

 
 

Other

223

53

97

18

55

223

0

 

Adjustment

None

10113

4105

3489

1847

672

8126

1987

 
 

Sex and/or age only

3099

1515

1153

399

32

1216

1883

 
 

Other (but not sex or age)

701

177

409

79

36

579

122

 
 

Sex and/or age plus other

2703

879

1071

445

308

2024

679

 

Derivation

Original

1853

649

649

379

176

1436

417

 
 

Standard calculations

9803

3865

3519

1811

608

7703

2100

 
 

Other methods

4960

2162

1954

580

264

2806

2154

 

a RRs relating to all lung cancer (all), squamous cell carcinoma (squamous) or adenocarcinoma (adeno) or to a near equivalent definition.

b “never/non” indicates never smoker or non smoker.

c Sets are dose response results for an identical definition of smoking product, strata and confounding variables. Sets vs. low are sets where the RR has been calculated compared to the level with the lowest expected risk, i.e. the smallest amount smoked, or the latest age of starting. Non-categorical RRs are typically where RRs and CIs are not available, but some other information was provided.

d RRs from principal studies.

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 3: RRs provides further detail.

For dose-related indices, Additional file 4: Dose Not Meta gives results originally presented in forms unsuitable for meta-analysis.

The meta-analyses and meta-regressions

The main findings are summarized in the following sections, with tables and forest plots. Additional file 5: Detailed Analysis Tables fully presents all the meta-analyses and meta-regressions conducted. The interested reader should first see Additional file 1: Methods, which lists the other files, and describes their content and structure.

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

Figures 1, 2, 3, 4 and 5 (all lung cancer), Figures 6, 7 (squamous) and Figure 8, 9 (adeno) present the results of the main meta-analyses for ever smoking any product (or cigarette smoking for studies without RRs for any product), based on most-adjusted RRs. Table 5 presents additional results subdivided by level of certain characteristics, while Table 6 presents results of some alternative meta-analyses of ever smoking. From these findings, various observations can be made.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig1_HTML.jpg
Figure 1

Forest plot of ever smoking of any product and all lung cancer – part 1. Table 5 presents the results of a main meta-analysis for all lung cancer based on 328 relative risk (RR) and 95% confidence interval (CI) estimates for ever smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale in Figures 1, 2, 3, 4, 5. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT), with the exception of study LIU4 shown at the end of Figure 5. In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig2_HTML.jpg
Figure 2

Forest plot of ever smoking of any product and all lung cancer – part 2. This is a continuation of Figure 1, presenting further individual study data included in the main meta-analysis for all lung cancer shown in Table 5. For study DORGAN separate estimates, within sex, are shown for whites then blacks. For study HUMBLE they are shown for non-hispanic whites then hispanics, and for study KELLER for whites then non-whites.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig3_HTML.jpg
Figure 3

Forest plot of ever smoking of any product and all lung cancer – part 3. This is a continuation of Figure 2, presenting further individual study data included in the main meta-analysis for all lung cancer shown in Table 5.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig4_HTML.jpg
Figure 4

Forest plot of ever smoking of any product and all lung cancer – part 4. This is a continuation of Figure 3, presenting further individual study data included in the main meta-analysis for all lung cancer shown in Table 5.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig5_HTML.jpg
Figure 5

Forest plot of ever smoking of any product and all lung cancer – part 5. This is a continuation of Figure 4, presenting the remaining individual study data included in the main meta-analysis for all lung cancer shown in Table 5. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI. Note that the sizes of the squares for the two estimates from study LIU4 indicate the relative weight of the male and female data, but are not comparable with the sizes of the squares for the other estimates.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig6_HTML.jpg
Figure 6

Forest plot of ever smoking of any product and squamous – part 1. Table 5 presents the results of a main meta-analysis for squamous based on 102 relative risk (RR) and 95% confidence interval (CI) estimates for ever smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale in Figures 6, 7. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. For study SCHWAR separate estimates, within sex, are shown for whites then blacks.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig7_HTML.jpg
Figure 7

Forest plot of ever smoking of any product and squamous – part 2. This is a continuation of Figure 6, presenting the remaining individual study data included in the main meta-analysis for squamous shown in Table 5. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig8_HTML.jpg
Figure 8

Forest plot of ever smoking of any product and adeno – part 1. Table 5 presents the results of a main meta-analysis for adeno based on 107 relative risk (RR) and 95% confidence interval (CI) estimates for ever smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale in Figures 8, 9. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. For study SCHWAR separate estimates, within sex, are shown for whites then blacks.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig9_HTML.jpg
Figure 9

Forest plot of ever smoking of any product and adeno – part 2. This is a continuation of Figure 8, presenting the remaining individual study data included in the main meta-analysis for adeno shown in Table 5. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

Table 5

Main meta-analyses for ever smoking of any product (or cigarettes if any product not available) a

Characteristic

Level

Statisticb

All lung cancerc

Squamousd

Adenoe

All

All

n

328

102

107

  

F

4.22 (4.16-4.28)

9.52 (8.94-10.13)

3.44 (3.27-3.61)

  

R

5.50 (5.07-5.96)

10.47 (8.88-12.33)

2.84 (2.41-3.35)

  

H, PH

22.84, p < 0.001

5.17, p < 0.001

8.78, p < 0.001

  

PE

p < 0.001

NS

p < 0.01

Sex

Male

n

171

49

51

  

F

3.74 (3.67-3.82)

10.74 (9.82-11.74)

4.09 (3.76-4.44)

  

R

6.18 (5.49-6.95)

11.98 (9.68-14.82)

3.55 (2.83-4.45)

 

Female

n

108

42

45

  

F

3.95 (3.86-4.05)

8.86 (8.05-9.75)

3.27 (3.05-3.50)

  

R

4.43 (3.84-5.10)

8.97 (6.95-11.57)

2.32 (1.78-3.02)

 

Combined

n

49

11

11

  

F

8.26 (7.94-8.60)

7.04 (5.76-8.60)

2.29 (1.93-2.71)

  

R

6.09 (4.98-7.44)

10.70 (4.89-23.40)

2.52 (1.56-4.08)

 

Between levels

PB

<0.01

NS

<0.05

Location

North America

n

116

38

40

  

F

8.86 (8.63-9.10)

12.69 (11.63-13.84)

5.75 (5.36-6.16)

  

R

7.49 (6.78-8.27)

13.42 (10.45-17.24)

4.37 (3.48-5.48)

 

United Kingdom

n

29

4

4

  

F

5.22 (4.72-5.78)

4.75 (3.00-7.51)

2.74 (1.52-4.94)

  

R

5.83 (4.54-7.49)

6.27 (2.49-15.83)

2.68 (1.31-5.47)

 

Scandinavia

n

32

7

7

  

F

6.43 (5.88-7.04)

8.67 (5.88-12.78)

2.04 (1.49-2.78)

  

R

6.39 (5.29-7.71)

8.62 (4.81-15.43)

2.05 (1.37-3.06)

 

Other Europe

n

50

15

15

  

F

5.55 (5.22-5.90)

6.56 (5.72-7.52)

2.30 (1.99-2.65)

  

R

6.09 (4.95-7.51)

8.87 (5.50-14.31)

2.72 (2.01-3.68)

 

China

n

51

12

12

  

F

2.77 (2.72-2.83)

5.65 (4.71-6.78)

1.48 (1.28-1.70)

  

R

2.69 (2.50-2.88)

6.39 (4.73-8.63)

1.48 (1.28-1.70)

 

Japan

N

18

8

11

  

F

3.19 (2.91-3.49)

13.94 (9.71-20.00)

1.74 (1.47-2.06)

  

R

3.21 (2.68-3.85)

14.54 (9.78-21.62)

1.80 (1.34-2.41)

 

Other Asia

N

18

12

12

  

F

3.79 (3.41-4.20)

7.87 (6.31-9.81)

1.88 (1.56-2.26)

  

R

3.76 (2.72-5.18)

8.02 (5.54-11.60)

1.87 (1.29-2.71)

 

Other or multiregion

n

14

6

6

  

F

6.25 (5.45-7.16)

16.70 (10.07-27.70)

4.20 (2.91-6.06)

  

R

7.41 (5.72-9.60)

16.70 (10.07-27.70)

4.20 (2.91-6.06)

 

Between levels

PB

<0.001

<0.01

<0.001

Start year of study

Before 1960

n

54

14

14

  

F

3.96 (3.71-4.23)

4.35 (3.66-5.18)

1.64 (1.27-2.10)

  

R

4.67 (3.75-5.82)

5.89 (3.89-8.92)

1.64 (1.27-2.10)

 

1960-69

n

52

14

14

  

F

5.16 (4.88-5.45)

11.87 (9.75-14.44)

4.38 (3.78-5.08)

  

R

5.45 (4.60-6.46)

12.88 (7.71-21.52)

3.62 (2.00-6.54)

 

1970-79

n

71

26

31

  

F

4.58 (4.34-4.82)

8.76 (7.74-9.92)

2.47 (2.21-2.76)

  

R

5.05 (4.27-5.96)

10.08 (7.21-14.09)

2.69 (2.14-3.37)

 

1980-89

n

114

40

40

  

F

4.11 (4.04-4.17)

11.42 (10.46-12.47)

4.17 (3.90-4.45)

  

R

5.95 (5.18-6.83)

11.74 (9.40-14.66)

3.23 (2.48-4.20)

 

1990 or later

n

37

8

8

  

F

5.28 (4.83-5.77)

12.39 (8.51-18.05)

1.76 (1.44-2.17)

  

R

6.22 (4.89-7.92)

12.21 (7.56-19.72)

1.99 (1.40-2.83)

 

Between levels

PB

NS

<0.1

<0.01

Study type

Case–control

n

262

93

98

  

F

4.12 (4.06-4.18)

9.46 (8.89-10.08)

3.41 (3.24-3.59)

  

R

5.32 (4.87-5.82)

10.31 (8.70-12.22)

2.78 (2.33-3.32)

 

Prospectivef

n

66

9

9

  

F

6.01 (5.69-6.34)

12.23 (8.00-18.69)

3.95 (3.11-5.01)

  

R

6.24 (5.34-7.28)

12.78 (7.29-22.41)

3.66 (2.67-5.03)

 

Between levels

PB

<0.1

NS

NS

National cigarette tobacco type

Virginia

n

50

9

9

  

F

5.60 (5.22-6.00)

12.69 (9.36-17.20)

4.36 (3.48-5.48)

  

R

6.24 (5.16-7.54)

13.80 (6.53-29.17)

4.37 (3.01-6.34)

 

Blended

n

225

80

85

  

F

7.48 (7.32-7.65)

10.12 (9.46-10.83)

3.90 (3.69-4.12)

  

R

6.30 (5.79-6.87)

11.07 (9.21-13.31)

3.07 (2.55-3.69)

 

Other

n

53

13

13

  

F

2.77 (2.72-2.83)

5.56 (4.65-6.66)

1.46 (1.27-1.67)

  

R

2.68 (2.49-2.87)

6.15 (4.60-8.23)

1.46 (1.27-1.67)

 

Between levels

PB

<0.001

<0.01

<0.001

Any proxy use

Nog

n

227

76

79

  

F

6.87 (6.72-7.03)

8.95 (8.37-9.56)

3.41 (3.23-3.61)

  

R

5.51 (5.02-6.04)

9.64 (7.99-11.64)

2.63 (2.15-3.20)

 

Yes

n

101

26

28

  

F

3.15 (3.09-3.20)

14.65 (12.30-17.46)

3.56 (3.13-4.04)

  

R

5.39 (4.84-6.02)

13.82 (10.45-18.27)

3.61 (2.73-4.76)

 

Between levels

PB

NS

<0.05

<0.1

Full histological confirmation

No

n

245

59

59

  

F

3.86 (3.80-3.92)

7.21 (6.57-7.90)

2.43 (2.24-2.63)

  

R

5.25 (4.80-5.74)

9.39 (7.54-11.68)

2.56 (2.09-3.15)

 

Yes

n

83

43

48

  

F

7.67 (7.38-7.98)

11.97 (11.01-13.02)

4.37 (4.09-4.66)

  

R

6.30 (5.47-7.25)

12.32 (9.78-15.52)

3.22 (2.53-4.10)

 

Between levels

PB

<0.05

<0.1

NS

Number of casesh

100-249

n

115

22

27

  

F

3.74 (3.51-3.99)

6.02 (4.86-7.45)

1.93 (1.67-2.24)

  

R

4.43 (3.86-5.09)

8.39 (5.91-11.92)

2.31 (1.71-3.12)

 

250-499

n

86

31

31

  

F

4.85 (4.59-5.12)

8.89 (7.51-10.52)

2.37 (2.10-2.68)

  

R

5.75 (4.95-6.69)

10.17 (7.81-13.22)

2.37 (1.81-3.09)

 

500-999

n

64

18

18

  

F

4.93 (4.68-5.19)

8.26 (6.92-9.85)

2.40 (2.07-2.77)

  

R

6.17 (5.25-7.25)

11.35 (7.79-16.53)

2.86 (2.08-3.92)

 

1000+

n

63

31

31

  

F

4.15 (4.08-4.21)

10.51 (9.74-11.35)

4.61 (4.32-4.92)

  

R

6.14 (5.15-7.32)

10.88 (8.16-14.51)

3.77 (2.82-5.02)

 

Between levels

PB

<0.01

NS

<0.1

Smoking product

Any

n

205

54

55

  

F

3.79 (3.73-3.85)

6.86 (6.16-7.65)

2.42 (2.20-2.66)

  

R

5.41 (4.90-5.97

8.94 (7.02-11.39)

2.27 (1.87-2.76)

 

Cigarettes (ignoring

n

114

46

50

 

other products)

F

6.52 (6.31-6.73)

10.99 (10.18-11.85)

3.94 (3.71-4.19)

  

R

5.54 (4.87-6.30)

11.86 (9.57-14.71)

3.46 (2.70-4.44)

 

Cigarettes only

n

9

2

2

  

F

8.11 (7.11-9.26)

38.79 (18.74-80.31)

4.26 (3.15-5.74)

  

R

6.83 (4.63-10.08)

38.79 (18.74-80.31)

4.26 (3.15-5.74)

 

Between levels

PB

NS

<0.001

<0.001

Unexposed base

Never any product

n

236

64

67

  

F

3.84 (3.78-3.90)

8.06 (7.37-8.82)

2.57 (2.38-2.77)

  

R

5.31 (4.84-5.81)

9.68 (7.81-12.01)

2.46 (2.09-2.89)

 

Never cigarettes

n

92

38

40

  

F

7.01 (6.77-7.26)

11.04 (10.13-12.02)

4.30 (4.02-4.60)

  

R

5.96 (5.17-6.88)

11.92 (9.24-15.38)

3.56 (2.66-4.78)

 

Between levels

PB

NS

NS

<0.05

Number of adjustment factors

0

n

164

53

54

  

F

7.12 (6.92-7.33)

7.93 (7.20-8.74)

2.40 (2.21-2.60)

  

R

5.44 (4.86-6.09)

9.86 (7.79-12.49)

2.61 (2.11-3.23)

 

1

n

69

18

20

  

F

5.13 (4.90-5.37)

12.59 (10.37-15.30)

3.24 (2.81-3.73)

  

R

5.48 (4.72-6.37)

11.34 (7.36-17.47)

2.66 (1.74-4.06)

 

2+

n

95

31

33

  

F

3.40 (3.34-3.46)

10.48 (9.59-11.45)

4.61 (4.29-4.95)

  

R

5.56 (4.87-6.34)

11.02 (8.35-14.54)

3.30 (2.50-4.36)

 

Between levels

PB

NS

NS

NS

a Within each study, results for ever smokers are selected in the following preference order, within each sex, for:

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods);

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group.

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.01, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PE = probability value for Egger’s test of publication bias similarly expressed, PB = probability value for between levels (see Methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Or nested case–control or case-cohort in the case of 5 estimates for all lung cancer, 4 for squamous and 4 for adeno.

g Or not known in the case of 10 estimates for all lung cancer, 2 for squamous, and 2 for adeno.

h In the study as a whole.

Table 6

Some alternative meta-analyses for ever smoking compared to those in Table 5

Analysis description

Statisticb

All lung cancerc

Squamousd

Adenoe

As Table 5 a

n

328

102

107

 

F

4.22 (4.16-4.28)

9.52 (8.94-10.13)

3.44 (3.27-3.61)

 

R

5.50 (5.07-5.96)

10.47 (8.88-12.33)

2.84 (2.41-3.35)

 

H, PH

22.84, p < 0.001

5.17, p < 0.001

8.78, p < 0.001

Using more precise outcome definitionf

n

317

74

87

 

F

4.23 (4.17-4.29)

10.43 (9.72-11.20)

3.58 (3.39-3.78)

 

R

5.59 (5.15-6.07)

11.56 (9.68-13.81)

2.99 (2.49-3.58)

 

H, PH

23.48, p < 0.001

4.18, p < 0.001

9.18, p < 0.001

Using least rather than most adjusted estimates

n

331

102

107

 

F

4.23 (4.17-4.29)

9.49 (8.93-10.09)

3.38 (3.21-3.55)

 

R

5.48 (5.06-5.93)

10.37 (8.83-12.18)

2.83 (2.39-3.34)

 

H, PH

23.36, p < 0.001

5.23, p < 0.001

9.57, p < 0.001

Omitting study LIU4

n

326

NAg

NAg

 

F

6.47 (6.34-6.60)

  
 

R

5.52 (5.10-5.97)

  
 

H, PH

12.54, p < 0.001

  

Preferring results for cigarettes to results for any product

n

327

102

107

 

F

4.73 (4.66-4.80)

9.48 (8.91-10.08)

3.43 (3.27-3.61)

 

R

5.49 (5.10-5.92)

10.44 (8.88-12.29)

2.82 (2.39-3.32)

 

H, PH

19.39, p < 0.001

5.12, p < 0.001

8.72, p < 0.001

Selecting results for cigarettes onlyh

n

54

11

11

 

F

4.37 (4.28-4.47)

9.05 (7.84-10.45)

1.93 (1.70-2.18)

 

R

6.45 (5.41-7.70)

11.50 (7.47-17.69)

2.87 (1.49-5.55)

 

H, PH

22.68, p < 0.001

4.57, p < 0.001

16.64, p < 0.001

Selecting results specific for age <56 years

n

38

10

10

 

F

5.79 (5.15-6.51)

11.04 (7.08-17.20)

4.94 (3.73-6.56)

 

R

6.57 (4.94-8.74)

14.73 (6.83-31.76)

4.17 (1.86-9.35)

 

H, PH

4.17, p < 0.001

2.35, p < 0.05

7.00, p < 0.001

Selecting results specific for age 50–70 years

n

31

6

4

 

F

5.77 (5.29-6.29)

16.32 (11.11-23.95)

5.62 (3.91-8.07)

 

R

6.46 (4.99-8.35)

17.30 (10.78-27.74)

5.31 (3.20-8.79)

 

H, PH

7.67, p < 0.001

1.37, NS

1.14, NS

Selecting results specific for age 65+ years

n

37

2

2

 

F

2.88 (2.78-3.00)

15.00 (6.46-34.80)

1.73 (0.99-3.02)

 

R

5.48 (4.59-6.55)

15.00 (6.46-34.80)

1.73 (0.99-3.02)

 

H, PH

9.66, p < 0.001

0.02, NS

0.19, NS

a See Table 5 for details of the definition of this analysis.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.01, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PB = probability value for between levels (see methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Only including results for all lung cancer, squamous cell carcinoma specifically, or adenocarcinoma specifically.

g Not applicable as results by histological type were not available for study LIU4.

h See also Table 13 (footnote c).

First, the RRs for all three outcomes are markedly heterogeneous. As shown in Table 5, H is estimated as 22.84 for all lung cancer, 5.17 for squamous and 8.78 for adeno (p < 0.001). Individual RRs vary up to 125.27 for all lung cancer (study STUCKE for males), 92.66 for squamous (ABRAHA/males), and 34.45 for adeno (SCHWAR/males). Based on random-effects estimates, a positive association is seen, strongest for squamous (RR 10.47, 95% CI 8.88-12.33, based on 102 RRs), but also clearly evident for all lung cancer (5.50, 5.07-5.96, n = 328) and adeno (2.84, 2.41-3.35, n = 107). Although the strength of association varies markedly by study, the consistency of direction is clear, with only two of the all lung cancer RRs, none of the 102 squamous RRs, and nine of the 107 adeno RRs below 1.0.

As shown in Table 6, the overall estimates for each outcome were virtually unchanged by using least-adjusted rather than most-adjusted estimates. They were slightly increased by restricting attention to estimates using a more precise outcome definition, the random-effects estimates changing to 5.59 (5.15-6.07) for the 317 estimates specifically for all lung cancer, 11.56 (9.68-13.81) for the 74 estimates specifically for squamous cell carcinoma, and 2.99 (2.49-3.58) for the 87 estimates specifically for adenocarcinoma. The overall estimates for each outcome were virtually unchanged when RRs for ever smoking cigarettes were preferred to RRs for ever smoking any product. This is partly due to many studies providing only one type of RR, so that for all lung cancer, for example, 250 of the 328 RRs are common to both meta-analyses. A much smaller number of estimates were available for cigarette only smoking; RRs from these were slightly higher: 6.45 (5.41-7.70, n = 54) for all lung cancer, 11.50 (7.47-17.69, n = 11) for squamous, and 2.87 (1.49-5.55, n = 11) for adeno. Estimates were also extracted specifically for populations of age <56, 50–70 or 65+ years (with age determined at baseline for prospective studies). As shown in Table 6, data were rather limited for squamous and adeno, particularly for older populations. For all lung cancer, the three RRs: 6.57 (4.94-8.74, n = 38) for age <56 years, 6.46 (4.99-8.35, n = 31) for age 50–70 years, and 5.48 (4.59-6.55, n = 37) for age 65+ years were all consistent with the overall RR of 5.50, with no clear trend.

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 5 being summarized below, based on the random-effects estimates.

Sex

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.

Location

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 5 are based on a preference order of any product, cigarettes (ignoring other products) and cigarettes only. For all lung cancer, where 205 of the 328 estimates were for any product, 114 were for cigarettes and 9 for cigarettes only, there was no evidence that the RRs included varied by smoking product. For squamous and adeno (both p < 0.001), however, RRs were lowest for smoking any product, intermediate for cigarettes, and highest for cigarettes only (though based on only two RRs for cigarettes only for each outcome).

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 5: Detailed Analysis Tables) also includes results by levels of some other characteristics. In an attempt to evaluate the independent role of a whole range of characteristics, preliminary meta-regression analyses were conducted for each outcome (results not shown). As a result, it was decided to present findings for a fixed model involving six major characteristics (see Table 7), test the effect of each by deleting each of the six individually from the fixed model (and also by allowing each to enter a step-wise model in order of significance), and test the effect of a range of other characteristics by adding each individually into the fixed model (see Additional file 5: Detailed Analysis Tables). The main conclusions to be drawn from these analyses are summarized below.
Table 7

Meta-regression results for ever smoking of any product (or cigarettes if any product not available) a

Characteristic

Level

All lung cancer

Squamous

Adeno

  

Estimateb(SEc)

pd

Estimateb(SEc)

pd

Estimateb(SEc)

pd

Constant

 

+1.280 (0.052)

 

+1.281 (0.174)

 

+0.368 (0.178)

 

Sex

Male

Base

NS

Base

NS

Base

<0.05

 

Female

−0.040 (0.016)

 

−0.046 (0.072)

 

−0.275 (0.058)

 
 

Combined

+0.018 (0.029)

 

−0.130 (0.141)

 

+0.102 (0.138)

 

Location

North America

Base

<0.001

Base

<0.001

Base

<0.001

 

United Kingdom

−0.108 (0.057)

 

−0.861 (0.266)

 

−0.535 (0.324)

 
 

Scandinavia

−0.095 (0.051)

 

−0.484 (0.241)

 

−0.630 (0.190)

 
 

Other Europe

−0.319 (0.039)

 

−0.609 (0.114)

 

−0.731 (0.107)

 
 

China

−1.320 (0.024)

 

−1.028 (0.120)

 

−1.356 (0.094)

 
 

Japan

−0.858 (0.053)

 

−0.562 (0.226)

 

−1.158 (0.119)

 
 

Other Asia

−0.646 (0.060)

 

−0.390 (0.158)

 

−0.557 (0.127)

 
 

Other or multiregion

−0.173 (0.076)

 

−0.031 (0.301)

 

−0.024 (0.213)

 

Start year of study

Before 1960

Base

<0.001

Base

<0.001

Base

<0.05

 

1960-69

+0.384 (0.047)

 

+0.819 (0.154)

 

+0.750 (0.166)

 
 

1970-79

+0.430 (0.045)

 

+0.802 (0.130)

 

+0.672 (0.150)

 
 

1980-89

+0.783 (0.042)

 

+0.990 (0.134)

 

+0.857 (0.155)

 
 

1990 or later

+0.872 (0.063)

 

+1.788 (0.263)

 

+0.892 (0.200)

 

Study type

Case–control

Base

<0.01

Base

NS

Base

NS

 

Prospectivee

+0.238 (0.036)

 

+0.395 (0.233)

 

+0.352 (0.140)

 

Number of casesf

100-249

Base

<0.001

Base

<0.05

Base

<0.05

 

250-499

+0.101 (0.044)

 

+0.251 (0.152)

 

+0.265 (0.107)

 
 

500-999

+0.293 (0.043)

 

+0.729 (0.162)

 

+0.550 (0.121)

 
 

1000+

+0.290 (0.038)

 

+0.655 (0.145)

 

+0.594 (0.100)

 

Number of adjustment factors

0

Base

<0.05

Base

<0.05

Base

<0.1

 

1

−0.171 (0.034)

 

+0.477 (0.147)

 

+0.391 (0.110)

 
 

2+

+0.017 (0.025)

 

−0.226 (0.097)

 

+0.272 (0.078)

 

a Based on the same data as for Table 5. See that table for further definition of RRs selected for analysis, and numbers of estimates of each characteristic level.

b Estimates are of log RR. The predicted RR of a given estimate can be calculated by adding the constant to the values for the level of each characteristic applicable to the estimate (taking the value for a base level as zero) and taking the exponential of the result.

c SE = standard error.

d The p value is estimated from the drop in deviance from removing the characteristic from the fixed model using an F-test. It is expressed as p < 0.001, p < 0.01, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

e Or nested case–control or case-cohort in the case of 5 estimates for all lung cancer, 4 for squamous and 4 for adeno.

f In the study as a whole.

Note For the forward stepwise analyses, deviances, degrees of freedom and p values for inclusion in order of inclusion are as follows:

All lung cancer: Constant 7470.075 on 327 d.f. (p < 0.001), location 2247.358 on 320 d.f. (p < 0.001), start year of study 1599.339 on 316 d.f. (p < 0.001), number of cases 1523.722 on 313 d.f. (p < 0.01), study type 1497.854 on 312 d.f. (p < 0.05) and number of adjustment variables 1463.482 on 310 d.f. (p < 0.05). Fixed model deviance 1454.810 on 308 d.f.

Squamous: Constant 522.221 on 101 d.f. (p < 0.001), start year of study 419.586 on 97 d.f. (p < 0.001) and location 308.715 on 90 d.f. (p < 0.001). Fixed model deviance 260.432 on 82 d.f.

Adeno: Constant 930.356 on 106 d.f. (p < 0.001), location 431.955 on 99 d.f. (p < 0.001), number of cases 369.648 on 96 d.f. (p <0.01), start year of study 328.896 on 92 d.f. (p < 0.05) and sex 307.336 on 90 d.f. (p < 0.05). Fixed model deviance 284.147 on 87 d.f.

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 5), study type (p < 0.01, higher risks in prospective studies) and number of cases (p < 0.001, higher risks in larger studies). There was no significant effect of sex, and the weakly significant (p < 0.05) effect for number of adjustment factors was associated with an erratic pattern, with lower RRs where the number of factors was 1, and higher RRs where it was 0 or 2+. The heterogeneity for the fixed model including all the six characteristics included in Table 7 was 4.72 per d.f., with the model explaining 80.5% of the overall variation between the RRs. Inspection of standardized residuals revealed eight estimates where the value was outside the range +/− 2.5 SEs : MILLS/males (RR 1.33, fitted 3.35), LOMBA2/females (RR 1.33, fitted 5.07), TIZZAN/males (RR 1.93, fitted 3.50), WANG4/males (RR 1.16, fitted 2.01), PERNU/males (RR 8.93, fitted 4.37), LUBIN2/males (RR 8.50, fitted 5.47), BOFFET/males (RR 14.20, fitted 7.78) and JUSSAW/males (RR 16.83, fitted 3.77). Only two other characteristics studied significantly (p < 0.05) improved the fit of the model, both related to study location. One was a variable subdividing “Other Europe” (i.e. other than UK and Scandinavia) into five smaller regions, with risk relatively low in the Balkans (Greek and Turkish studies) and relatively high in multiregional studies compared with the rest, and the other a variable subdividing “Other Asia” (i.e. other than China or Japan) into three smaller regions, with risk higher in India compared to Hong Kong and the rest of Asia (Taiwan, Thailand, Singapore and South Korea). No independent effect was evident for national cigarette tobacco type. Additional analysis (data not shown) confirmed the strong independent effect of start year of study separately within studies conducted in North America, Europe and Asia, though the tendency for higher RRs in more recent studies was stronger in North America than in Europe, and the pattern of variation was more erratic for Asia. It also confirmed the strong independent effects of location and start year of study separately for males and for females.

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 7) was 3.18 per d.f., the model explaining 49.9% of the overall variation. Two standardized residuals were outside the range +/− 2.5 SEs : STAYNE/males (RR 3.47, fitted 10.50) and LUBIN2/males (RR 16.66, fitted 8.41). Two other characteristics significantly improved the model fit. One was national cigarette tobacco type, with RRs higher where flue-cured Virginia tobacco was smoked, than where blended tobacco was smoked. Also, RRs were higher (p < 0.01) where they had been derived by a relatively complex method (see Methods) than where they were as reported originally, or derived by more standard methods.

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 7) was 3.27 per d.f., the model explaining 69.5% of the overall variation. Two standardized residuals were outside the range +/− 2.5 SEs : LOMBA2/females (RR 0.53, fitted 2.32) and WYNDER6/females (RR 13.99 fitted 6.22). Four other characteristics significantly improved the model fit. One was “Other Asia” (p < 0.05) where RRs were high in India (based on a single RR from JUSSAW) and relatively low in Hong Kong, Taiwan, Thailand, Singapore and South Korea. National cigarette tobacco type was also significant (p < 0.05), with RRs for blended higher than for Virginia, opposite to the finding for squamous. RRs were also lower where there was any use of proxy respondents (p < 0.05). Also, RRs varied (p < 0.001) by the detailed definition of adenocarcinoma used. This appeared to be mainly because of a low RR for “not squamous or undifferentiated”, a definition used only for LOMBA2/females, where the standardized residual of −3.721 SEs was the largest for any RR (see also above).

The fixed model (Table 7) considered how RR estimates varied by six main characteristics and additional analyses (see Additional file 5: Detailed Analysis Tables) tested whether adding in further characteristics improved the model fit. Characteristics which did not improve the fit for any of the three outcomes considered included whether there was adjustment for specific factors (such as age), the age of the subjects studied, the definition of smoking product, the definition of the unexposed base, whether the study was conducted in a population working in a risky occupation, and whether the study procedures required full histological confirmation.

B. Risk from current smoking

Figures 10, 11, 12 (all lung cancer), Figure 13 (squamous) and Figure 14 (adeno) present the results of the main meta-analyses for current smoking of any product. As before, RRs for smoking of cigarettes are used if RRs for any product smoking are not available, and RRs are most-adjusted. For prospective studies, current smoking refers to smoking status as at baseline. Table 8 presents additional results by level of the same set of characteristics considered in Table 5, while Table 9 presents results of alternative meta-analyses of current smoking.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig10_HTML.jpg
Figure 10

Forest plot of current smoking of any product and all lung cancer – part 1. Table 8 presents the results of a main meta-analysis for all lung cancer based on 195 relative risk (RR) and 95% confidence interval (CI) estimates for current smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale in Figures 10, 11, 12. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. For study DORGAN separate estimates, within sex, are shown for whites then blacks. For study HUMBLE they are shown for non-hispanic whites then hispanics, and for study SCHWAR for whites then non-whites.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig11_HTML.jpg
Figure 11

Forest plot of current smoking of any product and all lung cancer – part 2. This is a continuation of Figure 10, presenting further individual study data included in the main meta-analysis for all lung cancer shown in Table 8. For study KELLER separate estimates, within sex, are shown for whites then non-whites.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig12_HTML.jpg
Figure 12

Forest plot of current smoking of any product and all lung cancer – part 3. This is a continuation of Figure 11, presenting the remaining individual study data included in the main meta-analysis for all lung cancer shown in Table 8. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI. For study KREUZE separate estimates, within sex, are shown for age ≤ 45 and 55–69.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig13_HTML.jpg
Figure 13

Forest plot of current smoking of any product and squamous. Table 8 presents the results of a main meta-analysis for squamous based on 41 relative risk (RR) and 95% confidence interval (CI) estimates for current smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig14_HTML.jpg
Figure 14

Forest plot of current smoking of any product and adeno. Table 8 presents the results of a main meta-analysis for adeno based on 44 relative risk (RR) and 95% confidence interval (CI) estimates for current smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

Table 8

Main meta-analyses for current smoking of any product (or cigarettes, if any product not available) a

Characteristic

Level

Statisticb

All lung cancerc

Squamousd

Adenoe

All

All

n

195

41

44

  

F

9.29 (9.07-9.52)

13.77 (12.75-14.87)

4.77 (4.49-5.07)

  

R

8.43 (7.63-9.31)

16.91 (13.14-21.76)

4.21 (3.32-5.34)

  

H, PH

13.76, p < 0.001

7.22, p < 0.001

12.28, p < 0.001

  

PE

p < 0.05

NS

NS

Sex

Male

n

108

22

22

  

F

8.68 (8.36-9.02)

13.11 (11.85-14.51)

5.54 (5.04-6.09)

  

R

9.16 (8.00-10.49)

17.73 (12.78-24.59)

5.56 (4.06-7.61)

 

Female

n

68

17

20

  

F

8.06 (7.75-8.38)

13.44 (11.86-15.23)

4.40 (4.05-7.79)

  

R

6.76 (5.65-8.08)

14.77 (9.42-23.17)

3.20 (2.18-4.71)

 

Combined

n

19

2

2

  

F

13.19 (12.55-13.86)

34.23 (23.43-50.00)

3.11 (2.35-4.11)

  

R

12.09 (9.38-15.60)

34.23 (23.43-50.00)

3.57 (1.06-12.07)

 

Between levels

PB

<0.001

<0.01

<0.1

Location

North America

n

84

24

24

  

F

12.45 (12.09-12.82)

17.99 (16.29-19.85)

7.63 (7.05-8.25)

  

R

11.68 (10.61-12.85)

20.95 (15.41-28.48)

6.72 (5.50-8.21)

 

United Kingdom

n

25

0

0

  

F

6.90 (6.10-7.81)

  
  

R

7.53 (5.40-10.50)

  
 

Scandinavia

n

21

2

2

  

F

8.16 (7.30-9.12)

15.51 (6.63-36.28)

4.66 (2.67-8.13)

  

R

8.68 (7.14-10.54)

15.51 (6.63-36.28)

4.69 (2.62-8.40)

 

Other Europe

n

23

6

6

  

F

5.88 (5.43-6.38)

12.22 (10.16-14.69)

2.65 (2.20-3.18)

  

R

8.65 (5.98-12.51)

13.66 (7.38-25.30)

3.30 (1.93-5.65)

 

China

n

5

0

0

  

F

3.07 (2.56-3.68)

  
  

R

2.94 (2.23-3.88)

  
 

Japan

n

18

8

11

  

F

3.68 (3.43-3.95)

6.85 (5.77-8.13)

2.11 (1.87-2.37)

  

R

3.55 (3.05-4.14)

11.25 (6.89-18.35)

1.87 (1.42-2.47)

 

Other Asia

n

7

0

0

  

F

2.91 (2.26-3.76)

  
  

R

2.90 (2.04-4.13)

  
 

Other or multiregion

n

12

1

1

  

F

7.09 (6.10-8.24)

10.40 (3.31-32.66)

7.90 (2.99-20.85)

  

R

9.88 (6.89-14.17)

10.40 (3.31-32.66)

7.90 (2.99-20.85)

 

Between levels

PB

<0.001

NS

<0.001

Start year of study

Before 1960

n

22

6

5

  

F

6.13 (5.70-6.59)

6.87 (4.93-9.08)

3.35 (2.43-4.62)

  

R

6.39 (4.70-8.69)

11.05 (4.07-30.00)

2.92 (1.17-7.28)

 

1960-69

n

40

7

7

  

F

5.43 (5.12-5.75)

10.55 (9.07-12.26)

4.22 (3.76-4.74)

  

R

6.44 (5.21-7.95)

15.48 (7.08-33.83)

4.55 (2.50-8.30)

 

1970-79

n

41

8

11

  

F

7.27 (6.79-7.79)

14.53 (12.21-17.29)

2.99 (2.55-3.50)

  

R

7.34 (5.94-9.06)

16.43 (8.67-31.14)

3.41 (2.10-5.53)

 

1980-89

n

70

18

19

  

F

12.35 (11.97-12.75)

16.70 (14.93-18.67)

6.38 (5.84-6.96)

  

R

10.18 (9.02-11.49)

19.69 (15.08-25.71)

5.06 (3.65-7.02)

 

1990 or later

n

22

2

2

  

F

10.32 (9.10-11.70)

20.79 (10.16-42.55)

2.28 (1.63-3.19)

  

R

12.81 (8.70-18.85)

19.39 (6.38-58.88)

3.62 (0.92-14.29)

 

Between levels

PB

<0.001

NS

NS

Study type

Case–control

n

128

30

34

  

F

9.69 (9.43-9.95)

13.59 (12.56-14.70)

4.71 (4.42-5.01)

  

R

8.56 (7.58-9.68)

16.21 (12.23-21.50)

3.88 (2.96-5.07)

 

Prospectivef

n

67

11

10

  

F

8.04 (7.65-8.46)

18.87 (12.90-27.59)

5.93 (4.59-7.66)

  

R

8.15 (6.87-9.67)

19.63 (12.21-31.56)

5.95 (4.07-8.69)

 

Between levels

PB

NS

NS

p < 0.1

National cigarette tobacco type

Virginia

n

34

2

2

  

F

6.75 (6.12-7.44)

31.44 (15.03-65.78)

6.93 (4.35-11.07)

  

R

8.01 (6.16-10.41)

31.44 (15.03-65.78)

6.93 (4.35-11.07)

 

Blended

n

154

39

42

  

F

9.70 (9.46-9.95)

13.65 (12.63-14.75)

4.74 (4.45-5.04)

  

R

8.92 (8.01-9.94)

16.41 (12.68-21.24)

4.10 (3.21-5.23)

 

Other

n

7

0

0

  

F

3.13 (2.64-3.72)

  
  

R

3.09 (2.50-3.83)

  
 

Between levels

PB

<0.001

NS

p < 0.1

Any proxy use

Nog

n

156

35

38

  

F

9.24 (9.00-9.48)

13.09 (12.09-14.18)

4.67 (4.39-4.98)

  

R

8.04 (7.17-9.01)

15.78 (12.00-20.74)

3.88 (2.99-5.03)

 

Yes

n

39

6

6

  

F

9.68 (9.05-10.36)

27.96 (20.74-37.69)

6.88 (5.27-8.97)

  

R

10.03 (8.32-12.09)

27.96 (20.74-37.69)

6.88 (5.27-8.97)

 

Between levels

PB

<0.05

<0.01

p < 0.01

Full histological confirmation

No

n

144

24

23

  

F

8.87 (8.62-9.12)

11.53 (10.05-13.23)

3.99 (3.59-4.43)

  

R

7.91 (7.00-8.93)

19.20 (12.62-29.22)

5.59 (3.98-7.84)

 

Yes

n

51

17

21

  

F

10.45 (9.99-10.92)

14.94 (13.61-16.40)

5.25 (4.87-5.67)

  

R

10.08 (8.46-12.01)

14.77 (10.61-20.57)

3.20 (2.28-4.49)

 

Between levels

PB

<0.05

NS

p < 0.05

Number of casesh

100-249

n

56

8

11

  

F

5.50 (4.96-6.11)

5.62 (3.96-7.98)

2.54 (2.02-3.19)

  

R

6.90 (5.46-8.72)

11.28 (5.08-25.04)

2.45 (1.54-3.90)

 

250-499

n

48

9

9

  

F

8.47 (7.79-9.22)

16.67 (11.49-24.18)

3.20 (2.59-3.95)

  

R

8.60 (7.02-10.52)

17.09 (11.28-25.91)

3.83 (2.41-6.09)

 

500-999

n

38

4

4

  

F

7.56 (7.04-8.13)

22.44 (13.58-37.07)

7.35 (5.12-10.55)

  

R

9.54 (7.65-11.89)

22.44 (13.58-37.07)

7.35 (5.12-10.55)

 

1000+

n

53

20

20

  

F

10.01 (9.74-10.29)

14.15 (13.03-15.35)

5.18 (4.84-5.54)

  

R

9.03 (7.63-10.69)

17.87 (12.92-24.70)

4.97 (3.54-6.97)

 

Between levels

PB

NS

NS

p <0.01

Smoking product

Any

n

85

9

11

  

F

8.00 (7.64-8.37)

17.58 (11.99-25.77)

2.61 (2.16-3.14)

  

R

7.57 (6.47-8.84)

17.76 (11.75-26.86)

2.40 (1.59-3.61)

 

Cigarettes (ignoring

n

95

26

28

 

other products)

F

9.84 (9.56-10.14)

13.51 (12.47-14.64)

5.11 (4.79-5.46)

  

R

8.95 (7.76-10.33)

16.43 (12.08-22.33)

5.02 (3.76-6.70)

 

Cigarettes only

n

15

6

5

  

F

9.77 (8.92-10.69)

17.80 (11.39-27.83)

5.69 (4.00-8.09)

  

R

10.51 (7.70-14.34)

18.04 (9.79-33.27)

5.56 (2.61-11.85)

 

Between levels

PB

NS

NS

p < 0.05

Unexposed base

Never any product

n

134

24

27

  

F

8.80 (8.55-9.06)

9.80 (8.75-10.98)

3.01 (2.75-3.29)

  

R

8.24 (7.28-9.34)

14.05 (9.75-20.23)

3.10 (2.37-4.07)

 

Never cigarettes

n

61

17

17

  

F

10.43 (10.00-10.88)

18.44 (16.60-20.48)

7.17 (6.59-7.80)

  

R

8.89 (7.52-10.51)

21.71 (16.38-28.76)

6.61 (4.89-8.95)

 

Between levels

PB

NS

<0.1

<0.001

Number of adjustment variables

0

n

86

16

17

  

F

10.84 (10.46-11.23)

14.93 (13.02-17.12)

4.28 (3.83-4.79)

  

R

9.40 (8.02-11.03)

17.15 (10.78-27.27)

3.90 (2.54-6.00)

 

1

n

62

15

14

  

F

7.80 (7.43-8.19)

19.11 (15.33-23.83)

3.25 (2.76-3.83)

  

R

7.28 (6.14-8.63)

18.27 (12.55-26.60)

3.46 (2.27-5.29)

 

2+

n

47

10

13

  

F

8.49 (8.13-8.87)

12.24 (11.04-13.57)

5.58 (5.13-6.05)

  

R

8.54 (7.02-10.39)

15.20 (9.40-24.58)

5.68 (3.80-8.49)

 

Between levels

PB

p < 0.1

NS

NS

a Within each study, results for current smokers are selected in the following preference order, within each sex, for:

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods);

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group.

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PE = probability value for Egger’s test of publication bias similarly expressed, PB = probability value for between levels (see Methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Or nested case–control or case-cohort in the case of 5 estimates for all lung cancer, 3 for squamous and 3 for adeno.

g Including not known.

h In the study as a whole.

Table 9

Some alternative meta-analyses for current smoking compared to those in Table 8

Analysis description

Statisticb

All lung cancerc

Squamousd

Adenoe

As Table 8 a

n

195

41

44

 

F

9.29 (9.07-9.52)

13.77 (12.75-14.87)

4.77 (4.49-5.07)

 

R

8.43 (7.63-9.31)

16.91 (13.14-21.76)

4.21 (3.32-5.34)

 

H, PH

13.76, p < 0.001

7.22, p < 0.001

12.28, p < 0.001

Using more precise outcome definitionf

n

187

33

40

 

F

9.93 (9.68-10.17)

12.74 (11.71-13.87)

4.40 (4.12-4.70)

 

R

8.79 (7.97-9.68)

16.43 (12.66-21.32)

4.05 (3.15-5.22)

 

H, PH

11.96, p < 0.001

5.70, p < 0.001

12.28, p < 0.001

Using least rather than most adjusted estimates

n

195

41

44

 

F

9.12 (8.91-9.34)

13.81 (12.79-14.92)

4.82 (4.53-5.12)

 

R

8.26 (7.49-9.12)

16.83 (13.12-21.60)

4.27 (3.37-5.40)

 

H, PH

13.91, p < 0.001

7.17, p < 0.001

12.33, p < 0.001

Denominator non-smoker rather than never smoker

n

188

36

38

 

F

3.99 (3.92-4.05)

3.59 (3.42-3.77)

2.65 (250–2.80)

 

R

3.75 (3.48-4.03)

4.71 (3.84-5.79)

2.46 (2.07-2.93)

 

H, PH

15.67, p < 0.001

12.71, p < 0.001

7.64, p < 0.001

Preferring results for cigarettes to results for any product

n

195

41

44

 

F

9.47 (9.25-9.69)

13.77 (12.75-14.87)

4.77 (4.49-5.07)

 

R

8.64 (7.83-9.54)

16.91 (13.14-21.76)

4.21 (3.32-5.34)

 

H, PH

13.72, p < 0.001

7.22, p < 0.001

12.28, p < 0.001

Selecting results for cigarettes onlyg

n

38

8

7

 

F

9.25 (8.81-9.71)

21.49 (16.73-27.61)

7.18 (5.71-9.04)

 

R

9.52 (7.89-11.49)

20.85 (14.84-29.29)

6.05 (3.69-9.92)

 

H, PH

10.61, p < 0.001

1.38, NS

2.98, p < 0.1

Selecting results specific for age <56 years

n

25

2

3

 

F

7.64 (6.69-8.73)

6.48 (2.90-14.52)

0.74 (0.42-1.32)

 

R

6.57 (4.68-9.23)

6.48 (2.90-14.52)

0.74 (0.42-1.32)

 

H, PH

4.17, p < 0.001

0.33, NS

0.21, NS

Selecting results specific for age 50–70 years

n

24

1

0

 

F

10.45 (9.65-11.31)

26.42 (9.78-71.36)

 
 

R

9.62 (7.10-13.05)

26.42 (9.78-71.36)

 
 

H, PH

9.99, p < 0.001

NA

 

Selecting results specific for age 65+ years

n

27

0

0

 

F

8.79 (8.06-9.58)

  
 

R

9.07 (6.83-12.04)

  
 

H, PH

8.37, p < 0.001)

  

a See Table 8 for details of the definition of this analysis.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PB = probability value for between levels (see Methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Only including results for all lung cancer, squamous cell carcinoma specifically, or adenocarcinoma specifically.

g See also Table 13 (footnote c).

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 9) by preferring least, rather than most, adjusted RRs, by restricting to a more precise outcome definition, or by preferring RRs for current smoking of cigarettes to those for current smoking of any product. Again estimates based specifically on cigarette only smoking were slightly higher than those shown in Table 8 – 9.52 (7.89-11.49, n = 38) for all lung cancer, 20.85 (14.84-29.29, n = 8) for squamous, and 6.05 (3.69-9.92, n = 7) for adeno. More so than in Table 6, data by age were rather limited for squamous and adeno. For all lung cancer estimates were 6.57 (4.68-9.23, n = 25) for age <56 years, 9.62 (7.10-13.05, n = 24) for age 50–70 years, and 9.07 (6.83-12.04, n = 27) for age 65+ years, no clear trend being evident. Table 9 also includes results for the comparison current vs. non-current smokers. The RRs here (3.75, 3.48-4.03 for all lung cancer; 4.71, 3.84-5.79 for squamous; 2.46, 2.07-2.93 for adeno) were markedly lower than the corresponding estimates for current vs. never smokers, reflecting the increased risk in ex-smokers described later (see section D below).

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 8, the pattern of variation has a number of similarities to that for ever smoking in Table 5. Thus, as for ever smoking, RRs for all three outcomes tend to be higher for males, for North American studies, and where the unexposed base is never cigarettes, and smaller for older studies and smaller studies, with no clear variation by extent of adjustment. A tendency for RRs to be higher where data may be reported by proxy respondents seems somewhat stronger for current smoking, although based on few estimates for squamous and adeno. A tendency for RRs to be higher where the smoking product is cigarettes or cigarettes only than when it is any product is also evident, though not for squamous, whereas it was seen most clearly in squamous for ever smoking. There is also some indication that RRs are higher in prospective studies, though interestingly not for all lung cancer. Whereas for ever smoking, RRs for studies requiring full histological confirmation were higher than for those that did not for all three outcomes, the tendency was in the reverse direction for squamous and adeno for current smoking. For national cigarette tobacco type, current smoking RRs for squamous and adeno are virtually all for blended, so are unhelpful. For all lung cancer, RRs are quite similar for Virginia and blended, the significant (p < 0.001) variation shown in Table 8 arising because of the low RRs in the “Other” group, mainly for China.

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 10. Based on these results and those for other characteristics in Additional file 5: Detailed Analysis Tables various conclusions can be drawn.
Table 10

Meta-regression analyses for current smoking of any product (or cigarettes if any product not available) a

Characteristic

Level

All lung cancer

Squamous

Adeno

  

Estimateb(SEc)

pd

Estimateb(SEc)

pd

Estimateb(SEc)

pd

Constant

 

+1.566 (0.081)

 

+1.193 (0.239)

 

+0.816 (0.239)

 

Sex

Male

Base

<0.01

Base

NS

Base

<0.001

 

Female

−0.204 (0.029)

 

−0.002 (0.088)

 

−0.440 (0.067)

 
 

Combined

−0.043 (0.039)

 

+0.224 (0.459)

 

−0.612 (0.378)

 

Location

North America

Base

<0.001

Base

<0.05

Base

<0.001

 

United Kingdom

−0.345 (0.071)

 

No data

 

No data

 
 

Scandinavia

−0.417 (0.066)

 

−0.177 (0.513)

 

−0.298 (0.320)

 
 

Other Europe

−0.602 (0.057)

 

−0.440 (0.266)

 

−1.157 (0.178)

 
 

China

−1.528 (0.097)

 

No data

 

No data

 
 

Japan

−1.174 (0.056)

 

−1.174 (0.193)

 

−1.525 (0.136)

 
 

Other Asia

−1.221 (0.139)

 

No data

 

No data

 
 

Other or multiregion

−0.593 (0.088)

 

−1.221 (1.045)

 

−1.014 (0.754)

 

Start year of study

Before 1960

Base

<0.001

Base

<0.1

Base

<0.05

 

1960-69

+0.538 (0.063)

 

+1.374 (0.321)

 

+1.179 (0.231)

 
 

1970-79

+0.571 (0.058)

 

+0.896 (0.418)

 

+1.142 (0.258)

 
 

1980-89

+0.788 (0.051)

 

+1.276 (0.325)

 

+0.957 (0.224)

 
 

1990 or later

+1.169 (0.089)

 

+2.817 (0.823)

 

+1.982 (0.575)

 

Study type

Case–control

Base

<0.1

Base

NS

Base

NS

 

Prospectivee

+0.182 (0.047)

 

+0.404 (0.371)

 

+0.178 (0.224)

 

Number of casesf

100-249

Base

<0.1

Base

NS

Base

NS

 

250-499

+0.222 (0.071)

 

+0.420 (0.384)

 

−0.002 (0.195)

 
 

500-999

+0.266 (0.070)

 

+0.852 (0.400)

 

+0.646 (0.232)

 
 

1000+

+0.340 (0.062)

 

+0.803 (0.298)

 

+0.362 (0.149)

 

Number of adjustment factors

0

Base

NS

Base

<0.05

Base

NS

 

1

+0.002 (0.047)

 

+0.428 (0.277)

 

+0.195 (0.213)

 
 

2+

+0.069 (0.034)

 

−0.447 (0.175)

 

+0.283 (0.125)

 

a Based on the same data as for Table 8. See that table for further definition of RRs selected for analysis, and numbers of estimates of each characteristic level.

b Estimates are of log RR. The predicted RR of a given estimate can be calculated by adding the constant to the values for the level of each characteristic applicable to the estimate (taking the value for a base level as zero) and taking the exponential of the result.

c SE = standard error.

d The p value is estimated from the drop in deviance from removing the characteristic from the fixed model using an F-test. It is expressed as p < 0.001, p < 0.01, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

e Or nested case–control or case-cohort in the case of 5 estimates for all lung cancer, 3 for squamous and 3 for adeno.

f In the study as a whole.

Note For the forward stepwise analyses, deviances, degrees of freedom and p values for inclusion in order of inclusion are as follows:

All lung cancer: Constant 2669.216 on 194 d.f. (p < 0.001), location 1257.714 on 187 d.f. (p < 0.001), start year of study 918.536 on 183 d.f. (p < 0.001) and sex 869.479 on 181 d.f. (p < 0.01). Fixed model deviance 819.856 on 175 d.f.

Squamous: Constant 288.688 on 40 d.f. (p < 0.001), location 194.753 on 36 d.f. (p < 0.01), start year of study 143.741 on 32 d.f. (p < 0.05) and number of adjustment variables 100.916 on 30 d.f. (p < 0.01). Fixed model deviance 86.049 on 24 d.f.

Adeno: Constant 528.128 on 43 d.f. (p < 0.001), location 170.181 on 39 d.f. (p < 0.001), sex 128.397 on 37 d.f. (p < 0.01) and start year of study 89.243 on 33 d.f. (p < 0.05). Fixed model deviance 65.727 on 27 d.f.

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 10 was 4.68 per d.f., with the model explaining 69.3% of the overall variation between the current smoking RRs. Four standardized residuals were outside the range +/− 2.5 SEs : BROWN2/males (RR 11.30, fitted 15.86), TIZZAN/males (RR 1.90, fitted 3.68), CPSI/females (RR 3.20, fitted 6.59) and KREUZE/males aged 55–69 (RR 41.86, fitted 11.85). No other characteristic significantly improved the fit when added to the fixed model. Additional analysis (data not shown) confirmed the effect of start year of study separately for North America and Europe (though no such relationship was seen in Asia) and also confirmed that the effects of location and start year of study were evident separately for males and for females.

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 10) were significant, and then only at p < 0.05, and one of these was number of adjustment factors, where the pattern of response was erratic. Location was the other, with RRs again highest in North America and lowest in Asia. There were no estimates with large standardized residuals, and no other characteristic improved the model fit.

For adeno, three of the characteristics considered in Table 10 contributed significantly to the model, sex (p < 0.001), location (p < 0.001) and start year of study (p < 0.05), with the direction of effect similar to that noted earlier for ever smoking. There were no large standardized residuals, and the only additional characteristic which improved the model fit (p < 0.05) related to somewhat lower RRs being seen for studies with full histological confirmation.

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 11. The number of studies included increased from 236 to 242 for all lung cancer, from 73 to 78 for squamous and from 75 to 81 for adeno, compared with Table 5. Note that the slightly higher number of RR estimates in the current/ever analysis arises from inclusion there of more sex-specific results.
Table 11

Main meta-analyses for current or ever smoking of any product (or cigarettes, if not available) a

Preference

Statisticb

All lung cancerc

Squamousd

Adenoe

Ever smoking to current smoking

n

342

110

116

 

F

4.25 (4.20-4.31)

9.15 (8.63-9.70)

3.38 (3.23-3.55)

 

R

5.48 (5.07-5.93)

10.58 (9.04-12.37)

2.94 (2.52-3.43)

 

H, PH

22.46, p < 0.001

5.22, p < 0.001

8.61, p < 0.001

Current smoking to ever smoking

n

344

110

116

 

F

4.45 (4.39-4.51)

10.08 (9.51-10.69)

3.58 (3.41-3.76)

 

R

6.20 (5.68-6.77)

11.53 (9.73-13.66)

3.13 (2.67-3.67)

 

H, PH

28.33, p < 0.001

6.30, p < 0.001

8.99, p < 0.001

a Within each study, results are selected in the following preference order, within each sex, for:

smoking status – ever, current or current, ever according to analysis;

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods);

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group.

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PB = probability value for between levels (see Methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

As many of the RRs are common between the specific ever smoking analyses in Table 5 and the ever/current smoking analyses in Table 11, the meta-analysis RRs tend to be quite similar. However those for current/ever smoking are intermediate between those specifically for ever smoking (Table 5) and those specifically for current smoking (Table 8). For example, for all lung cancer, random-effects estimates are 5.50 (95% CI 5.07-5.96, n = 328) for ever smoking, 5.48 (5.07-5.93, n = 342) for ever/current smoking, 6.20 (5.68-6.77, n = 344) for current/ever smoking, and 8.43 (7.63-9.31, n = 195) for current smoking. The pattern of RRs by level of the characteristics studied for both ever/current and current/ever smoking tends to be quite similar to that for the specific analyses. Results for ever or current smoking by level of selected characteristics are therefore only presented in Additional file 5: Detailed Analysis Tables.

D. Risk from ex smoking

Figures 15, 16, 17 (all lung cancer), Figure 18 (squamous) and Figure 19 (adeno) present the results of the main meta-analyses for ex smoking of any product (or cigarettes if any product was not available), based on most-adjusted RRs. Some results by levels of characteristics are shown in Table 12.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig15_HTML.jpg
Figure 15

Forest plot of ex smoking of any product and all lung cancer – part 1. Table 12 presents the results of a main meta-analysis for all lung cancer based on 182 relative risk (RR) and 95% confidence interval (CI) estimates for ex smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale in Figures 15, 16, 17. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. For studies DORGAN and KELLER separate estimates, within sex, are shown for whites then blacks. For study HUMBLE they are shown for non-hispanic whites then Hispanics. For study KELLER the estimate shown for females is for whites.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig16_HTML.jpg
Figure 16

Forest plot of ex smoking of any product and all lung cancer – part 2. This is a continuation of Figure 15, presenting further individual study data included in the main meta-analysis for all lung cancer shown in Table 12. For study KELLER the estimate shown for females is for non-whites.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig17_HTML.jpg
Figure 17

Forest plot of ex smoking of any product and all lung cancer – part 3. This is a continuation of Figure 16, presenting the remaining individual study data included in the main meta-analysis for all lung cancer shown in Table 12. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI. For study KREUZE separate estimates, within sex, are shown for age ≤ 45 and 55–69.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig18_HTML.jpg
Figure 18

Forest plot of ex smoking of any product and squamous. Table 12 presents the results of a main meta-analysis for squamous based on 33 relative risk (RR) and 95% confidence interval (CI) estimates for ex smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig19_HTML.jpg
Figure 19

Forest plot of ex smoking of any product and adeno. Table 5 presents the results of a main meta-analysis for adeno based on 34 relative risk (RR) and 95% confidence interval (CI) estimates for ex smoking of any product (or cigarettes if any product not available). The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effect estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

Table 12

Main meta-analyses for ex smoking of any product (or cigarettes, if any product not available) a

Characteristic

Level

Statisticb

All lung cancerc

Squamousd

Adenoe

All

All

n

182

33

34

  

F

5.80 (5.63-5.96)

10.25 (9.34-11.24)

4.38 (4.04-4.73)

  

R

4.30 (3.93-4.71)

8.74 (6.94-11.01)

2.85 (2.20-3.70)

  

H, PH

6.98, <0.001

3.54, <0.001

7.91, <0.001

  

PE

p < 0.001

NS

p < 0.001

Sex

Male

n

100

17

17

  

F

5.15 (4.93-5.37)

9.31 (8.27-10.47)

4.59 (4.10-5.15)

  

R

4.48 (3.98-5.06)

8.41 (6.18-11.45)

3.45 (2.40-4.96)

 

Female

n

62

14

15

  

F

5.81 (5.51-6.14)

11.66 (9.94-13.68)

4.48 (4.00-5.02)

  

R

3.58 (3.00-4.29)

8.03 (5.18-12.45)

2.39 (1.55-3.69)

 

Combined

n

20

2

2

  

F

6.98 (6.61-7.37)

15.23 (9.63-24.08)

1.97 (1.35-2.88)

  

R

5.58 (4.23-7.36)

15.23 (9.63-24.08)

2.07 (0.67-6.38)

 

Between levels

PB

<0.05

<0.1

NS

Location

North America

n

80

18

17

  

F

6.79 (6.57-7.01)

10.83 (9.73-12.05)

5.69 (5.20-6.23)

  

R

5.44 (4.91-6.03)

9.43 (6.84-13.01)

4.08 (3.08-5.39)

 

United Kingdom

n

21

0

0

  

F

4.14 (3.48-4.92)

  
  

R

3.72 (2.51-5.50)

  
 

Scandinavia

n

21

2

2

  

F

2.67 (2.29-3.11)

4.06 (1.61-10.25)

1.48 (0.77-2.83)

  

R

2.62 (2.01-3.42)

4.06 (1.61-10.25)

1.48 (0.77-2.83)

 

Other Europe

n

24

6

6

  

F

3.57 (3.26-3.92)

9.10 (7.38-11.22)

2.27 (1.82-2.84)

  

R

3.96 (3.07-5.12)

8.42 (5.03-14.10)

2.58 (1.47-4.52)

 

China

n

5

0

0

  

F

3.46 (2.70-4.44)

  
  

R

3.09 (2.02-4.74)

  
 

Japan

n

14

6

8

  

F

2.35 (2.01-2.76)

9.32 (5.69-15.28)

1.60 (1.25-2.05)

  

R

2.40 (1.99-2.89)

9.32 (5.69-15.28)

1.60 (1.25-2.05)

 

Other Asia

n

5

0

0

  

F

2.13 (1.37-3.32)

  
  

R

2.12 (1.29-3.47)

  
 

Other or multiregion

n

12

1

1

  

F

5.77 (4.73-7.03)

3.60 (1.00-12.93)

4.80 (1.79-12.85)

  

R

5.84 (4.60-7.41)

3.60 (1.00-12.93)

4.80 (1.79-12.85)

 

Between levels

PB

<0.001

NS

<0.001

Start year of study

Before 1960

n

18

2

1

  

F

3.55 (3.19-3.94)

1.34 (0.71-2.52)

1.42 (0.29-6.82)

  

R

3.81 (2.84-5.11)

1.34 (0.71-2.52)

1.42 (0.29-6.82)

 

1960-69

n

36

5

5

  

F

4.06 (3.68-4.48)

11.29 (8.77-14.54)

3.56 (2.95-4.29)

  

R

3.32 (2.71-4.08)

11.29 (8.77-14.54)

2.80 (1.86-4.21)

 

1970-79

n

36

8

10

  

F

3.81 (3.50-4.14)

9.85 (8.08-12.02)

2.38 (1.95-2.91)

  

R

3.48 (2.85-4.25)

9.39 (6.00-14.68)

2.59 (1.75-3.84)

 

1980-89

n

70

16

16

  

F

6.91 (6.68-7.15)

10.97 (9.75-12.36)

5.67 (5.13-6.26)

  

R

5.22 (4.65-5.86)

10.35 (7.57-14.15)

3.37 (2.35-4.85)

 

1990 or later

n

22

2

2

  

F

4.73 (4.11-5.43)

8.38 (3.79-18.53)

1.58 (1.00-2.49)

  

R

5.17 (3.66-7.31)

7.58 (1.98-29.00)

2.22 (0.56-8.79)

 

Between levels

PB

<0.001

<0.001

NS

Study type

Case–control

n

123

28

30

  

F

6.28 (6.09-6.48)

10.71 (9.74-11.76)

4.44 (4.10-4.81)

  

R

4.88 (4.41-5.41)

9.94 (8.05-12.28)

2.96 (2.26-3.87)

 

Prospectivef

n

59

5

4

  

F

3.84 (3.58-4.12)

2.34 (1.35-4.03)

1.87 (1.04-3.36)

  

R

3.18 (2.70-3.74)

3.54 (1.38-9.09)

1.87 (1.04-3.36)

 

Between levels

PB

<0.001

<0.05

NS

National cigarette tobacco type

Virginia

n

30

2

2

  

F

3.95 (3.45-4.53)

9.22 (4.21-20.18)

2.03 (1.15-3.57)

  

R

3.79 (2.85-5.04)

9.22 (4.21-20.18)

2.27 (0.92-5.59)

 

Blended

n

147

31

32

  

F

5.94 (5.77-6.12)

10.26 (9.35-11.27)

4.44 (4.10-4.81)

  

R

4.45 (4.04-4.91)

8.68 (6.83-11.04)

2.89 (2.22-3.77)

 

Other

n

5

0

0

  

F

3.46 (2.70-4.44)

  
  

R

3.09 (2.02-4.74)

  
 

Between levels

PB

NS

NS

NS

Any proxy use

Nog

n

141

27

28

  

F

6.02 (5.84-6.21)

10.17 (9.23-11.20)

4.46 (4.11-4.84)

  

R

4.12 (3.70-4.59)

8.33 (6.38-10.89)

2.73 (2.04-3.65)

 

Yes

n

41

6

6

  

F

4.60 (4.26-4.96)

11.24 (8.01-15.78)

3.30 (2.42-4.52)

  

R

4.79 (4.20-5.47)

11.24 (8.01-15.78)

3.39 (2.25-5.11)

 

Between levels

PB

<0.1

NS

NS

Full histological confirmation

No

n

131

16

15

  

F

5.73 (5.53-5.93)

8.91 (7.03-11.30)

3.50 (2.89-4.23)

  

R

4.11 (3.68-4.60)

8.11 (5.05-13.01)

3.24 (2.13-4.94)

 

Yes

n

51

17

19

  

F

5.93 (5.65-6.23)

10.51 (9.50-11.62)

4.59 (4.21-5.00)

  

R

4.76 (4.02-5.63)

9.28 (7.08-12.15)

2.60 (1.85-3.65)

 

Between levels

PB

NS

NS

NS

Number of casesg

100-249

n

51

7

9

  

F

3.18 (2.79-3.64)

4.03 (2.17-7.49)

1.95 (1.40-2.70)

  

R

3.36 (2.65-4.25)

4.03 (2.17-7.49)

1.95 (1.40-2.70)

 

250-499

n

45

9

8

  

F

4.21 (3.80-4.66)

4.59 (3.17-6.65)

1.86 (1.36-2.54)

  

R

4.13 (3.42-4.99)

5.48 (2.84-10.58)

2.10 (1.21-3.64)

 

500-999

n

37

4

4

  

F

4.61 (4.21-5.04)

9.58 (5.65-16.25)

3.23 (2.13-4.90)

  

R

4.86 (4.07-5.80)

9.58 (5.65-16.25)

3.58 (1.79-7.13)

 

1000+

n

49

13

13

  

F

6.39 (6.19-6.60)

11.13 (10.08-12.28)

5.00 (4.59-5.45)

  

R

4.76 (4.13-5.48)

11.53 (8.87-14.99)

3.69 (2.60-5.22)

 

Between levels

PB

<0.05

<0.01

<0.05

Smoking product

Any

n

81

9

9

  

F

4.76 (4.51-5.02)

8.13 (5.16-12.79)

1.60 (1.21-2.12)

  

R

4.09 (3.53-4.74)

8.13 (5.16-12.79)

1.68 (1.17-2.40)

 

Cigarettes (ignoring

n

90

23

25

 

other products)

F

6.38 (6.16-6.60)

10.75 (9.77-11.83)

4.77 (4.40-5.18)

  

R

4.49 (3.98-5.06)

9.99 (7.93-12.58)

3.35 (2.54-4.41)

 

Cigarettes only

n

11

1

0

  

F

4.96 (4.36-5.64)

1.23 (0.60-2.52)

 
  

R

4.18 (2.63-6.66)

1.23 (0.60-2.52)

 
 

Between levels

PB

NS

<0.001

<0.01

Unexposed base

Never any product

n

121

17

18

  

F

5.64 (5.44-5.85)

8.41 (7.12-9.94)

2.38 (2.06-2.76)

  

R

4.35 (3.89-4.88)

6.63 (4.39-10.02)

2.17 (1.61-2.94)

 

Never cigarettes

n

61

16

16

  

F

6.08 (5.80-6.37)

11.19 (10.00-12.51)

5.60 (5.10-6.15)

  

R

4.18 (3.56-4.91)

11.13 (8.48-14.60)

3.83 (2.78-5.27)

 

Between levels

PB

NS

<0.05

<0.05

Number of adjustment factors

0

n

86

16

16

  

F

6.10 (5.87-6.34)

9.81 (8.41-11.45)

2.82 (2.47-3.22)

  

R

4.84 (4.26-5.50)

9.11 (6.95-11.94)

2.61 (1.91-3.58)

 

1

n

48

10

9

  

F

4.40 (4.11-4.71)

7.03 (5.21-9.47)

2.13 (1.66-2.73)

  

R

3.96 (3.37-4.65)

6.43 (3.31-12.47)

2.17 (1.56-3.03)

 

2+

n

48

7

9

  

F

6.23 (5.91-6.58)

11.28 (9.94-12.80)

6.64 (5.97-7.39)

  

R

3.81 (3.11-4.66)

11.09 (6.78-18.13)

4.42 (3.05-6.40)

 

Between levels

PB

<0.1

NS

<0.05

a Within each study, results for ex smokers are selected in the following preference order, within each sex, for:

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods);

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group.

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PE = probability value for Egger’s test of publication bias similarly expressed, PB = probability value for between levels (see Methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Or nested case–control or case-cohort in the case of 5 estimates for all lung cancer, 3 for squamous and 3 for adenocarcinoma.

g In the study as a whole.

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 5: Detailed Analysis Tables.

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 12 the sources of variation for all lung cancer are generally quite similar to those seen for ever smoking in Table 5 and for current smoking in Table 8. Thus, RRs are higher for males, for North America, for more recent studies and for larger studies. Interestingly RRs are clearly lower for prospective than for case–control studies. Numbers of ex smoking RRs are less for squamous (33) and for adeno (34) than for all lung cancer (182), but nevertheless some associations are evident in relation to location for adeno, to study type for squamous, to number of adjustment factors for adeno, and to number of cases, smoking product and unexposed base for both squamous and adeno. Meta-regression analyses were not attempted for ex smoking.

E. Risk from smoking specific products compared to smoking of any product

Table 13 summarizes the results of meta-analyses for all lung cancer for cigarette only smokers, smokers of pipes/cigars only, smokers of pipes only, and smokers of cigars only. In each analysis, the base is never smokers of any product. The results for ever smoking of pipes/cigars only are also shown in Figure 20.
Table 13

Meta-analyses for smoking of cigarettes, cigars and pipes (all lung cancer) a

Product smoked

Statisticb

Ever smoking

Current smoking

Ex smoking

Cigarettes only

n

53c

35c

21

 

F

4.37 (4.27-4.47)

9.32 (8.87-9.80)

4.36 (4.05-4.69)

 

R

6.36 (5.33-7.59)

9.57 (7.90-11.59)

4.22 (3.29-5.40)

 

H, PH

22.95, p < 0.001

10.91, p < 0.001

7.96, p < 0.001

Pipes/cigars only

n

38

26

7

 

F

3.46 (3.20-3.73)

3.74 (3.29-4.26)

2.00 (1.50-2.65)

 

R

2.92 (2.38-3.57)

4.76 (3.44-6.59)

2.00 (1.50-2.65)

 

H, PH

3.60, p < 0.001

4.18, p < 0.001

0.46, NS

Pipes only

n

23

12

5

 

F

3.36 (2.95-3.81)

5.28 (4.55-6.13)

3.32 (2.42-4.55)

 

R

3.31 (2.51-4.35)

5.20 (3.50-7.73)

2.69 (1.53-4.72)

 

H, PH

3.49, p < 0.001

5.43, p < 0.001

2.66, p < 0.05

Cigars only

n

15

15

5

 

F

2.73 (2.32-3.21)

4.05 (3.61-4.54)

3.27 (2.36-4.52)

 

R

2.95 (1.91-4.56)

4.67 (3.49-6.25)

2.85 (1.45-5.61)

 

H, PH

5.68, p < 0.001

4.27, p < 0.001

4.11, p < 0.01

Mixed

n

27

9

7

 

F

7.87 (7.22-8.59)

9.63 (8.46-10.96)

4.79 (4.10-5.60)

 

R

7.37 (5.97-9.11)

9.60 (8.37-11.00)

5.51 (3.88-7.82)

 

H, PH

4.09, p < 0.001

1.05, NS

3.72, p < 0.01

a Within each study, results for the relevant smoking product and smoking status are selected in the following preference order, within each sex, for:

unexposed group – never any product, near equivalent (see Methods);

follow-up period – longest available;

lung cancer type – all or nearest available, must include at least squamous cell carcinoma and adenocarcinoma;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PB = probability value for between levels (see Methods) similarly expressed.

c Results differ from those shown earlier (Tables 6, 9) because RRs with unexposed group “never cigarettes” are excluded here.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig20_HTML.jpg
Figure 20

Forest plot of ever pipe and/or cigar smoking and all lung cancer. Table 13 presents the results of a meta-analysis for all lung cancer based on 56 relative risk (RR) and 95% confidence interval (CI) estimates for ever pipe and/or cigar smoking. The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effects estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

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 5: Detailed Analysis Tables.

Table 13 also shows results for lung cancer for mixed smokers. For ever, current and ex smoking, the random-effects RRs are slightly, but not significantly, higher than those for smokers of cigarettes only. Available results for squamous and adeno are again limited, and mainly for ever smokers. The RRs for squamous (9.78, 4.94-19.35, n = 6) and for adeno (2.48, 1.25-4.95, n = 6) do not clearly differ from the RRs for squamous (11.09, 7.19-17.09, n = 10) and for adeno (2.63, 1.32-5.24, n = 10) for smokers of cigarettes only.

F. Risk by type of cigarette smoked

Table 14 summarizes results by type of cigarette smoked. For filter and plain cigarette smoking results are shown for three comparisons, including, for studies where there is a choice, the nearest available equivalents to only filter vs. only plain (with results for all lung cancer also shown in Figure 21), ever filter vs. only plain, and only filter vs. ever plain. Results are also shown for the comparison of handrolled and manufactured cigarette smoking, and for mentholated vs. non-mentholated cigarette smoking, with results for all lung cancer also shown in Figures 22 and 23.
Table 14

Meta-analyses by type of cigarette smoked a

Type of cigarette smoked

Statisticb

All lung cancerc

Squamousd

Adenoe

Only filter vs. only plainf

n

42

13

10

 

F

0.67 (0.64-0.72)

0.58 (0.52-0.64)

0.88 (0.75-1.03)

 

R

0.69 (0.61-0.78)

0.52 (0.40-0.68)

0.84 (0.66-1.08)

 

H, PH

3.18, p < 0.001

4.73, p < 0.001

1.90, p < 0.05

Ever filter vs. only plaing

n

42

11

10

 

F

0.79 (0.75-0.83)

0.85 (0.79-0.91)

1.00 (0.89-1.12)

 

R

0.73 (0.65-0.82)

0.55 (0.41-0.74)

0.99 (0.84-1.16)

 

H, PH

3.60, p < 0.001

7.73, p < 0.001

1.35, NS

Only filter vs. ever plainh

n

42

13

10

 

F

0.67 (0.63-0.71)

0.87 (0.81-0.92)

1.05 (0.93-1.18)

 

R

0.70 (0.62-0.78)

0.69 (0.57-0.83)

0.98 (0.80-1.21)

 

H, PH

3.30, p < 0.001

3.15, p < 0.001

1.88, p < 0.05

Handrolled vs. manufacturedi

n

20

5

4

 

F

1.27 (1.16-1.40)

1.47 (1.24-1.76)

2.12 (1.53-2.96)

 

R

1.29 (1.12-1.49)

1.62 (1.18-2.21)

2.09 (0.83-5.25)

 

H, PH

1.81, p < 0.05

2.61, p < 0.05

6.54, p < 0.001

Mentholated vs. non-mentholated

n

6

1

1

 

F

0.99 (0.86-1.14)

1.04 (0.75-1.44)

0.96 (0.73-1.27)

 

R

0.98 (0.80-1.20)

1.04 (0.75-1.44)

0.96 (0.73-1.27)

 

H, PH

1.89, p < 0.1

NA

NA

a Within each study, results for the relevant smoking product and smoking status are selected in the following preference order, within each sex, for:

cigarette type – see notes f to i;

unexposed group – see notes f to i;

smoking product – any, cigarettes (ignoring other products), cigarettes only;

smoking status – ever, current;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

follow-up period – longest available;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1), PB = probability value for between levels (see Methods) similarly expressed.

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Or nearest available.

Preference order for cigarette type – filter only/NOS, always, mainly, both, equally, ever.

Preference order for comparison group – plain only/NOS, always, mainly, ever.

g Or nearest available.

Preference order for cigarette type – filter ever, equally, both, mainly, always, only/NOS.

Preference order for comparison group – plain only/NOS, always, mainly, ever.

h Or nearest available.

Preference order for cigarette type – filter only/NOS, always, mainly, both, equally, ever.

Preference order for comparison group – plain ever, mainly, always, only/NOS.

i Preference order for cigarette type – handrolled any, both, mainly, only.

Preference order for comparison group – manufactured only ever, only current, any, ever.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig21_HTML.jpg
Figure 21

Forest plot of only filter vs. only plain cigarette smoking and all lung cancer. Table 14 presents the results of a meta-analysis for all lung cancer based on 42 relative risk (RR) and 95% confidence interval (CI) estimates for only filter vs. only plain cigarette smoking. The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted in order of sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effects estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig22_HTML.jpg
Figure 22

Forest plot of handrolled vs. manufactured cigarette smoking and all lung cancer. Table 14 presents the results of a meta-analysis for all lung cancer based on 20 relative risk (RR) and 95% confidence interval (CI) estimates for handrolled vs. manufactured cigarette smoking. The individual study estimates are shown numerically and graphically on a logarithmic scale. The studies are sorted on sex within study reference (REF) within start year of study (START) within continent (CONT). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effects estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-12-385/MediaObjects/12885_2012_Article_3417_Fig23_HTML.jpg
Figure 23

Forest plot of mentholated vs. non-mentholated cigarette smoking of any product and all lung cancer. Table 14 presents the results of a meta-analysis for all lung cancer based on six relative risk (RR) and 95% confidence interval (CI) estimates for mentholated vs. non-mentholated cigarette smoking. The individual study estimates are shown numerically and graphically on a logarithmic scale sorted on sex within study reference (REF) within start year of study (START) within continent (CONT). The studies are sorted in order of sex within study reference (REF). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse-variance of log RR). Arrows indicate where the CI extends outside the range allocated. Also shown are the combined random-effects estimates. These are represented by a diamond of standard height, with the width indicating the 95% CI.

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 14). The reductions for all lung cancer and squamous are evident in both sexes and all continents (see Additional file 5: Detailed Analysis Tables).

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

Table 15 summarizes the results of meta-analyses using RRs categorized by number of cigarettes (or cigarette equivalents) smoked per day and based on data for ever/current smoking and for smoking of any product (or cigarettes if not available). These are based on those 140 studies for all lung cancer, 36 for squamous, and 34 for adeno which provided data that could be used in the meta-analyses. For all three outcomes, results are shown for one of the sets of “key values” (see Methods). For all lung cancer, squamous and adeno, a clear increase is seen for RRs for categories including 5, but not 20, cigarettes/day, with the meta-analysis RR increasing monotonically with increasing amount smoked. Random-effects estimates for categories including 45, but not 20 cigarettes/day, are 13.69 (11.80-15.89, n = 128) for all lung cancer, 27.65 (20.42-37.44, n = 37) for squamous and 4.80 (3.29-7.01, n = 34) for adeno. The increase with amount smoked is also clearly evident when an alternative set of key values (1, 10, 20, 30, 40, 999) is used, though numbers of available RRs are quite sparse for the higher key values, when least-adjusted RRs are considered, and in both sexes (see Additional file 5: Detailed Analysis Tables). The key value analyses do not use results for all the dose–response data available, as a number of the studies use broad dose–response categories (such as 1–20 or 20+ cigs/day) which span more than one of the key values. Additional file 5: Detailed Analysis Tables also includes results for alternative definitions of smoking status and product smoked, which show a similarly clear dose–response. For example, for current smoking of any product, the RRs for squamous rise from 9.92 (7.41-13.28, n = 8) for key value 5 cigs/day to 39.16 (23.67-64.79, n = 12) for key value 45 cigs/day. Additional file 4: Dose Not Meta also includes available results for some other studies which present dose–response data in a form that cannot readily be included in the meta-analyses (e.g. where the only available comparison is with an inappropriate base group). These results do not appear inconsistent with those summarized in Table 15.
Table 15

Meta-analyses for number of cigarettes smoked a

Amount smoked

Statisticb

All lung cancerc

Squamousd

Adenoe

Number of setsf

 

190

48

46

About 5 cigs/dayg

n

174

41

39

 

F

3.25 (3.17-3.34)

6.07 (5.50-6.70)

2.70 (2.47-2.96)

 

R

3.49 (3.13-3.89)

4.98 (3.93-6.31)

1.83 (1.40-2.39)

 

H, PH

10.77, p < 0.001

3.85, p < 0.001

6.19, p < 0.001

About 20 cigs/dayh

n

113

30

28

 

F

5.30 (5.18-5.43)

12.36 (10.89-14.03)

3.58 (3.18-4.04)

 

R

7.33 (6.29-8.54)

11.86 (8.92-15.76)

2.73 (2.06-3.61)

 

H, PH

22.45, p < 0.001

3.72, p < 0.001

4.27, p < 0.001

About 45 cigs/dayi

n

128

37

34

 

F

10.17 (9.89-10.45)

28.95 (25.42-32.98)

7.20 (6.38-8.13)

 

R

13.69 (11.80-15.89)

27.65 (20.42-37.44)

4.80 (3.29-7.01)

 

H, PH

14.89, p < 0.001

3.98, p < 0.001

7.69, p < 0.001

a Within each study, results are selected in the following preference order, within each sex, for:

smoking status – ever, current;

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods);

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

Results are by number of cigarettes or cigarette equivalents.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Number of sets of RRs available for the key value analysis, where base for comparison is never smoked.

g Category for which results are provided includes 5 cigs/day but does not include 20 cigs/day.

h Category for which results are provided includes 20 cigs/day but does not include 5 or 45 cigs/day.

i Category for which results are provided includes 45 cigs/day but does not include 20 cigs/day.

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

Table 16 summarizes meta-analysis results for age of starting to smoke based on data for ever/current smoking and for smoking of any product (or cigarettes if not available). Random-effects RRs for earliest compared to latest starting, and selecting results least-adjusted for other aspects of smoking, are significantly elevated for all lung cancer (2.35, 2.08-2.65, n = 73), squamous (2.23, 1.66-2.98, n = 18) and adeno (1.99, 1.48-2.67, n = 17). Alternatively selecting results most-adjusted for other aspects of smoking, the RR for all lung cancer is 2.20 (1.96-2.47, n = 73). The increase in risk with earlier starting is consistent with the results of the key value analyses, with, for example, random-effects estimates relative to never smokers for squamous rising from 11.06 (6.87-17.81, n = 14) for categories including 26 years but not including 18 years to 31.07 (17.93-53.85, n = 6) for categories including 14, but not 18 years. As seen in Additional file 5: Detailed Analysis Tables, a similar pattern is generally seen for other definitions of smoking status and product smoked, although data for smokers of pipes and/or cigars are very limited.
Table 16

Meta-analyses for age started to smoke a

Age started

Statisticb

All lung cancerc

Squamousd

Adenoe

Number of setsf

 

69

15

14

About age 26 yearsg

n

60

14

13

 

F

2.70 (2.62-2.79)

10.42 (8.25-13.15)

3.79 (3.12-4.60)

 

R

3.89 (3.33-4.56)

11.06 (6.87-17.81)

3.21 (2.12-4.87)

 

H, PH

8.73, p < 0.001

3.36, p < 0.001

4.09, p < 0.001

About age 18 yearsh

n

29

6

5

 

F

7.75 (7.18-8.37)

20.15 (15.26-26.61)

9.74 (7.63-12.43)

 

R

7.48 (5.94-9.42)

20.28 (13.92-29.53)

8.84 (6.14-12.73)

 

H, PH

7.44, p < 0.001

1.60, NS

1.80, NS

About age 14 yearsi

n

35

6

5

 

F

11.11 (10.23-12.06)

29.91 (22.62-39.54)

13.62 (10.78-17.22)

 

R

10.32 (8.04-13.26)

31.07 (17.93-53.85)

12.34 (7.23-21.08)

 

H, PH

7.42, p < 0.001

3.28, p < 0.01

3.76, p < 0.01

Earliest vs. latestj

n

73

18

17

 

F

1.69 (1.64-1.74)

1.99 (1.72-2.29)

1.94 (1.64-2.29)

 

R

2.35 (2.08-2.65)

2.23 (1.66-2.98)

1.99 (1.48-2.67)

 

H, PH

4.52, p < 0.001

3.19, p < 0.001

2.62, p < 0.001

a Within each study, results are selected in the following preference order, within each sex, for:

smoking status – ever, current;

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods), but see also footnote j;

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Number of sets of RRs available for the key value analysis, where base for comparison is never smoked.

g Category for which results are provided includes 26 years but does not include 18 years.

h Category for which results are provided includes 18 years but does not include 14 or 26 years.

i Category for which results are provided includes 14 years but does not include 18 years.

j For this analysis only, the exposed and unexposed group have the same smoking status, product and cigarette type. There is an additional preference to select the results with least adjustment for other aspects of smoking, followed by a preference to select the results for the earliest (=exposed) and latest (=unexposed) starters. Alternatively preferring results with most adjustment for other aspects of smoking gives n = 73, F = 1.67 (1.62-1.72), R = 2.20 (1.96-2.47), H, PH = 4.01, p < 0.001 for all lung cancer.

I. Risk by duration of smoking

Table 17 is laid out similarly to Table 16 and also presents results for ever/current smoking. Random-effects RRs for longest compared to shortest duration of smoking, and selecting results least adjusted for other aspects of smoking, are significantly elevated for all lung cancer (3.56, 2.90-4.35, n = 76), squamous (3.93, 3.10-4.97, n = 27) and adeno (2.64, 2.04-3.43, n = 23). Alternatively selecting results most adjusted for other aspects of smoking, the RR for all lung cancer is 3.00 (2.57-3.49, n = 77). The increase in risk with longer duration is consistent with the results of the key value analyses, with, for example, random-effects estimates for all lung cancer rising from 2.48 (2.09-2.95, n = 55) for categories including 20 years but not including 35 years to 10.13 (7.66-13.39, n = 45) for categories including 50, but not 35 years. A clear trend of risk with increasing duration is also seen for other definitions of smoking status and product smoked (see Additional file 5: Detailed Analysis Tables). Data for pipe and cigar smoking are limited, though even so there is some evidence of a trend. Thus, for all lung cancer longest to shortest RRs are elevated, both in smokers of pipes only (4.32, 1.57-11.89, n = 5) and smokers of cigars only (2.43, 1.02-5.79, n = 3).
Table 17

Meta-analyses for duration of smoking a

Duration of smoking

Statisticb

All lung cancerc

Squamousd

Adenoe

Number of setsf

 

72

26

23

About 20 yearsg

n

55

23

21

 

F

2.46 (2.31-2.63)

6.46 (5.60-7.45)

2.33 (2.04-2.66)

 

R

2.48 (2.09-2.95)

4.66 (3.03-7.16)

1.72 (1.20-2.46)

 

H, PH

5.70, p < 0.001

6.52, p < 0.001

6.04, p < 0.001

About 35 yearsh

n

39

15

12

 

F

6.17 (5.80-6.55)

18.25 (15.61-21.34)

5.13 (4.43-5.95)

 

R

5.90 (4.75-7.32)

14.06 (7.45-26.52)

3.53 (1.81-6.88)

 

H, PH

10.39, p < 0.001

11.37, p < 0.001

15.91, p < 0.001

About 50 yearsi

n

45

16

13

 

F

13.46 (12.61-14.36)

26.27 (22.20-31.09)

5.24 (4.41-6.23)

 

R

10.13 (7.66-13.39)

27.18 (13.36-55.28)

5.25 (2.70-10.20)

 

H, PH

15.58, p < 0.001

13.13, p < 0.001

12.82, p < 0.001

Longest vs. shortestj

n

76

27

23

 

F

3.81 (3.62-4.02)

3.55 (3.25-3.89)

2.39 (2.09-2.72)

 

R

3.56 (2.90-4.35)

3.93 (3.10-4.97)

2.64 (2.04-3.43)

 

H, PH

11.48, p < 0.001

4.23, p < 0.001

3.00, p < 0.001

a Within each study, results are selected in the following preference order, within each sex, for:

smoking status – ever, current;

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods), but see also footnote j;

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

Results are then selected for:

sex - single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Number of sets of RRs available for the key value analysis, where base for comparison is never smoked.

g Category for which results are provided includes 20 years but does not include 35 years.

h Category for which results are provided includes 35 years but does not include 20 or 50 years.

i Category for which results are provided includes 50 years but does not include 35 years.

j For this analysis only, the exposed and unexposed group have the same smoking status, product and cigarette type. There is an additional preference to select the results with least adjustment for other aspects of smoking, followed by a preference to select the results for the longest (=exposed) and shortest (=unexposed) duration smokers. Alternatively preferring results with most adjustment for other aspects of smoking gives n = 77, F = 2.67 (2.53-2.82), R = 3.00 (2.57-3.49), H, PH = 5.82, p < 0.001 for all lung cancer.

J. Risk by duration of quitting (vs. never smoking)

Table 18 presents results for duration of quitting (vs. never smoking) based on results for smoking of any product (or cigarettes if not available). Random-effects RRs for shortest compared to longest duration of quitting, selecting results least adjusted for other aspects of smoking, are significantly elevated for all lung cancer (3.97, 3.32-4.75, n = 65), squamous (6.22, 3.75-10.30, n = 14) and adeno (3.32, 1.98-5.58, n = 14). Alternatively selecting results most adjusted for other aspects of smoking, the RR for all lung cancer is 3.61 (3.04-4.28, n = 65). The increase in risk with shorter duration of quitting is consistent with the results of the key value analyses, with, for example, random-effects estimates relative to never smokers for adeno rising from 2.10 (1.49-2.94, n = 12) for categories including 12 years but not including 7 years to 6.73 (3.46-13.12, n = 6) for categories including 3, but not 7 years. A clear trend of risk with increasing duration of quitting is also seen for cigarette smoking (or any product if not available), and for cigarette only smoking (see Additional file 5: Detailed Analysis Tables). Data for pipe and cigar smoking were too limited for reliable conclusions.
Table 18

Meta-analyses for duration of quitting (vs. never smoked) a

Duration of quitting

Statisticb

All lung cancerc

Squamousd

Adenoe

Number of setsf

 

68

16

16

About 12 yearsg

n

53

13

12

 

F

3.62 (3.34-3.93)

7.76 (6.07-9.91)

2.13 (1.64-2.76)

 

R

2.97 (2.48-3.55)

5.89 (3.85-9.08)

2.10 (1.49-2.94)

 

H, PH

3.93, p < 0.001

1.69, p < 0.1

1.45, NS

About 7 yearsh

n

33

6

6

 

F

6.07 (5.56-6.63)

14.34 (11.10-18.54)

3.29 (2.47-4.39)

 

R

5.08 (4.24-6.10)

14.34 (11.10-18.54)

3.74 (2.23-6.25)

 

H, PH

3.20, p < 0.001

0.49, NS

2.33, p < 0.05

About 3 yearsi

n

43

6

6

 

F

9.69 (8.96-10.47)

24.95 (19.45-31.99)

5.05 (3.85-6.64)

 

R

8.60 (7.22-10.23)

26.22 (17.19-39.98)

6.73 (3.46-13.12)

 

H, PH

3.93, p < 0.001

1.46, NS

3.86, p < 0.01

Shortest vs. longestj

n

65

14

14

 

F

3.94 (3.68-4.22)

5.09 (4.33-5.99)

2.63 (2.11-3.28)

 

R

3.97 (3.32-4.75)

6.22 (3.75-10.30)

3.32 (1.98-5.58)

 

H, PH

5.47, p < 0.001

6.00, p < 0.001

4.41, p < 0.001

a Within each study, results for ex smokers are selected in the following preference order, within each sex, for:

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

unexposed group – never any product, never cigarettes, near equivalent (see Methods) but see also footnote j;

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

Results are then selected for:

sex – single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Number of sets of RRs available for the key value analysis, where base for comparison is never smoked.

g Category for which results are provided includes 12 years but does not include 7 years.

h Category for which results are provided includes 7 years but does not include 3 or 12 years.

i Category for which results are provided includes 3 years but does not include 7 years.

j For this analysis only, the exposed and unexposed group have the same smoking status, product and cigarette type. There is an additional preference to select the results with least adjustment for other aspects of smoking, followed by a preference to select the results for the shortest (=exposed) and longest (=unexposed) duration quitters. Alternatively preferring results with most adjustment for other aspects of smoking gives n = 65, F = 3.59 (3.35-3.85), R = 3.61 (3.04-4.28), H, PH = 4.79, p < 0.001 for all lung cancer. Note that the “shortest” group, as reported by some studies, may omit (unlimited) recent quitters.

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 19 are generally the inverse of those in the shortest vs. longest analysis in Table 18 (exceptions arising for studies which combined current smokers and recent quitters of more than 2 years). While the key value analyses shown in Table 19 echo the trends shown in Table 18, they also show that for shorter term quitting (categories including 3 but not 7 years) there is no evidence of a decline in risk from quitting. Thus the RRs for all lung cancer (0.95, 0.84-1.08, n = 41) and adeno (1.02, 0.85-1.22, n = 6) are close to 1.00, and the RR for squamous (1.15, 1.03-1.28, n = 6) is slightly elevated. Longer quit durations are, however, clearly associated with a reduction in risk. For all lung cancer, almost 40% of the RRs used in the key value analyses included short-term quitters (of up to 2 years) in the current smoker base. No difference was seen between those RRs and those with a more precisely defined current smoker base.
Table 19

Meta-analyses for duration of quitting (vs. current smoking) a

Duration of quitting

Statisticb

All lung cancerc

Squamousd

Adenoe

Number of setsf

 

58

11

11

About 3 yearsg

n

41

6

6

 

F

0.98 (0.93-1.04)

1.15 (1.03-1.28)

1.02 (0.85-1.22)

 

R

0.95 (0.84-1.08)

1.15 (1.03-1.28)

1.02 (0.85-1.22)

 

H, PH

3.55 p < 0.001

0.51, NS

0.74, NS

About 7 yearsh

n

29

4

4

 

F

0.60 (0.56-0.64)

0.74 (0.65-0.85)

0.73 (0.58-0.92)

 

R

0.57 (0.50-0.64)

0.74 (0.65-0.85)

0.73 (0.58-0.92)

 

H, PH

2.09, p < 0.001

0.09, NS

0.59, NS

About 12 yearsi

n

48

9

9

 

F

0.32 (0.30-0.34)

0.40 (0.35-0.47)

0.50 (0.41-0.60)

 

R

0.28 (0.24-0.32)

0.27 (0.18-0.40)

0.39 (0.26-0.58)

 

H, PH

4.22, p < 0.001

4.07, p < 0.001

3.68, p < 0.001

Longest vs. shortestj

n

61

12

12

 

F

0.23 (0.21-0.25)

0.19 (0.16-0.22)

0.30 (0.23-0.37)

 

R

0.24 (0.20-0.29)

0.14 (0.08-0.25)

0.21 (0.10-0.46)

 

H, PH

5.21, p < 0.001

6.68 p < 0.001

9.44, p < 0.001

a Within each study, results for ex smokers are selected in the following preference order, within each sex, for:

smoking product – any, cigarettes (ignoring other products), cigarettes only;

cigarette type – any, manufactured (with or without handrolled), manufactured only;

adjustment for other aspects of smoking – least available;

comparison group – current smokers, current and recent smokers (up to 2 years);

follow-up period – longest available;

lung cancer type – see notes c to e;

race – all or nearest available, otherwise by race;

overlapping studies – principal, subsidiary;

age – whole study, widest available age group;

Results are then selected for:

sex –- single sex results, combined sex results;

adjustment for potential confounders – most available.

b n = number of estimates combined, F = fixed-effect meta-analysis RR (95% CI), R = random-effects meta-analysis RR (95% CI), H = heterogeneity chisquared per degree of freedom, PH = probability value for heterogeneity expressed as p < 0.001, p < 0.05, p < 0.1 or NS (p ≥ 0.1).

c All or nearest available, must include at least squamous cell carcinoma and adenocarcinoma.

d Squamous cell carcinoma or nearest available, but not including adenocarcinoma.

e Adenocarcinoma or nearest available, but not including squamous cell carcinoma.

f Number of sets of RRs available for the key value analysis, where base for comparison is never smoked.

g Category for which results are provided includes 3 years but does not include 7 years.

h Category for which results are provided includes 7 years but does not include 3 or 12 years.

i Category for which results are provided includes 12 years but does not include 7 years.

j For this analysis only, the exposed and unexposed group have the same smoking status (i.e. ex-smokers), product and cigarette type. There is a preference (instead of that for comparison group) to select the results for the longest (=exposed) and shortest (=unexposed) duration quitters. Note that (unlike the inverse results shown in Table 18), the “shortest” quitters here may omit recent quitters, but subject to a limit of no more than two years.

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.