case study cigarette smoking and lung cancer

• Research article
• Open access
• Published: 19 December 2018

Risk of lung cancer in relation to various metrics of smoking history: a case-control study in Montreal

• T. Remen   ORCID: orcid.org/0000-0001-8370-7455 1 ,
• J. Pintos 1 ,
• M. Abrahamowicz 2 &
• J. Siemiatycki 1  

BMC Cancer volume  18 , Article number:  1275 ( 2018 ) Cite this article

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Few epidemiologic findings are as well established as the association between smoking and lung cancer. It is therefore somewhat surprising that there is not yet a clear consensus about the exposure-response relationships between various metrics of smoking and lung cancer risk. In part this is due to heterogeneity of how exposure-response results have been presented and the relative paucity of published results using any particular metric of exposure. The purposes of this study are: to provide new data on smoking-lung cancer associations and to explore the relative impact of different dimensions of smoking history on lung cancer risk.

Based on a large lung cancer case-control study (1203 cases and 1513 controls) conducted in Montreal in 1996–2000, we estimated the lifetime prevalence of smoking and odds ratios in relation to several smoking metrics, both categorical and continuous based on multivariable unconditional logistic regression.

Odds ratios (ORs) for ever vs never smoking were 7.82 among males and 11.76 among females. ORs increased sharply with every metric of smoking examined, more so for duration than for daily intensity. In models using continuous smoking variables, all metrics had strong effects on OR and mutual adjustment among smoking metrics did not noticeably attenuate the OR estimates, indicating that each metric carries some independent risk-related information. Among all the models tested, the one based on a smoking index that integrates several smoking dimensions, provided the best fitting model. Similar patterns were observed for the different histologic types of lung cancer.

Conclusions

This study provides many estimates of exposure-response relationships between smoking and lung cancer; these can be used in future meta-analyses. Irrespective of the histologic type of lung cancer and the smoking metric examined, high levels of smoking led to high levels of risk, for both men and women.

Peer Review reports

The role of cigarette smoking in the etiology of lung cancer is strong and has been so recognized since at least the 1960s [ 1 ]. In the intervening years, a great deal of evidence has accumulated confirming the strong impact of smoking on cancer and extending it in various directions, such as the impact of smoking on women’s risks, the nature of dose-response relationships, the impact of quitting, the particular relationships between smoking and each of the main histologic types of lung cancer and many more [ 2 , 3 , 4 ]. One might imagine that all of this evidence can be put together to derive very precise estimates of the quantitative impact of smoking on lung cancer risk. But our recent review showed us that the amount of published evidence that can be assembled for meta-analyses regarding exposure-response is rather limited [ 5 ]. While there have been quite a few publications showing exposure-response results for smoking and lung cancer, they use different metrics (duration, intensity, pack-years, categorical, continuous, etc.) and different strategies for control of confounding, so that the number of results that can fairly be juxtaposed or meta-analyzed, using a common exposure metric and type of model, is limited. Providing high quality statistical evidence on smoking–lung cancer associations, including by histologic subtypes, remains an important objective because such information will be useful for public health purposes, to build lung cancer risk prediction models that can be used to advise healthy patients about their risks related to their past and possible future smoking behaviors, to understand mechanisms of carcinogenesis, and to provide information that may be useful in a legal context, for compensation or litigation purposes.

In carrying out a large case-control study of lung cancer in the Montreal area to explore the possible etiologic role of scores of occupational and environmental factors in lung cancer [ 6 ], we of course collected a detailed smoking history from each subject. We use this dataset to address two objectives: a) provide evidence of exposure-response relationships between smoking history and lung cancer, using a variety of smoking metrics and formats that might be used in future meta-analyses; b) explore the relative impact of different dimensions of smoking history and how these interact in predicting risk [ 7 , 8 , 9 , 10 ].

Cases and controls

The population-based case–control study included all lung cancer cases, males and females aged 35–75 years residing in Montreal and its surrounding suburbs and who were Canadian citizens. Histologically confirmed incident cases of lung cancer diagnosed between January 1996 and December 1997 were ascertained through active monitoring of pathology reports in the 18 participating hospitals in the metropolitan Montreal region, providing almost complete (≈98%) coverage of lung cancer diagnosis in the area. Histology of lung cancer was coded according to World Health Organization/International Agency for Research on Cancer technical report 31 [ 11 ].

Controls were randomly sampled from population-based electoral lists, frequency-matched to cases by age group (±5 years), gender and residential area. Further details about the study can be found elsewhere [ 12 ]. Ethics approval was obtained from all collaborating institutions, and written informed consent was obtained for all participants.

Data collection

A face-to-face interview was conducted by one of our bilingual interviewers (English and French). If the subject was deceased or too ill to respond, we attempted to conduct the interview with a close next of kin proxy, usually the surviving spouse. The questionnaire was designed to collect information on sociodemographic and lifestyle characteristics, including smoking history, and a detailed semi-structured history of all jobs ever held.

Smoking history

Detailed self-reported information was collected about cigarette smoking habits including smoking status, ages at initiation and cessation, periods of interruption and average number of cigarettes smoked per day over the subject’s lifetime. Smokers were defined as those who smoked regularly (at least one cigarette per week) during at least 6 months, and at least 100 cigarettes in their lifetime, the others being considered “never smokers”. Since early symptoms of lung cancer can lead to changes in smoking behavior, in order to avoid reverse causality bias, we discounted the two years before index date in computing each of the smoking variables. This cutpoint of two years was recommended by Leffondré et al. [ 7 ], based on their fitting of models with different cutpoints. Thus “current smokers” were defined as subjects who still smoked at interview or had quit smoking less than 2 years before the reference date (i.e. date of diagnosis for cases and date of interview for controls), and former smokers were those who quit at least 2 years before this reference date. Smoking duration was defined as the difference between age at index date for current smokers, or age of cessation for former smokers, and age at initiation, and then subtracting total duration of any temporary cessation periods. Cumulative smoking exposure was represented by two alternative constructed variables: pack-years and cumulative smoking index (CSI). The pack-years variable was computed by multiplying the average number of cigarettes smoked per day by duration of smoking in years, and dividing by 20 (cigarettes per pack). The CSI is an index comprising all the smoking dimensions collected from study subjects in a function that is biologically motivated and that optimizes predictive power [ 13 , 14 ]. Leffondre et al. proposed a modified version of CSI, adapted specifically for lung cancer, and demonstrated that the resulting aggregate exposure measure improved the fit of data, compared with conventional modeling of separate effects of different smoking components [ 14 ].

The equation is: CSI = (1–0.5 dur*/τ ) (0.5 tsc*/τ ) ln(int + 1), where

The latter two parameters, δ and τ, are estimated by trial-and-error so as to optimize the fit to data [ 13 , 14 ].

Other covariates

Detailed information was collected on sociodemographic characteristics, including ethnicity, education and family income.

In addition, from the detailed employment history and description of each job, a team of chemists and industrial hygienists examined each completed questionnaire and translated each job into a list of potential exposures using a checklist of 294 agents that included many IARC-recognized Group 1 Lung Carcinogens [ 15 , 16 ].

Statistical analysis

Analyses were performed separately for men and women, and either with all histologies combined or by histologic type. When simply using the term “lung cancer”, we mean all histologies combined.

All associations were estimated using multivariable unconditional logistic regression. When several variables were tested simultaneously, Wald statistics were used to compare the contribution of each variable in a model while Akaike information criterion (AIC) was used to compare the goodness of fit between the different models.

We assessed the relations between lung cancer and various smoking metrics, including duration, daily intensity, time since cessation, pack-years, and CSI. For CSI, its parameters were a priori set to values established by Leffondre et al.: half-life = 26 years and lag = 1 year (males) or 0.7 year (females) [ 14 ]. Initially the smoking metrics were analyzed one-at-a-time. Subsequently we conducted analyses with selected multiple smoking metrics in the same models. Analyses involving the time since cessation variable were performed among smokers only. For models involving all subjects, with nonsmokers being the reference group, an indicator of ever smoking was used and continuous smoking variables were centered by subtracting the mean value of the smoking variable from the original value for all smokers, while keeping 0 for never smokers [ 7 ]. For each model, the smoking variables under study and the non-smoking covariates were forced into the model.

Some analyses were conducted with continuous smoking variables transformed into categorical variables, while others were conducted on the continuous variables. For the latter, different functions were used to model the relations between continuous smoking metrics and the logit of the lung cancer risk, including (i) linear and (ii) logarithmic functions models as well as fractional polynomials (FP) [ 17 ]. In FP analyses, for each continuous variable X, one or two terms of the form X p were fitted with powers p chosen from (− 2, − 1, − 0.5, 0, 0.5, 1, 2, and 3) to optimize goodness of fit, i.e. minimize the model’s deviance [ 17 ].

The following covariates were included in all models: age (continuous), respondent status (self, proxy), ethnic origin (dummy variables: French / British Isles / Italian / other Europeans / other), educational level (elementary, secondary, post-secondary), socioeconomic status (SES) as measured by median household income of the residential neighborhood, derived from census information (continuous) and exposure to those IARC Group 1 occupational lung carcinogens that had at least 1% lifetime prevalence in our study population. The following occupational exposures (lifetime prevalence as indicated) satisfied these criteria: diesel engine emissions (23.8%), crystalline silica (15.9%), benzo[a]pyrene (15.3%), chrysotile asbestos (10.9%), nickel and its compounds (6.2%), chromium VI and its compounds (4.5%) and cadmium and its compounds (2.2%). These were included in the models as qualitative ordinal variables for men: no exposure, ‘non-substantial’ exposure and ‘substantial’ exposure, where the two exposure subsets were distinguished by duration of exposure, concentration of exposure and number of hours per week of exposure. Among women, due to much lower prevalence of occupational exposures, binary variables (ever vs never exposed) were preferred.

Some sensitivity analyses were carried out with study subjects restricted to those who answered for themselves, i.e. excluding proxy responses.

The population attributable fraction (PAF) was estimated as PAF =  p exp \( \left(\frac{OR-1}{OR}\right) \) where p exp represents the ratio of the number of exposed cases to the total number of cases [ 18 ]. A 95% confidence interval (CI) for the PAF was derived by replacing the point estimate of the relevant OR by, respectively, the lower and upper boundaries of the corresponding 95% CI.

All statistical analyses were performed using SAS® 9.4 software. The %MFP8 macro was used for determining the transformation of continuous variables using fractional polynomials [ 19 ].

Selected characteristics of the study population

A total of 1434 eligible lung cancer cases were invited to participate in the study and, of those, 1203 (84%) agreed to participate. Of the 2182 population controls approached, 1513 (69%) agreed to participate. Of the 2716 participating subjects, 11 were excluded due to missing smoking information. Table 1 presents the main characteristics of the 2705 subjects included in this analysis. Briefly, 60% of the study subjects were male, a great majority were French Canadian and the mean age of our population was 63.4 years [SD = 8.5]. For both genders, cases were more likely than controls to be of French ancestry ( p  < 0.001), to have a lower educational level ( p  < 0.001) and a lower family reported income ( p  ≤ 0.001), and to have had a proxy respond on their behalf ( p  < 0.001). Adenocarcinoma was the predominant histologic type among women, whereas squamous cell carcinomas were more prevalent among men. Information about lifetime prevalence of occupational exposure to IARC Group 1 lung carcinogens of the study subjects is shown in (Additional file 1 : Table S1).

Characteristics of smoking histories of lung cancer cases and controls

Smoking characteristics of the study population are presented in Table 2 . Nearly all cases (97.6% of male cases and 93.1% of female cases) had regularly smoked cigarettes, compared to about two-thirds of controls (82.3% of men and 49.3% of women). Very few smoking cases or smoking controls had smoked for fewer than 20 years, or had averaged fewer than 20 cigarettes per day, or had accumulated fewer than 20 pack-years of smoking. As expected, compared with smoking controls, smoking cases had longer durations of smoking ( p  < 0.001), higher daily intensities ( p  < 0.001), younger ages at starting smoking ( p  < 0.001) and shorter periods since quitting smoking ( p  < 0.001).

Lung cancer risk in relation to smoking

As expected and shown in Table 3 , for both sexes, subjects who had been regular smokers were at higher risk of developing lung cancer than nonsmokers. Table 3 also shows the OR of lung cancer as a function of categories of exposure for each of several smoking metrics. Risk of lung cancer increases with duration of smoking, and with intensity of smoking, as well as with the cumulative exposure measures, Pack-years and CSI. All of the trend tests across the categories of these variables were highly statistically significant ( p  < 0.0001). For both sexes, our results highlighted a positive and quite linear association between smoking duration and the logit of the lung cancer risk. Smoking cessation at least 2 years before the reference date was associated with a reduction of the risk of lung cancer for both sexes ( p  < .0001 - data not shown). For the models exploring the role of the duration, intensity, cumulative index (i.e. pack-years) or time since cessation of smoking as categorical variables, the introduction of the second smoking variable (respectively intensity, duration, smoking status ± time since cessation, or pack-years of smoking) had no noticeable impact on the risk estimates of the primary exposure metric, though as expected, the inclusion of a second source of information on smoking in the model improved the model fit (data not shown). In both sexes, duration of smoking is a stronger predictor of risk than daily intensity of smoking, as indicated by Wald test statistics.

Models based on continuous smoking variables are presented in Table 4 . For both sexes and among all the models tested, the one built with the CSI index as a linear variable provided the best fitting model, as indicated by the lowest AIC. Another model that included two smoking dimensions (i.e. pack-years and time since cessation) comes close in terms of AIC index. If for duration of smoking, a linear association with the logit of the lung cancer risk is consistently observed, the use of logarithms of the values of intensity or pack-years provided superior fit to the model that used un-transformed value. More complex fractional polynomials models, shown in footnotes of Table 4 , did not substantially improve the fit over the linear or log transformation.

Histological types

Table 5 shows ORs for selected smoking metrics with men and women combined to optimize power, for all lung cancers combined and for each histologic type. All histologic types of lung cancer were strongly associated with smoking. The ORs between ever regular smoking and lung cancer were close to 10, considering the statistical variability, for each of squamous cell, large cell and adenocarcinoma, and it was undefined for small cell lung cancer because there were no non-smokers among the 205 cases.

Sensitivity analysis limited to self-respondents

Since cases were more likely than controls to have had a proxy respond on their behalf, we adjusted for proxy status in the main analyses. But, as a further insight into the possible impact of using proxies, we re-ran some analyses among self-respondents only, and compared these with the results of combining self and proxy respondents (see Additional file 2 : Table S2). Among men, the adjusted OR for a binary indicator of ever smoking and lung cancer was 7.82 (95% CI [4.59–13.30]) in analyses that included all respondents, and 6.96 (95% CI [3.82–12.68]) in analyses restricted to self-respondents. Among women the OR was 11.76 (95% CI [7.50–18.42]) in analyses including all respondents, and 12.17 (95% CI [7.45–19.85]) in analyses restricted to self-respondents. When considering the CSI index, the OR corresponding to a one unit increase in CSI was slightly lower among self-respondents than among all respondents. But in all of these contrasts, the confidence limits between self-respondent and all respondent results overlapped considerably, and none of the substantive inferences would have changed.

Population attributable fraction

Given the overall OR estimate, its confidence limits and the observed prevalence of smoking among cases (96%), we estimate that the Population attributable fraction was 0.858 (0.819–0.887). The estimates were almost identical in men and women.

Although tobacco smoking is the main cause of lung cancer in humans, there is no widely accepted estimate of the exposure-response relationship between smoking and lung cancer. This is partly due to a false impression that the smoking-lung cancer association is so well established that there is little to be learned from additional attention to the issue. Because the analysis and description of dose-response relationships involves such idiosyncratic methodologies and parametrizations, there are really not a tremendous number of published results that can be usefully assembled for meta-analyses or other attempts at synthesizing knowledge. Finally, there remains a great deal to learn about the mechanisms of carcinogenesis by studying valid and generalizable dose-response relationships. The addition of new evidence from studies such as ours will hopefully increase the likelihood that reasonably representative estimates can be derived from the world body of evidence.

As well as describing the smoking history of a North American study population at the end of the twentieth century, this paper provides new estimates of the relationship between cigarette smoking and lung cancer risk for both sexes.

There were significant changes in design of cigarettes (filters, “light”, etc.) in the 1960s and 1970s, and in contrast with many previous studies that had been conducted from the 1950s to the 1980s and that evaluated risks of smoking the types of cigarettes marketed in the middle of the twentieth century, our study covers a population that was largely exposed to the types of cigarettes that came into widespread usage in the last part of the twentieth century. Cigarette smoking was a prevalent habit in this population, certainly among men, but even among women. Among men, 97.5% of cases and 82.3% of controls had ever smoked regularly, while among women, it was 93.1 and 49.4%. These numbers are in the same order of magnitude as those observed in a previous case-control study conducted in Montreal in the 1980’s [ 20 ] and in others in the United States [ 21 ]. Further, there were very few short duration or low daily intensity smokers.

To provide useful and relevant information for various purposes, different parametrizations and different statistical risk models were created. There are many more published results with categorical parametrization of smoking variables, namely duration, intensity and pack-years, than there are with any particular continuous parametrizations of smoking variables. There are more ways to model the shapes of continuous variables, while categorizations have more limited options for summarization. While there are advantages to the flexibility of continuous variable modelling in a given study, when a meta-analysis of many studies is called for, using the more common categorical variables is a useful strategy. Models were also built either with each smoking variable studied separately or combined with each other.

For the association between binary smoker/nonsmoker variable and lung cancer, we observed an OR of 7.82 [4.59–13.30] for men, a risk slightly lower than the one we derived from a meta-analysis covering studies conducted in North America and Europe [ 5 ]. Our estimate is slightly higher than the one (OR = 6.18 95% CI [5.49–6.95]) observed in a recent meta-analysis based on a larger number of studies [ 3 ], but those included studies in other parts of the world which were not comparable to ours in terms of history of smoking and ethnic profile of the population. For women, the corresponding OR is 11.76 [7.50–18.42], which is higher than the one (OR = 4.43 95% CI [3.84–5.10]) computed in the meta-analysis cited above [ 3 ]. Gender susceptibility to cigarette smoking-attributable lung cancer, a topic under debate in recent years [ 22 , 23 , 24 , 25 , 26 ], will be addressed in a separate paper.

There is more published evidence concerning smoking duration and intensity as distinct predictors of risk than any other metrics. Of these, duration of regular smoking seems to be the more important predictor of lung cancer risk [ 4 ]. For both sexes, our results highlighted a positive and quite linear association between smoking duration and the logit of the lung cancer risk. In our analyses, particular attention was paid to the reconstruction of the smoking duration variable which excluded any temporary or permanent periods of cessation. It is conceivable that the lower predictive value of smoking intensity is due to the fact that duration of smoking may be recalled and reported with greater accuracy than average daily intensity over the lifetime smoking history. Obtaining a good estimate of smoking intensity is very challenging due to the potential variability in the true number of cigarettes smoked per day over different periods within a long smoking “career”, and the difficulty of recalling such variability over a long time span. The estimate used in our study was based on the reported average number of cigarettes smoked per day throughout the smoking history of the subject, an estimate often used in epidemiological studies [ 27 ]. Log-transformation for intensity of smoking yielded best fit of the data, suggesting that the impact of increasing daily intensity by a fixed number of cigarettes per day is more harmful for light smokers than for heavy smokers, as suggested elsewhere [ 10 , 28 ].

“Pack-years” smoked, calculated as the average number of packs of cigarettes smoked per day, multiplied by the cumulative number of years during which a person smoked, is the simplest and most commonly reported cumulative smoking exposure metric. Use of the “pack-year” index has been criticized [ 8 , 29 , 30 ] on the grounds that it gives equivalent weight to intensity and duration as contributors to the risk of lung cancer, and it does not explicitly account for time since quitting. Nevertheless, the pack-years variable has the virtue of simplicity, it partially accounts for time since quitting since length of time since quitting implies shorter duration and is a strong predictor of the risk of various smoking-related diseases [ 31 , 32 , 33 ]. For some purposes, this simple but powerful metric is perfectly adequate, while for other purposes, more sophisticated treatment of the components of a smoking history might be indicated. The CSI [ 34 ] is one such possible metric and as shown by Leffondre et al [ 14 ] and here, it is a very effective smoking metric, and indeed it performed very well compared with other models in predicting lung cancer risk.

In models using continuous smoking variables, all metrics had strong effects on OR and mutual adjustment among smoking metrics did not noticeably attenuate the OR estimates, indicating that each metric carries some independent risk-related information.

In any case, each of these metrics is an imperfect measure of inhaled dose because of intra and inter-individual variation in: (i) depth of inhalation, (ii) number of puffs taken per cigarette and (iii) retention time in the lung [ 4 ].

Finally, in our study population, we estimated that, irrespective of gender, about 86% (95% CI [81–89%]) of the lung cancer cases were attributable to cigarette smoking. That proportion is consistent with previous findings [ 35 , 36 ].

Besides presenting a portrait of the smoking-lung cancer association in North America at the end of the twentieth century, this study provides a panorama of estimates of this association derived from several modeling strategies and several parameterizations of the smoking variables. This provides new material for future meta-analyses using any of the smoking metrics presented here. Among the notable substantive findings are: the high risk estimates of all types of lung cancer due to smoking despite the changes over time in composition and tar output of cigarettes; the high risk estimates among women, and consequent high attributable fractions; the clear message of increased risk with even the simplest metrics of exposure; and the apparently stronger influence of duration of smoking than daily amount smoked on risk of lung cancer.

Abbreviations

Akaike information criterion

Cumulative Smoking Index

Fractional polynomial

International Agency for Research on Cancer

Socioeconomic status

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Acknowledgments

Lesley Richardson contributed to the design of the studies, and assisted in the development and coordination of the data collection methods. Exposure assessment methods were expertly developed and implemented by Michel Gérin, Louise Nadon, Ramzan Lakhani, Denis Bégin, and Benoit Latreille. A large number of research assistants and interviewers ensured the careful collection of data, in particular: Marie-Claire Goulet, Jerome Asselin, and Sally Campbell. The authors wish to express their gratitude for the collaboration of all Montreal area hospitals.

Funding for the study was provided by the Canadian Cancer Society, the Fonds de recherche du Québec - Santé, and the Canadian Institutes of Health Research. Dr. Siemiatycki’s research team was supported in part by the Canada Research Chairs programme and the Guzzo-SRC Chair in Environment and Cancer. The funding bodies had no role in designing the study or in data collection and analysis or in writing the manuscript.

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T. Remen, J. Pintos & J. Siemiatycki

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All co-authors contributed significantly to the research. JS designed the study included in this manuscript. TR conducted the literature review, statistical analysis, and prepared the first draft for all sections of the article with the help of JP and MA and supervision of JS. All co-authors participated in the editing and correction of the final text. All authors read and approved the final manuscript.

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This research was approved by the ethics committees of the Institut national de recherche scientifique-Institut Armand-Frappier (INRS-IAF) and McGill University. Ethics approval was also received from the following Montreal-area hospitals in which subjects were recruited: Montreal Chest Hospital Centre, Centre Hospitalier de Verdun, Cité de la santé, Hôpital Général Fleury, Hôtel Dieu de Montréal, Hôpital Jean-Talon, Hôpital Maisonneuve-Rosemont, Hôpital Notre Dame, Hôpital Sacré-Coeur, Hôpital St-Luc, Jewish General Hospital, Lakeshore Hospital, Montreal General Hospital, Queen Elizabeth Hospital, Reddy Memorial Hospital, Royal Victoria Hospital, Hôpital Santa Cabrini, Hôpital Ste. Jeanne-d’Arc and St Mary’s Hospital. All participants provided written informed consent.

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Additional file 1:.

Table S1. Lifetime prevalence of occupational exposure to IARC Group 1 lung carcinogens of the study subjects. This table presents the lifetime prevalence of occupational exposure to IARC Group 1 lung carcinogens (diesel engine emissions, crystalline silica, benzo[a]pyrene, chrysotile asbestos, nickel and its compounds, chromium (VI), cadmium and its compounds, arsenic and its compounds, beryllium and its compounds) by category of exposure (non-exposed, not substantial exposure or substantial exposure). (DOCX 18 kb)

Additional file 2:

Table S2. OR estimates between smoking-related variables and lung cancer risk by respondent type. This table presents the association between ever smoking (or CSI) and the logit of the lung cancer risk by respondent type. (DOCX 15 kb)

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Remen, T., Pintos, J., Abrahamowicz, M. et al. Risk of lung cancer in relation to various metrics of smoking history: a case-control study in Montreal. BMC Cancer 18 , 1275 (2018). https://doi.org/10.1186/s12885-018-5144-5

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DOI : https://doi.org/10.1186/s12885-018-5144-5

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Association between smoking and environmental tobacco smoke with lung cancer risk: a case–control study in the Fujian Chinese population

• Original Article
• Published: 10 May 2021
• Volume 30 , pages 2047–2057, ( 2022 )

Cite this article

• Jinman Zhuang 1 , 2 , 3   na1 ,
• Zhi qiang Liu 1 , 2 , 3   na1 ,
• Rendong Xiao 4   na1 ,
• Qiu ping Xu 5 ,
• Wei min Xiong 1 , 2 , 3 ,
• Lin Cai 1 , 2 , 3 &
• Fei He 1 , 2 , 3  

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To investigate the association between smoking, environmental tobacco smoke (ETS), and lung cancer risk.

This case–control study included 1622 newly diagnosed cases of lung cancer and 1622 healthy frequency-, age-, and gender-matched control participants. Epidemiological data were collected by in-person interviews using a standard questionnaire.

Smoking was a risk factor for lung cancer in men (odds ratio (OR) = 4.486, 95% confidence interval (95%CI) 3.586–5.611). In addition, decreased starting age, increased number of cigarettes smoked per day, duration of smoking, pack–years, and depth of inhalation were all risk factors that met the dose–response relationship ( P  < 0.001). The risk of lung cancer was lower among men who had quit smoking for more than 10 years compared to current smokers. Additionally, male smokers with lung squamous cell carcinoma were at a higher risk of lung cancer than male smokers with lung adenocarcinoma. Workplace ETS increased the risk for lung cancer for male nonsmokers (OR = 2.452, 95%CI 1.534–3.920). In contrast, household ETS increased the risk for lung cancer for female nonsmokers (OR = 2.224, 95%CI 1.644–3.009). Approximately 65.93% cases of lung cancer in men could be attributed to smoking, whereas approximately 31.03% cases of lung cancer among nonsmokers could be attributed to ETS.

Conclusions

Smoking is the main risk factor for lung cancer. Workplace ETS is associated with increased lung cancer risk in male nonsmokers, while household ETS is associated with increased lung cancer risk in nonsmoking women. Thus, smoking and ETS increase the risk of lung cancer and are major public health concerns.

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Acknowledgments

We thank all the staff from the Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University. We also would like to express our appreciation to the patients who participated in our study.

This study was supported by the National Natural Science Foundation of China [grant number 81402738].

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Jinman Zhuang, Zhi qiang Liu and Rendong Xiao contributed equally to this work.

Authors and Affiliations

Department of Epidemiology, School of Public Health, Fujian Medical University, Fuzhou, China

Jinman Zhuang, Zhi qiang Liu, Wei min Xiong, Lin Cai & Fei He

Fujian Provincial Key Laboratory of Environment factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, China

Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China

Department of Thoracic Surgery, The first affiliated hospital of Fujian Medical University, Fuzhou, China

Rendong Xiao & Xu Li

Medical Department, The Affifiliated Hospital of Putian University, Putian, China

Qiu ping Xu

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FH and LC conceived and designed the experiments; ZQL, QPX, and WMX did the survey; FH, ZQL, JMZ, and RDX analyzed the data; RDX and XL contributed materials; JMZ and RDX wrote the paper.

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Correspondence to Fei He .

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This study was approved by the Ethical Review Committee of Fujian Medical University (Fuzhou, China).

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Zhuang, J., Liu, Z.q., Xiao, R. et al. Association between smoking and environmental tobacco smoke with lung cancer risk: a case–control study in the Fujian Chinese population. J Public Health (Berl.) 30 , 2047–2057 (2022). https://doi.org/10.1007/s10389-021-01573-3

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DOI : https://doi.org/10.1007/s10389-021-01573-3

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Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies

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• Peer review
• Richard Peto , professor of medical statistics and epidemiology a ,
• Sarah Darby ( sarah.darby{at}ctsu.ox.ac.uk ) , professor of medical statistics a ,
• Harz Deo , statistician b ,
• Paul Silcocks , senior lecturer in epidemiology c ,
• Elise Whitley , lecturer in medical statistics d ,
• Richard Doll , emeritus professor of medicine a
• a Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Radcliffe Infirmary, Oxford OX2 6HE
• b Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford OX2 6HE
• c Trent Institute for Health Services Research, Queen's Medical Centre, Nottingham NG7 2UH
• d Department of Social Medicine, University of Bristol, Bristol BS8 2PR
• Correspondence to: S Darby
• Accepted 7 July 2000

Objective and design: To relate UK national trends since 1950 in smoking, in smoking cessation, and in lung cancer to the contrasting results from two large case-control studies centred around 1950 and 1990.

Setting: United Kingdom.

Participants: Hospital patients under 75 years of age with and without lung cancer in 1950 and 1990, plus, in 1990, a matched sample of the local population: 1465 case-control pairs in the 1950 study, and 982 cases plus 3185 controls in the 1990 study.

Main outcome measures: Smoking prevalence and lung cancer.

Results: For men in early middle age in the United Kingdom the prevalence of smoking halved between 1950 and 1990 but the death rate from lung cancer at ages 35–54 fell even more rapidly, indicating some reduction in the risk among continuing smokers. In contrast, women and older men who were still current smokers in 1990 were more likely than those in 1950 to have been persistent cigarette smokers throughout adult life and so had higher lung cancer rates than current smokers in 1950. The cumulative risk of death from lung cancer by age 75 (in the absence of other causes of death) rose from 6% at 1950 rates to 16% at 1990 rates in male cigarette smokers, and from 1% to 10% in female cigarette smokers. Among both men and women in 1990, however, the former smokers had only a fraction of the lung cancer rate of continuing smokers, and this fraction fell steeply with time since stopping. By 1990 cessation had almost halved the number of lung cancers that would have been expected if the former smokers had continued. For men who stopped at ages 60, 50, 40, and 30 the cumulative risks of lung cancer by age 75 were 10%, 6%, 3%, and 2%.

Conclusions: People who stop smoking, even well into middle age, avoid most of their subsequent risk of lung cancer, and stopping before middle age avoids more than 90% of the risk attributable to tobacco. Mortality in the near future and throughout the first half of the 21st century could be substantially reduced by current smokers giving up the habit. In contrast, the extent to which young people henceforth become persistent smokers will affect mortality rates chiefly in the middle or second half of the 21st century.

Introduction

Medical evidence of the harm done by smoking has been accumulating for 200 years, at first in relation to cancers of the lip and mouth, and then in relation to vascular disease and lung cancer. 1 The evidence was generally ignored until five case-control studies relating smoking, particularly of cigarettes, to the development of lung cancer were published in 1950, one in the United Kingdom 2 and four in the United States. 3 – 6 Cigarette smoking had become common in the United Kingdom, firstly among men and then among women, during the first half of the 20th century. By 1950 lung cancer rates among men in the United Kingdom had already been rising steeply for many years, but the relevance of smoking was largely unsuspected. 2 7 At that time about 80% of men and 40% of women smoked (fig 1 and BMJ 's website, table A). But few of the older smokers had smoked substantial numbers of cigarettes throughout their adult life, so even male lung cancer rates were still far from their maximum (except in younger men), and rates in women were much lower. Over the next few decades, a substantial decrease occurred in the United Kingdom in the prevalence of smoking (fig 1 ), in cigarette tar yields, and, eventually, in lung cancer rates (fig 2 ), and by 1990 male lung cancer mortality, although still high, was decreasing rapidly. 8 – 12

Trends in prevalence of smoking at ages 35–59 (left) and ≥60 (right) in men and women in the United Kingdom, 1950-98. Prevalences at ages 25–34 were 80% for men and 53% for women in 1948–52 and 39% for men and 33% for women in 1998. Further details are given on the BMJ 's website (table A)

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Trends in mortality from lung cancer in men and women in the United Kingdom, 1950-97: annual mortality per 10 5 at ages 35–54 (left) and 55–74 (right) years. Rate in each 20 year age range is mean of rates in the four component five year age groups. Age specific rates from 1950–2 to 1993–7 are given on BMJ 's website (tables B and C); at ages 35–54 and 55–74 in 1998 the rates were 17 and 243 (men) and 12 and 20 (women)

In this paper we relate the UK national trends in smoking, in smoking cessation, and in lung cancer to the contrasting results from two large case-control studies of smoking and lung cancer in the United Kingdom that were conducted 40 years apart, centred on the years 1950 2 7 and 1990. 8 The 1950 study was concerned with identifying the main causes of the rise in lung cancer and showed the predominant role of tobacco. The 1990 study was concerned not just with reconfirming the importance of tobacco but also with assessing the lesser effects of indoor air pollution of some houses by radon. 8 Because there has been widespread cessation of smoking (indeed, above age 50 there are now twice as many former cigarette as current cigarette smokers in the United Kingdom 10 ), the second study was able to assess the long term effects of giving up the habit at various ages.

Participants and methods

The 1950 study was conducted in London and four other large towns during 1948-52, and its methods have been described elsewhere. 2 7 It involved interviewing, as potential “cases,” patients younger than 75 years of age in hospital for suspected lung cancer and, as “controls,” age matched patients in hospital with various other diseases (some of which would, in retrospect, have been conditions associated with smoking). After patients in whom the initial diagnosis of lung cancer was eventually refuted were excluded from the cases, 1465 cases and 1465 controls remained. A preliminary report on 709 case-control pairs was published in 1950, and the full results were published two years later. 2 7

The 1990 study was conducted during 1988–93 in a part of southwest England that had not been included in the 1950 study. Potential cases were patients younger than 75 who were referred with suspected lung cancer to the five hospitals in Devon and Cornwall that investigated lung cancer. For each case a population control was obtained, selected randomly either from lists of the local family health services authority or from electoral rolls, and a hospital control was selected from patients whose current admission was for a disease not thought to be related to smoking. Controls were matched for age, sex, and broad area of residence to the patients with suspected lung cancer. Cases and controls were eligible for the 1990 study only if they were current residents of Devon or Cornwall, had lived in one of these two counties for at least 20 years, and could be interviewed in person by research assistants about smoking habits and other relevant characteristics. The final diagnosis of cases was sought; those who had a smoking related disease other than lung cancer were excluded; and the few who had a disease not known to be associated with smoking were transferred to the hospital control group. Similarly, in 1990 (although not in 1950) the final diagnosis of all the hospital controls was sought, and those whose main reason for being in hospital was a disease known to be related to smoking were excluded from the study.

The distributions of the smoking habits of the population controls and hospital controls in 1990 were closely similar, and the results are presented here with these two control groups combined. Further details of the study design and methods of data collection and analysis have been given elsewhere. 8 Information was obtained in the 1990 study about the smoking habits of 667 men and 315 women with a confirmed diagnosis of lung cancer and of 2108 male and 1077 female controls.

Statistical methods

Relative and cumulative risks.

Relative risks for men and women comparing particular categories of smoker with lifelong non-smokers in the 1990 study (and the ratios of the risks in former smokers to those in continuing smokers) were calculated by logistic regression with adjustment for age. 13 Further adjustment for social class, radon exposure, and county of residence made no material difference. Relative risks for men and women in the 1950 study were taken as the odds ratios indicated by the published frequency distributions of the age matched cases and controls. 7 Relative risks from the studies were then combined with national lung cancer mortality rates from 1950 and 1990 respectively to estimate the absolute hazards in various categories of smoker, former smoker, and non-smoker. Because they are linked to known national rates, these absolute risks are statistically stable among smokers (and among former smokers), even though the risks relative to lifelong non-smokers would not be stable as so few non-smokers develop the disease. Such calculations of absolute risk allow comparisons between different categories of smoker not only within this study but also between this and other studies that report absolute risks.

For the 1990 study, within one particular age group, the absolute lung cancer rates for the different smoking categories were obtained by multiplying the all ages relative risks for each of the smoking categories by a common factor. This factor was chosen so that combination of these risks with the prevalences of such smoking habits among study controls in that age group yielded the 1990 age specific lung cancer death rate in that age group. If, for one particular category of smoker, the lung cancer rates per 10 5 in all the five year age groups before age 75 add up to c , then the cumulative risk by age 75 is 1−exp(−5 c /10 5 ). For the 1950 study the relative risks were multiplied by 0.6 (men) and 0.5 (women) to yield the cumulative risk (%) by age 75. These factors were chosen to ensure that the population weighted means of the cumulative risks for lifelong non-smokers, former smokers, cigarette smokers, and other smokers were 4.7% (men) and 0.7% (women) as in the 1950 population. (The cumulative risk, which depends only on the age specific lung cancer rates up to age 75 and not on competing causes of death, is somewhat less than the lifetime risk.)

Use of statistically stable non-smoker rates from a large US study

The most reliable recent evidence on lung cancer rates among lifelong non-smokers in developed countries is that from a prospective study of mortality in one million Americans during the 1980s (see table D on BMJ 's website). 14 15 These American rates seem to correspond not only to what normally happens in the United States but also to what normally occurs in the United Kingdom, at least among professional men. For, when these figures were used to predict the total number of deaths from lung cancer among the non-smokers in a cohort of male British doctors that has been followed prospectively for 40 years from 1951 to 1991, 16 17 the number expected was 19.03; the number actually observed was 19 (R Doll, personal communication). The American lung cancer rates for non-smokers suggest cumulative risks by 75 years of age of 0.44% for men and 0.42% for women.

Cumulative risks for the different categories of smoker in the 1990 study are shown on the BMJ 's website (table E), representing the probabilities of death from lung cancer before age 75: that calculated for lifelong non-smokers is 0.2% for men and 0.4% for women. The male rate is about half that in the American study but is based on only three cases, which is too few to be reliable. Conversely, the American results suggest that the cumulative risks calculated from the 1950 study—0.6% (men) and 0.5% (women) in lifelong non-smokers—may be slightly too high, although the rate in men is based on only seven cases and was inflated by problems with the 1950 male controls (see Results). We have therefore used the American results for non-smokers in most of our analyses. This does not affect the risk ratios comparing smokers and former smokers or the estimated absolute risks among smokers and former smokers.

Effects of current smoking in 1990 study

Most of the participants who were still current cigarette smokers in 1990 would have been cigarette smokers throughout adult life, and the cumulative risk of lung cancer by age 75 in this group was 15.9% for men and 9.5% for women (see BMJ 's website, table E). These cumulative risks reflect the death rates from lung cancer of cigarette smokers in 1990 and were obtained by combining the relative risks from the 1990 case-control study with national death rates. Had these men and women smoked as intensively when they were young as adolescent smokers do nowadays, the cumulative risks might have been greater. Only 34% of the male and 11% of the female controls who were current smokers had started before the age of 15 years, and the case-control comparisons indicate that smokers who had done so had double the risk of lung cancer of those who had started aged 20 or older (risk ratios adjusted for age and amount smoked were 2.3 (95% confidence interval 1.4 to 3.8) for men and 1.8 (0.9 to 3.4) for women).

Effects of cessation in 1990 study

A large number of men and, to a lesser extent, of women had stopped smoking well before 1990. Hence, particularly for men, robust estimates can be obtained from the 1990 data of the effects of prolonged cessation on the avoidance of risk (table 1 ).

Comparisons of risk of lung cancer between all current smokers, all former smokers, and lifelong non-smokers in 1990 study

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The ratio of the risk of lung cancer in those who have stopped smoking to that in continuing smokers gets progressively lower as the time since cessation gets longer, although it never gets quite as low as in lifelong non-smokers. Once people have started to smoke, however, the comparison that is relevant for them is of former smokers with continuing smokers, and table 1 contrasts the numbers of cases among former smokers with the numbers that would have been expected if smoking had continued. In the 1990 study there were substantially more former smokers than continuing smokers among the controls, and this widespread cessation had almost halved the number of cases that would have been expected if the former smokers had continued smoking. The risk ratios comparing former cigarette smokers with continuing cigarette smokers (see BMJ 's website, table F) are essentially the same as those in table 1 for all smokers and can be used to calculate the cumulative risks of lung cancer for men who stop smoking cigarettes at different ages (fig 3 ). The cumulative risks by 75 years of age are 15.9% for men who continue to smoke cigarettes and 9.9%, 6.0%, 3.0%, and 1.7% for those who stopped around 60, 50, 40, and 30 years of age. The pattern among women was similar: the cumulative risk of lung cancer by age 75 among continuing smokers was 9.5% compared with 5.3% and 2.2% among women who stopped around 60 and 50 years of age, respectively. The risk seemed even smaller for women who had stopped earlier in life, but the number of such women was too small for statistical stability. The results for smokers and for former smokers in table 1 and figure 3 are not affected by any assumptions that may be made about non-smoker risks.

Effects of stopping smoking at various ages on the cumulative risk (%) of death from lung cancer up to age 75, at death rates for men in United Kingdom in 1990. (Non-smoker risks are taken from a US prospective study of mortality 14 )

Comparison of findings for smoking in 1950 and 1990 studies

The hazards at the death rates among current smokers in the 1990 study, when the male lung cancer epidemic was well past its peak, can be compared with the hazards at the death rates among current smokers in the 1950 study, 2 7 when the epidemic was still increasing rapidly, except among men in early middle age (table 2 ).

Absolute risks in smokers unaffected by biases in 1950 male controls

The findings in the earlier study were reported for categories of smoking that differ slightly from those now considered appropriate, but this probably makes little difference. In addition, the hospital controls in the earlier study included an unknown, but appreciable, proportion of patients who were in hospital for conditions that were subsequently shown to be related to smoking but were not known to be so in 1950. This means that the proportion of smokers was higher than in the general population and also that the relative risks estimated from the 1950 study for different levels of smoking were too low. Both effects will have been relatively unimportant for women, as few women at that time had been smoking long enough to have been admitted to hospital because of a smoking related disease. Even for men, they will have had little effect on the calculated absolute risk among smokers. If, for example, the male rate of hospital admission for the control diseases was about 1.5 times as great among smokers as among non-smokers, then correction for this would multiply the relative risk of lung cancer in male smokers by about 1.5 and would indicate that the percentage of current smokers in the study areas was not 86%, but about 80% (which was about the percentage in the country as a whole). But this correction would have no material effect on the cumulative risk calculated for cigarette smokers (and little effect on that calculated for other smokers or former smokers), as the weighted average has to remain 4.7% to match the 1950 male death rates. It would merely reduce the cumulative risk calculated for male non-smokers from 0.6% to about 0.4%, thereby bringing it closer to that in US non-smokers.

Smoking status versus cumulative risk of death from lung cancer by age 75, from 1950 and 1990 studies

Changes in prevalence of smoking

One clear difference between the 1950 and 1990 study results in table 2 is that many of the controls in the 1990 study had given up smoking, so there was a large decrease in the prevalence of smoking between the two studies. (In both 1950 (after correction) and 1990, the prevalence of smoking among controls resembled that in national surveys.) The reduction in the proportion currently smoking cigarettes was smaller in women than in men. Among women who still smoked in 1990, a higher proportion smoked heavily than was the case in 1950, and a substantially larger proportion had started before the age of 20 (68% in 1990 and 24% in 1950 among women, compared with 83% and 76% respectively among men). Moreover, the way that women smoke a cigarette has become more like the way men do. 22 Nevertheless, among women old enough to be in the 1990 study more than half of those who had been cigarette smokers had given up the habit, and an even greater proportion of the men had done so. A recent national survey confirms that among men and women aged over 50 in the United Kingdom, the number of former cigarette smokers is double the number of continuing cigarette smokers. 10 But those who are continuing smokers nowadays may well have smoked substantial numbers of cigarettes throughout adult life, whereas national cigarette sales during the first few decades of the last century 9 18 show that few of the older smokers in 1950 can have done so.

Changes in lung cancer rates among continuing smokers

Another clear difference between the two studies is that the cumulative risk of lung cancer among smokers increased substantially. The increase occurred not only among women (among whom the cumulative risk for cigarette smokers was 1.0% in 1950 and 9.5% in 1990) but also among men (among whom it increased from 5.9% at 1950 cigarette smoker lung cancer rates to 15.9% at 1990 rates). As lung cancer mainly occurs above the age of 55, the increase in the cumulative risk is mainly because current smokers aged 55–74 in 1950 were less likely to have smoked a substantial number of cigarettes throughout adult life than current smokers in 1990. 18 19 Among younger men, however, the death rate from lung cancer decreased more rapidly than the prevalence of smoking (figs 1 and 2 ), indicating lower death rates from lung cancer in 1990 than 1950 among male cigarette smokers in early middle age.

Prolonged cigarette smoking

The 1990 study provides reliable evidence, particularly among men, about the absolute effects of prolonged cigarette smoking and about the effects of prolonged cessation (table 1 , fig 3 ). Information about the effects of prolonged cigarette smoking could not have been obtained in 1950 because the habit became widespread in the United Kingdom (firstly among men and then among women) only during the first half of the 20th century. By 1950 the increase in smoking was too recent to have had its full effects on disease rates, except perhaps among men in early middle age. The fact that by 1990 many of the current smokers would have smoked substantial numbers of cigarettes throughout adult life is the chief reason for the large increase in the cumulative risk of lung cancer among continuing smokers. 19 For the same reason, increases in the risks associated with smoking were also seen between the first 20 years (1951–71) and the next 20 years (1971–91) of follow up in the prospective study of smoking and death among British doctors, 17 and between the two large prospective studies carried out by the American Cancer Society in the 1960s and 1980s. 15 20

At the lung cancer rates for female cigarette smokers in 1950 the cumulative risk of death from lung cancer before age 75 (in the absence of other causes of death) would have been only 1% compared with 10% at 1990 rates. The effect of longer exposure (together with the effect of changes in the way women smoke cigarettes 22 ) overwhelms the lesser effect of the reduction in cigarette tar yields (and of other changes in cigarette composition) over this period. 19

Among male cigarette smokers the cumulative risk of death from lung cancer by age 75 increased from 6% in 1950 to about 16% in 1990. Again the most plausible explanation for this increase is that the effect among continuing smokers aged 55–74 of a greater duration of smoking substantial numbers of cigarettes outweighed the effect of changes in cigarette composition. At ages 35-54, there was a twofold decrease between 1950 and 1990 in the prevalence of smoking among men, but, particularly at ages 35-44, male mortality from lung cancer in the United Kingdom decreased more rapidly than the prevalence of smoking (figs 1 and 2 ), suggesting a decrease in hazard among smokers. These increases and decreases in the hazards among smokers, together with large changes in smoking uptake rates and cessation rates, underlie the large fluctuations in UK lung cancer death rates shown in fig 2 and reviewed in more detail elsewhere. 19 21 23

Prolonged cessation

In the 1990 study we were able to assess the effects of prolonged cessation among those who had smoked cigarettes for many years. Although efforts to change from cigarettes to other types of tobacco, or from smoking substantial numbers of cigarettes to smoking smaller numbers, seemed to confer only limited benefit (table 2 ), stopping smoking confers substantial benefit. Figure 3 indicated that even people who stop smoking at 50 or 60 years of age avoid most of their subsequent risk of developing lung cancer, and that those who stop at 30 years of age avoid more than 90% of the risk attributable to tobacco of those who continue to smoke (see fig 3 and BMJ 's website, table G). In the United Kingdom widespread cessation has roughly halved the number of cases of lung cancer that would now be occurring, as by 1990 it had already almost halved the number that would have occurred in the study (table 1 ).

Past and future trends in total mortality attributable to tobacco

Despite cessation of smoking and improvements in cigarette composition, lung cancer is still the chief neoplastic cause of death in the United Kingdom, and tobacco causes even more deaths from other diseases than from lung cancer. 14 15 The changes since 1950 in tobacco-attributable mortality from diseases other than lung cancer can be estimated indirectly from national mortality statistics. 14 15 Such estimates indicate that in 1965 the United Kingdom probably had the highest death rate from tobacco related diseases in the world, but that since then the number of deaths in middle age (35–69) from tobacco has decreased by about half, from 80 000 in 1965 to 43 000 in 1995. Nevertheless, cigarette smoking remains the largest single cause of premature death in the United Kingdom and eventually kills about half of those who persist in the habit. 17 The 1990 study assessed the effects of stopping smoking only on lung cancer, but a comparably large benefit of stopping was found for all cause mortality in the prospective study of smoking and death among British doctors. 17 This reinforces similar evidence from many other countries that even in middle age those who stop smoking avoid most of their subsequent risk of being killed by tobacco.

Two thirds of those in the United Kingdom who are still current smokers say they want to give up the habit, 10 and the extent to which they succeed in doing so will be the chief determinant of the number of deaths caused by tobacco over the next few decades. Both in the United Kingdom and elsewhere, 24 25 the extent to which young people become cigarette smokers over the next few decades will strongly affect mortality only in the middle and second half of the 21st century, but mortality in the first half of the century will be affected much less by the numbers of new smokers who start than by the numbers of current smokers who stop.

What is already known on this topic

Smoking is a cause of most deaths from lung cancer in the United Kingdom

Early studies could not reliably assess the effects of prolonged cigarette smoking or of prolonged cessation

What this study adds

If people who have been smoking for many years stop, even well into middle age, they avoid most of their subsequent risk of lung cancer

Stopping smoking before middle age avoids more than 90% of the risk attributable to tobacco

Widespread cessation of smoking in the United Kingdom has already approximately halved the lung cancer mortality that would have been expected if former smokers had continued to smoke

As most current smokers in the United Kingdom have consumed substantial numbers of cigarettes throughout adult life, their risks of death from lung cancer are greater than earlier studies had suggested

Mortality from tobacco in the first half of the 21st century will be affected much more by the number of adult smokers who stop than by the number of adolescents who start

Acknowledgments

We thank the individuals and research assistants who took part in both studies; the staff in hospitals, general practices, and the South and West Cancer Intelligence Unit; Cathy Harwood and Anthea Craven for secretarial assistance; and Jillian Boreham for graphics.

Contributors: RD planned the 1950 study with A Bradford-Hill and planned the 1990 study with SD. SD, RD, HD, PS, and EW conducted and analysed the 1990 study in the Imperial Cancer Research Fund Cancer Epidemiology Unit. RP, SD, and RD planned and wrote the paper. SD is the guarantor.

Funding direct support to Clinical Trial Service Unit from the Medical Research Council (which also funded the 1950 study), the British Heart Foundation, and the Imperial Cancer Research Fund. The 1990 study was funded by the Imperial Cancer Research Fund; the National Radiological Protection Board; the Department of Health; the Department of the Environment, Transport and the Regions; and the European Commission.

Competing interests None declared.

• Wynder EL ,
• Goldstein H ,
• Gerhardt PR
• Ballard GP ,
• Whitley E ,
• Silcocks P ,
• Thakrar B ,
• Nicolaides-Bouman A ,
• Office for National Statistics
• World Health Organization
• Stata Corporation
• Boreham J ,
• Wheatley K ,
• Sutherland I
• Kiryluk S ,
• Day-Lalley CA ,
• Flanders WD ,

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• Published: 22 February 2022

Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study

• Peidong Zhang 1 , 2   na1 ,
• Pei-Liang Chen 1   na1 ,
• Zhi-Hao Li 1 ,
• Ao Zhang 3 ,
• Xi-Ru Zhang 1 ,
• Yu-Jie Zhang 1 ,
• Dan Liu 1 &
• Chen Mao   ORCID: orcid.org/0000-0002-6537-6215 1 , 4  

British Journal of Cancer volume  126 ,  pages 1637–1646 ( 2022 ) Cite this article

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• Lung cancer
• Risk factors

Genetic variation increases the risk of lung cancer, but the extent to which smoking amplifies this effect remains unknown. Therefore, we aimed to investigate the risk of lung cancer in people with different genetic risks and smoking habits.

This prospective cohort study included 345,794 European ancestry participants from the UK Biobank and followed up for 7.2 [6.5–7.8] years.

Overall, 26.2% of the participants were former smokers, and 9.8% were current smokers. During follow-up, 1687 (0.49%) participants developed lung cancer. High genetic risk and smoking were independently associated with an increased risk of incident lung cancer. Compared with never-smokers, HR per standard deviation of the PRS increase was 1.16 (95% CI, 1.11–1.22), and HR of heavy smokers (≥40 pack-years) was 17.89 (95% CI, 15.31–20.91). There were no significant interactions between the PRS and the smoking status or pack-years. Population-attributable fraction analysis showed that smoking cessation might prevent 76.4% of new lung cancers.

Conclusions

Both high genetic risk and smoking were independently associated with higher lung cancer risk, but the increased risk of smoking was much more significant than heredity. The combination of traditional risk factors and additional PRS provides realistic application prospects for precise prevention.

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Lung cancer is the most commonly diagnosed cancer and has the highest mortality worldwide among the general population and males, and it has the second leading mortality and the third incidence among females. In 2018, there were more than 2 million new cases and 1.7 million deaths from lung cancer [ 1 ]. Tobacco exposure is the leading cause of lung cancer, despite differences in the intensity of smoking and the type of cigarettes, and ~90% of lung cancers are attributed to smoking [ 2 ]. In addition, genetic factors also play essential roles in cancer development. Twin studies [ 3 ] and heritability estimation based on genome-wide association studies (GWASs) [ 4 , 5 ] indicated that genetic factors contribute far less to incident lung cancer than environmental factors, including smoking. However, population-based prospective studies of smoking and genetic risk in lung cancer have not been fully validated.

Over the past decade, GWASs have identified multiple susceptibility loci associated with lung cancer risk, including TP63 , TERT , CDKN2A/B and CHRNA3/5 [ 6 , 7 , 8 , 9 ]. However, while consistently and significantly associated with the lung cancer risk, each common variant’s impact is modest. Aggregating multiple single-nucleotide polymorphisms (SNPs) with tiny functions to generate a composite polygenic risk score (PRS) may explain the genetic risk of complex diseases [ 10 ]. In addition, multiple genes, including CHRNA3/5 , were strongly associated with lung cancer, smoking behaviours [ 11 ], and nicotine addiction [ 12 ]. Although previous studies have reported a significant association with lung cancer based on case-control designs [ 13 , 14 ], the relevance of combining these risk scores and smoking for individual subjects and whether smoking and genetic risk have a synergistic effect remains uncertain. Therefore, we hypothesised that smoking and genetic risk are independently associated with incident lung cancer.

This study’s primary purpose was to investigate whether there are differences in the association between smoking and new-onset lung cancer among individuals with low, intermediate or high genetic risk in a large population-based cohort. The second aim was to investigate the possible interaction between genetic risk and smoking for incident lung cancer.

Study design

The UK Biobank study started in 2006 and, until 2010, recruited >500,000 participants aged 40–69 years from the general population at 22 assessment centres throughout the UK [ 15 ]. Participants provided information on smoking and other potentially health-related aspects through extensive baseline questionnaires, verbal interviews and physical measurements. Moreover, blood samples were collected for genotyping.

Participants were excluded if they withdrew from the study ( n  = 1298), their genotype data does not meet the quality control conditions, related to another one more than second-degree, or were non-European ancestry ( n  = 44,072). Besides, participants with missing data on smoking or covariates were excluded ( n  = 75,546). Participants with a history of cancer at baseline were also excluded ( n  = 35,814).

Polygenic risk score

Polygenic risk scores were created following an additive model for previously published common genetic variants associated with lung cancer. To identify relevant risk loci, we began by searching the NHGRI-EBI GWAS Catalog of published GWAS [ 16 ]. Then, we reviewed both the original manuscript and supplementary materials to identify SNPs, risk alleles, and effect sizes. SNPs were selected for each locus according to the criteria of independent ( r 2  < 0.1), common (minor allele frequencies [MAF] > 0.01 in 1000 Genomes Project European population), UK Biobank available, large sample size in the development cohort, and smallest P value. The number of risk alleles (0, 1 or 2) for everyone was summed after multiplication with the effect size between the SNPs and each trait. A total of 33 SNPs from eight studies were used (eTable  1 in the Supplement) [ 8 , 9 , 17 , 18 , 19 , 20 , 21 , 22 ]. This polygenic risk score was then z-standardised based on values for all individuals and categorised into low (lowest quintile), intermediate (quintiles 2–4) and high (highest quintile) risk.

Smoking status and pack-years

Touchscreen questionnaires collected information on smoking status and pack-years at baseline. Detailed definitions of smoking status and the pack-years of smoking were provided in eTable  2 in the Supplement. All participants were categorised as never, former or current smoking according to their smoking status, and as no (0), light (0.1–19.9), intermediate (20–39.9), or heavy (≥40) smoking according to the pack-years of smoking.

Participants with incident lung cancer were identified as having a diagnosis in national cancer registries after baseline assessment. Diagnoses were recorded using the International Classification of Diseases-9 (ICD-9) and ICD-10 coding system (eTable  3 in Supplement). Death was ascertained via linkage to death registries. We calculated the follow-up time from the date of attendance to the date of first diagnosis, date of death, March 31, 2016 for Wales and England, and October 31, 2015 for Scotland, whichever occurred first.

All models were adjusted for age, sex, education, socioeconomic status (household income and Townsend deprivation index [ 23 ]), body mass index (BMI), physical activity, diet, alcohol consumption, passive smoking, occupational exposure, the relatedness of individuals in the sample and first 20 principal components of ancestry. Body mass index (BMI) (kg/m 2 ) was calculated for all UK Biobank participants based on their measured weight and height. Duration and intensity of physical activity were ascertained by touchscreen questionnaires based on the validated International Physical Activity Questionnaire [ 24 ]. A healthy diet was calculated based on the Dietary Approaches to Stop Hypertension (DASH) recommendation, associated with multiple cancer types [ 25 , 26 ]. Alcohol consumption was calculated based on US Dietary Guidelines for Americans 2015–2020 [ 27 ]. Exposure to tobacco smoke from others at home or outside for more than an hour per week was considered passive smoking. Occupational exposure is based on self-reported exposure to asbestos, paints, thinners, glues, pesticides, diesel exhaust, or other chemical smog at work.

Statistical analyses

Baseline characteristics of participants were summarised across incident lung cancer status as a percentage for categorical variables, mean (standard deviation [SD]) for normally distributed variables, and median (interquartile range) for skewed variables. The association between genetic-risk categories, smoking categories, and the combination of genetic and smoking categories (nine categories with low genetic risk and never-smoking as a reference, 12 categories with low genetic risk and no smoking pack-years as a reference) and incident lung cancer were explored using multivariable Cox proportional hazard models. The assumption for proportional hazards was evaluated by tests based on Schoenfeld residuals [ 28 ]; violation of this assumption was not observed in our analyses. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to assess each model’s predictive ability, including PRS, smoking, and the combination. The associations between PRS and incident lung cancer were evaluated on a continuous scale with restricted cubic spline curves based on multivariable Cox proportional hazards models. Moreover, interactions between polygenic risk scores and smoking status or pack-years were tested. The population-attributable fractions (PAFs), which estimate the proportion of events that would have been prevented if all individuals had been in the never-smoking category, were calculated [ 29 ]. The distribution of smoking status in the Health Survey for England (HSE) [ 30 ] and European Prospective Investigation into Cancer and Nutrition (EPIC) [ 31 ] with better representation to England and the European population were included in the analysis to deal with the incomplete representation of the UK Biobank [ 32 ].

Several sensitivity analyses were conducted to verify the robustness of the results. The risk of incident lung cancer was analysed using genetic-risk quintiles and pack-years of smoking in more subdivided groups. The association was also adjusted for self-reported and hospital diagnosed chronic obstructive pulmonary disease (COPD) and chronic pulmonary infections (definitions in eTable 3) at baseline, which may be important confounding factors [ 33 , 34 ]. The sensitivity analysis excluded participants who had third-degree or higher relatedness to further reduce non-random distribution of risk genes, developed outcomes within the first two years of follow-up to avoid reverse causality, and had a mismatch between calculation and self-reported never-smoking. Moreover, stratified analyses were performed to estimate potential modification effects according to sex (female or male), age (<60 or ≥60 years). Analyses were undertaken using R v3.6.1 (R Center for Statistical Computing, Vienna, Austria). P value < 0.05 (two-sided) was considered significant.

Participants characteristics

A total of 345,794 European individuals with a complete genotype and phenotype were included in the analysis of incident lung cancer, and their detailed information is shown in Fig.  1 . Their mean (SD) age was 56.3 (8.0) years, and 186,330 (53.9%) were female. The PRS was normally distributed among all participants (eFigure  1 in Supplement). There were 90,727 (26.2%) former smokers and 33,994 (9.8%) current smokers, among which 40,889 (11.8%) individuals had intermediate smoking exposure (20–39.9 pack-years) and 19,027 (5.5%) individuals had heavy smoking exposure (≥40 pack-years). The participant characteristics are provided in Table  1 .

BMI body mass index, TDI Townsend deprivation index.

Over 2,454,915 person-years of follow-up (median [interquartile range] length of follow-up, 7.2 [6.5–7.8] years), there were 1687 cases of incident lung cancer. Participants who developed incident lung cancer were slightly older, more likely to be male, had more smoking exposure, had less physical activity, and had an unhealthy diet. Meanwhile, they also had higher genetic risks.

Associations of genetic risk with incident lung cancer

With the increase in genetic risk, the incidence rate and hazard ratio (HR) of lung cancer gradually increased. After additional adjustment for smoking status or pack-years, the HRs of the high genetic-risk group were 1.73 (95% confidence interval [CI], 1.48–2.02) and 1.69 (95% CI, 1.44–1.97) compared with the low genetic-risk group, and the HRs per SD of PRS increase were 1.16 (95% CI, 1.11–1.22) and 1.16 (95% CI, 1.10–1.21). This result was almost the same as before the adjustment (Table  2 ). When genetic-risk quintiles were used instead of categories, the same results trend was observed (eTable  4 in Supplement). Figure  2a shows the cumulative risk of incident lung cancer in each genetic-risk group during follow-up.

Cumulative risk of incident lung cancer during follow-up according to genetic risk ( a ), smoking status ( b ) and smoking pack-years ( c ).

Associations of smoking with incident lung cancer

With the changing smoking status and increasing pack-years, the incidence and HR of lung cancer were also increased. After additional adjustment for PRS, the HRs of the current or heavy smoking group were 14.54 (95% CI, 12.47–16.94) and 17.80 (95% CI, 15.23–20.81), respectively, compared with the never-smoking group. This result was almost the same as before the adjustment (Table  3 ). When the number of smoking pack-years was given in more subdivided categories, the same trend of results was observed (eTable  5 in Supplement). Figure  2 b and c shows the cumulative risk of incident lung cancer in each smoking status and pack-year group during follow-up.

Associations of smoking and genetic risk with incident lung cancer

In each genetic-risk group, the incidence and HR of lung cancer increased with the smoking status deteriorating and pack-years increasing. Compared with the low genetic risk and never-smoking group, there was no significant difference of incident lung cancer risk in the high genetic risk but never-smoking group, while the HR of the low genetic risk but the current smoking group was 11.31 (95% CI, 7.84–16.33). A similar pattern was observed among genetic risk and smoking pack-year groups. The highest risks were observed among individuals with high genetic risk and current smoking (HR, 22.46 [95% CI, 15.99–31.53]) compared with low genetic risk and never-smoking. Individuals with high genetic risk and heavy smoking had a much higher risk of incident lung cancer (HR, 27.02 [95% CI, 19.28–37.88]) compared with those with low genetic risk and no smoking (Fig.  3 ). There was no significant interaction between the PRS and the smoking status or pack-years (both P for interaction > 0.05).

Risk of incident lung cancer according to genetic risk and smoking status ( a ) or genetic risk and smoking pack-years ( b ). The vertical line indicates the reference value of 1.

Further analyses stratified by genetic-risk category showed that the association between smoking and lung cancer appeared to increase with increasing genetic risk (Table  4 ). In the low, intermediate and high genetic-risk groups, the HRs of current smoking were 10.75 (95% CI, 7.28–15.88), 14.86 (95% CI, 12.22–18.07), and 16.85 (95% CI, 12.25–23.19), respectively, compared with never-smoking. Similarly, the HRs of heavy smoking were 16.22 (10.97–23.97), 17.06 (13.97–20.84) and 21.22 (15.34–29.35) compared with no smoking.

The same pattern of associations was observed in a series of sensitivity analyses with additional adjustment for COPD and chronic pulmonary infections, excluding participants who had third-degree or higher relatedness, excluding participants who developed outcomes within two years of baseline, and those who had a mismatch between calculation and self-reported never-smoking. (eTables  6 and 7 in the Supplement). Stratified analyses were performed by age and sex (eTables  8 and 9 in the Supplement), but the results were not markedly different among male and female or the <60 years and ≥60 years groups.

Population-attributable fractions

Since there was no significant interaction between PRS and smoking, the population-attributable fractions were calculated regardless of genetic risk. If all individuals had never smoked, 76.4% (95% CI, 73.4–79.2, based on smoking status) to 75.3% (95% CI, 72.0–78.2, based on smoking pack-years) new-onset lung cancer events might have been prevented during follow-up. If all current smokers quit smoking and the former smokers remained, the new-onset events might have been reduced by 26.4% (95% CI, 25.8–27.0). Further analyses stratified by genetic-risk category showed that 73.4% (95% CI, 64.5–80.4), 76.1% (95% CI, 72.2–79.6), and 79.1% (95% CI, 73.0–83.9) of incident lung cancer cases were attributed to smoking among the low, intermediate and high genetic-risk populations. When the smoking status proportional in HSE and EPIC were included, the PAFs of smoking were 83.2% (95% CI, 80.9–85.3) and 85.1% (95% CI, 83.1–87.0), respectively (eTable  10 in the Supplement).

In this large population-based prospective cohort study of more than 345,000 European individuals, high genetic risk and smoking status were independently associated with an increased risk of incident lung cancer events. Among never-smokers, there was no significant difference in the incident risk between each genetic group. The high genetic risk was two-fold higher than that of low genetic risk for current smokers. A similar pattern was observed for genetic risk and smoking pack-year groups. Meanwhile, there was no significant interaction between the PRS and smoking status or pack-years for incident lung cancer, and smoking cessation or reduction can provide similar protection against lung cancer regardless of genetic risk. The PAF analysis hypothesised that ~76% of new-onset lung cancer events might have been prevented if all individuals had never smoked.

To our knowledge, this study is by far the most extensive and fully adjusted prospective study of lung cancer incidence treating smoking as a single modifiable factor and incorporating multiple genetic-risk factors. Many common variants with minor effects have been identified as associated with a high risk of lung cancer, and the PRS can indicate their combined impact. Previous studies used 19 SNPs to construct a PRS for non-small cell lung cancer and showed predictive effects in a prospective study of 95,408 individuals [ 9 ]. Compared with this previous study, the present study included a larger sample size and more SNPs to increase the power for risk estimation. Meanwhile, we used the upper and lower quintiles to categorise the high and low genetic-risk groups [ 35 , 36 ], which may reduce the accuracy for the high genetic-risk group but warn a broader population that they need to carry out PRS-informed disease screening or life planning for life-threatening lung cancer. It also ensured that the comparison between the combined smoking and genetic-risk subgroups had sufficient statistical power.

Compared with another study based on the UK Biobank [ 37 ], the current PRS contains fewer highly independent SNPs in each locus to avoid overinflation of the GWAS summary results caused by many linkage disequilibrium SNPs. Therefore, this PRS may have better generalisations in other populations [ 38 ]. The current results showed similar HRs after adjusting for confounding factors (economic and social background, lifestyle factors, occupational exposure). Compared with case-control studies [ 39 , 40 ], prospective studies may lose some statistical power, but estimates of the absolute risk support using the PRS to predict incident lung cancer [ 10 , 41 ]. Regarding the role of PRS in never-smokers, our results suggest that their incident risk did not achieve statistical significance as the PRS group increased. Among never-smokers, the post hoc study powers for incident lung cancer in those with intermediate and high genetic risk were only 0.243–0.293. Therefore, we speculate that more outcome events may bring different results with the extension of follow-up time. To sum up, we believe that PRS could be a powerful tool for lung cancer risk assessment as it provides additional information independent of smoking and combining it with traditional risk factors could contribute to a better prediction of lung cancer.

We observed a strong association between smoking and incident lung cancer, independent of genetic risk, and the increased risk was much greater than the genetic risk. This means that smoking will significantly offset low genetic-risk benefits, consistent with a previous study [ 9 ]. However, we followed the same grouping method and found that the risk values were much more significant than those in a previous study (eTable  11 in the Supplement). Sample size, confounding factors, subtle differences in smoking habits, and outcome data sources may be the reasons for the differences. We observed similar associations between smoking and lung cancer with other relevant studies [ 42 , 43 ]. Based on a study of the contemporary population, although smoking, a long-recognised risk factor has undergone tremendous changes in production, composition and use method [ 44 ], it still plays a decisive role in lung cancer occurrence. Therefore, smoking cessation is still the most significant and cost-effective way to prevent lung cancer.

Previous studies believed that smoking was responsible for 80%~90% of lung cancer [ 2 , 43 , 45 ], and a study showed that 63.6% of lung cancer are attributable to comprehensive modifiable factors, including smoking and air pollution [ 37 ]. We found that the entire population would avoid 76.4% of lung cancer cases by becoming never-smokers. The slight reduction in this proportion is probably because of the reduction in smoking prevalence (23.3% of individuals were current smokers in The European Prospective Investigation into Cancer and Nutrition cohort [ 43 ]), manifesting the achievement of tobacco use control. In addition, differences in sample, methodology, and confounders’ representativeness also contribute to the different PAFs between studies. Furthermore, we also estimated the attribution of smoking by a more natural form of PAFs called the generalised impact fraction [ 46 ]. Our results showed that if all current smokers stop smoking and former smokers remain, the expected reduction in lung cancer cases would be 26%, again highlighting the efficiency of smoking cessation.

GWASs have shown that a locus may be simultaneously associated with smoking preference and lung cancer [ 12 , 47 , 48 ]. The interaction between smoking and genetic risk for lung cancer is a topic worth discussing, as it may help explain some of the missing heritability in lung cancer susceptibility [ 49 ]. Variants at the 15q25 locus have been confirmed by several studies associated with increased tobacco addiction and lung cancer risk [ 47 , 48 ], but a significant gene-environment interaction is controversial [ 50 , 51 ]. Some studies suggested that there were significant gene-smoking interactions at 10q25 [ 52 ], 14q22, 15q22 [ 53 ] and 19q13 [ 54 ]. In this study, there was no significant PRS-smoking interaction for lung cancer. This may be because the combination of multiple loci may mask the potential interaction, and the model selection and the specific definition of smoking habits may also affect the results. Besides, the number of positive cases observed in this cohort was far less than in large-scale GWASs, so there may be insufficient statistical power. However, based on the analysis of adjusting for extensive potential confounding factors and using the two smoking measures, we still believe that PRS and smoking promote lung cancer independently.

Strengths and limitations

This study has several strengths. Many participants from the UK Biobank study provided complete exposure information, and the extensive phenotype information provided many covariates that could be adjusted in the model to eliminate potential confounders. A more detailed grouping of lifetime tobacco exposure showed a typical dose-response relationship. Furthermore, the study population was utterly independent of previous GWASs that identified the risk loci and their effect sizes, which avoided overfitting to some extent.

Several limitations also need to be considered. First, the analysis was conducted on overall lung cancer without constructing PRS and assessing their effects for more detailed lung cancer classifications, which may mask their heterogeneity. Second, additional variants or genetic patterns associated with lung cancer are likely to be identified in the future, which may refine estimates of genetic risk. Third, PRS based on GWASs of European ancestry may limit its application in a larger population due to the differences in risk alleles, allele frequency, and the effect sizes of risk alleles. Fourth, smoking behaviours were self-reported and may have recall and misclassification bias, and there may be differences in the distribution of individuals excluded due to lacking smoking information. Fifth, smoking was not randomly assigned. Although analyses were adjusted for several covariates and sensitivity analyses, the possibility of unmeasured confounding remained. Sixth, the current study included 936 (0.27%) participants with inconsistent information on never-smoking and 0 pack-years of smoking. This may be due to the difference between the self-reported state and participants’ calculated state with minimal smoking exposure. Although we excluded these people in the sensitivity analysis, there may still be potential inconsistencies. Finally, the potential “healthy volunteer” selection bias in the UK biobank may be accompanied by a lower proportion of the smoking population and underestimated PAF. A mild increase in PAF was found using representative England and European population structures.

In conclusion, high genetic risk and smoking were independently associated with higher lung cancer risk, and there were no interactions between these risk factors. Polygenic risk assessment can provide important information beyond a variety of environmental exposures. This study provided new insights to quantitatively evaluate the role of smoking and genetics in lung cancer.

Data availability

The dataset supporting the conclusions of this article is available in the UK Biobank upon request ( https://www.ukbiobank.ac.uk/ ).

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Acknowledgements

We are grateful to UK Biobank participants. This research has been conducted using the UK Biobank resource ( https://www.ukbiobank.ac.uk ) under application number 43795.

This work was supported by the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2019), the National Natural Science Foundation of China (82103931 and 82003443), the Guangzhou Science and Technology Project (202002030255), and Young Elite Scientists Sponsorship Program by CAST (2019QNRC001). The funders had no role in the study design or implementation; data collection, management, analysis or interpretation; manuscript preparation, review or approval; or the decision to submit the manuscript for publication.

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These authors contributed equally: Peidong Zhang, Pei-Liang Chen.

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Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China

Peidong Zhang, Pei-Liang Chen, Zhi-Hao Li, Xi-Ru Zhang, Yu-Jie Zhang, Dan Liu & Chen Mao

The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Peidong Zhang

State Key Laboratory of Molecular Neuroscience and Center of Systems Biology and Human Health, Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China

Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Prof. Mao had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. PDZ and CM contributed to the study design and supervised the whole project. PDZ, ZHL, PLC, AZ and CM contributed to the data interpretation, data analysis, and manuscript writing. CM, PDZ, PLC, XRZ, YJZ and DL contributed to the data curation and funding acquisition. PDZ and PLC contributed equally to this work. All the authors reviewed or revised the manuscript.

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Zhang, P., Chen, PL., Li, ZH. et al. Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study. Br J Cancer 126 , 1637–1646 (2022). https://doi.org/10.1038/s41416-022-01736-3

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• Volume 8, Issue 10
• Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis
• Article Text
• Article info
• Citation Tools
• Rapid Responses
• Article metrics

• Linda M O’Keeffe 1 , 2 ,
• http://orcid.org/0000-0003-2185-0162 Gemma Taylor 1 , 2 , 3 , 4 ,
• Rachel R Huxley 5 , 6 ,
• Paul Mitchell 7 ,
• Mark Woodward 6 , 8 , 9 ,
• Sanne A E Peters 8
• 1 MRC Integrative Epidemiology Unit at the University of Bristol , Bristol Medical School, University of Bristol , Bristol , UK
• 2 Population Health Sciences , Bristol Medical School, University of Bristol , Bristol , UK
• 3 UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology , University of Bristol , Bristol , UK
• 4 Department of Psychology , University of Bath , Bath , UK
• 5 College of Science, Health and Engineering , La Trobe University , Melbourne , Australia
• 6 The George Institute for Global Health , University of New South Wales , Sydney , New South Wales , Australia
• 7 Olivia Newton-John Cancer and Wellness Centre , Austin Health and Olivia Newton-John Cancer Research Institute , Heidelberg , Victoria , Australia
• 8 The George Institute for Global Health , University of Oxford , Oxford , UK
• 9 Department of Epidemiology , John Hopkins University , Baltimore , Maryland , USA
• Correspondence to Dr Linda M O’Keeffe; linda.okeeffe{at}bristol.ac.uk

Objectives To investigate the sex-specific association between smoking and lung cancer.

Design Systematic review and meta-analysis.

Data sources We searched PubMed and EMBASE from 1 January 1999 to 15 April 2016 for cohort studies. Cohort studies before 1 January 1999 were retrieved from a previous meta-analysis. Individual participant data from three sources were also available to supplement analyses of published literature.

Eligibility criteria for selecting studies Cohort studies reporting the sex-specific relative risk (RR) of lung cancer associated with smoking.

Results Data from 29 studies representing 99 cohort studies, 7 million individuals and >50 000 incident lung cancer cases were included. The sex-specific RRs and their ratio comparing women with men were pooled using random-effects meta-analysis with inverse-variance weighting. The pooled multiple-adjusted lung cancer RR was 6.99 (95% Confidence Interval (CI) 5.09 to 9.59) in women and 7.33 (95% CI 4.90 to 10.96) in men. The pooled ratio of the RRs was 0.92 (95% CI 0.72 to 1.16; I 2 =89%; p<0.001), with no evidence of publication bias or differences across major pre-defined participant and study subtypes. The women-to-men ratio of RRs was 0.99 (95% CI 0.65 to 1.52), 1.11 (95% CI 0.75 to 1.64) and 0.94 (95% CI 0.69 to 1.30), for light, moderate and heavy smoking, respectively.

Conclusions Smoking yields similar risks of lung cancer in women compared with men. However, these data may underestimate the true risks of lung cancer among women, as the smoking epidemic has not yet reached full maturity in women. Continued efforts to measure the sex-specific association of smoking and lung cancer are required.

• systematic review
• lung cancer
• sex-specific

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/ .

https://doi.org/10.1136/bmjopen-2018-021611

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Strengths and limitations of this study

Evidence on the sex-specific association of smoking and lung cancer was meta-analysed in over 7 million participants across 99 cohort studies.

Several subgroup analyses were performed to examine the robustness of findings across different population subgroups.

However, the smoking epidemic is not yet fully mature in women and risks of lung cancer in women may still be underestimated.

Detailed data on smoking behaviour and data on specific subtypes of lung cancer were not available.

Introduction 

Lung cancer is the leading cause of cancer death worldwide with 1.7 million global deaths attributed to cigarette smoking in 2015. 1 Tobacco use is the leading cause of lung cancer; 55% of lung cancer deaths in women and over 70% of lung cancer deaths in men are due to smoking. 1 These global estimates, however, mask major differences in smoking prevalence in men and women across populations, with rates below 5% for women in most Asian and African countries to 40% and above for men in many parts of Asia and Eastern Europe. 2 In addition, smoking behaviour varies significantly by sex. For example, compared with women, men smoke more cigars and pipes, 3 take puffs of longer duration and leave shorter butts, 4 which each could potentially predispose them to greater risks of smoking-related lung cancer. Substantial physiological differences between the sexes may also result in sex differences in the effects of smoking, particularly for women. For example, compared with men, women have a smaller lung size and different airway behaviour, 5 which may increase their susceptibility to lung cancer at lower levels of smoking. A recent meta-analysis showed that cigarette smoking confers a greater coronary hazard in women compared with men, which suggests the possibility that this may also be true for the risk of smoking-related lung cancer. 6

A study of 50-year trends in smoking-related mortality in the USA found that the relative risks of smoking-related lung cancer mortality were higher in men than women. 7 However, this sex difference was only apparent in the oldest cohorts with the longest follow-up, possibly reflecting greater cumulative tobacco exposure in men than in women. In contrast, a recent study in Korea, a population where smoking patterns continue to differ between the sexes, suggested that sex differences in the impact of smoking on lung cancer risk exist and differ by histological subtype. 8 Analyses of a large UK primary care database showed that moderate and heavy smoking more strongly increase the risks of lung cancer in women than in men. 9

Two recent meta-analyses examined the sex-specific association between smoking and lung cancer. In the most recent of these, men were found to have a greater risk of lung cancer associated with smoking compared with women. 10 However, virtually all data were from historical case–control studies, which have several limitations, and the three included prospective studies provided contradictory results. While a previous meta-analysis by Lee et al 11 included 287 cohort and case–control studies and provided sex-specific estimates, single-sex cohorts were also included, sex differences in the smoking-related risk of lung cancer were not formally compared within studies, and only studies published up to 1999 were included.

To resolve this uncertainty, we performed a systematic review and meta-analysis of prospective cohort studies published to date on the sex-specific association of smoking with the risk of fatal and non-fatal lung cancer. Our systematic review builds on these previous meta-analyses by adding literature from 1999 onwards and restricting the analyses to cohort studies, which are less prone to bias than case–control studies. In addition, we perform several predefined subgroup analyses which have not been performed in meta-analyses of cohort studies included in previous reviews and supplement our findings with results from three sources of individual participant data (IPD), not published previously. An important a priori consideration is the substantial sex difference in the maturity of the smoking epidemic with men being at a more advanced stage than women in most parts of the world. 2 This would be expected to translate into lower relative risk (RR) estimates for lung cancer in women than in men. Hence, the null hypothesis that smoking confers the same lung cancer hazard in both women and men, would be met if the ratio of the RRs (RRRs) for lung cancer (women:men) was less than unity (reflecting a greater hazard in men than women). However, if the RRRs were found to be unity (or higher) then this would suggest a greater hazard associated with tobacco exposure in women than in men.

Search strategy

This review was conducted using a predefined protocol and in accordance to the Meta-analysis Of Observational Studies in Epidemiology guidelines (online supplementary eappendix 1 ). We systematically searched PubMed and EMBASE for studies published between 1 January 1999 and 15 April 2016 that reported on the relationship between smoking and lung cancer in men and women from a general population. The computer-based searches combined medical subject headings and free-text terms related to ‘tobacco/smoking’, ‘cancer’, ‘sex’ and ‘cohort studies’. The full search criteria are available in online supplementary eappendix 2 . Articles published before 1 January 1999 were retrieved from a previous systematic review. 11 The reference lists of all relevant original research and review articles were scanned to capture missed studies. Two authors (LMOK and GT) independently conducted the screening of studies and any disagreement was mediated by a third author (SAEP).

Supplementary file 1

Data extraction.

Data were extracted, in duplicate, from studies deemed to meet the eligibility criteria. These included details on general study characteristics (study name, duration of follow-up, year of publication), information about the studied population (prevalence of smoking, mean age, number of men and women, incidence of lung cancer, whether lung cancer was fatal or non-fatal and level of adjustment for covariates). We extracted sex-specific adjusted measures of RR and 95% confidence intervals (CIs).

Study selection

Observational cohort studies were included if they reported sex-specific RRs or equivalent, on the relationship between smoking and lung cancer. Studies were excluded if the variability around the point estimate was not reported, if they had not been adjusted for at least age, or if the study was performed in a population selected on the basis of prior lung cancer or another major underlying chronic disease. In the case of duplicate reports from the same study, the report with the longest follow-up or the highest number of cases was included. IPD from studies available to the authors were also used; the Asia Pacific Cohort Studies Collaboration (APCSC), the National Health and Nutrition Examination Survey III (NHANES III) and the Scottish Heart Health Extended Cohort Study (SHHEC). The Newcastle-Ottawa Scale assessment (NOS) was used to assess the methodological quality of all included studies, on a 9-point scale (online supplementary eappendix 3 and etable 1 ). 12

Meta-analysis

The primary analysis was a comparison of the sex-specific RR of lung cancer (fatal or non-fatal) in current smokers versus non-smokers (defined either as former or never smokers). For each study, we obtained the natural log of the sex-specific RRs and calculated the differences. The differences were pooled across studies using random-effects meta-analysis which allows the RR of lung cancer to vary from study to study, weighted by the inverse of the variances of the log RRs and then back-transformed to obtain the pooled women-to-men RRRs. The SE of the log RRR was calculated as the square root of the sum of the variance of the two sex-specific log RRs for each study. Pooled RRRs were computed separately for studies with only age-adjusted estimates and then for those studies with multiple-adjusted estimates. The set of multiple adjustments made was allowed to vary by study, but had to include at least one other risk factor in addition to age. The I² statistic was used to estimate the percentage of variability across studies due to between-study heterogeneity. The presence of publication bias was graphically examined using contour funnel plots, plotting the natural log of the RRR against its SE and tested using Begg’s test. Predefined subgroup analyses were conducted to obtain the adjusted RRRs by study region (Asia or non-Asia and Asia, Europe, USA, and Australia and New Zealand (ANZ)), year of study baseline (pre-1985 or post-1985), study endpoint (fatal only or fatal and non-fatal combined), number of cigarettes smoked per day (>0 to 10, 10–20, >20), study quality ≤6 vs >6 points) and follow-up time (≤10 vs >10 years). Random-effects meta-analyses were used for all subgroup analyses and differences between subgroups were examined using meta-regression. To include the largest number of studies available, we combined the age-adjusted and multiple-adjusted estimates, taking the maximum adjustment set available. In secondary analyses, we obtained the sex-specific RRs and RRRs comparing former smokers to never smokers and performed the same set of subgroup analyses. All analyses were performed using Stata V.12.0.

Patient and public involvement

There were no patients or applicable public involved in this review.

Of the 9519 unique records that were identified through the systematic search, 227 qualified for full-text evaluation ( figure 1 ). Of these, 25 separate studies provided information about sex differences in the association between smoking and lung cancer. This database was extended with IPD from APCSC (separately for Asia and ANZ), NHANES III and SHHEC leading to a total of 29 individual estimates, representing a total of 99 cohort studies available for meta-analysis.

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Flow chart of study selection. IPD, individual participant data.

The characteristics of the included studies are described in table 1 . Overall, data were available from 99 cohorts, including 7 113 303 individuals (46% women)—not accounting for two cohorts that used Census data—and at least 51 161 incident cases of lung cancer (31% women). Forty-six cohorts were from Asia (61% of the individuals), 6 were from the USA (28%), 37 were from Europe (10%) and 10 were from ANZ (1%). Of 29 studies, 4 studies had a quality score of 5 out of 9, 9 studies had a score of 6, 12 studies had a score of 7 and 4 studies with a score of 8 (online supplementary etable 1 ).

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Characteristics of included studies

Eighteen studies reported on the prevalence of smoking, which varied widely by study, region and sex. The prevalence of smoking ranged from 1% to 47% in women and from 1% to 70% in men. In all but two studies, the prevalence of smoking was higher in men than women, especially in Asia where typically less than 10% of women were smokers compared with over 50% of men. Smoking cessation rates were also higher among men (7%–61%) than women (<1%–39%).

Risk of lung cancer in current smokers versus non-smokers

Compared with non-smoking, current smoking was associated with an age-adjusted RR of lung cancer of 7.48 (95% CI 5.29 to 10.60) in women and 8.78 (95% CI 6.13 to 12.57) in men ( table 2 and online supplementary efigure 1 ). The pooled age-adjusted women-to-men RRR was 0.81 (95% CI 0.62 to 1.04), with substantial between-study heterogeneity (I 2 =86%; p<0.001) ( table 2 and online supplementary efigure 2 ). The multiple-adjusted RR of lung cancer associated with current smoking was 6.99 (95% CI 5.09 to 9.59) in women and 7.33 (95% CI 4.90 to 10.96) in men ( table 2 and figure 2 ). The corresponding RRR was 0.92 (95% CI 0.72 to 1.16) and between-study heterogeneity was substantial (I 2 =89%; p<0.001) ( table 2 and figure 3 ). There was no evidence of publication bias based on the Begg’s test (p=0.75) (online supplementary efigure 3 ).

Multiple-adjusted relative risk (RR) for incident lung cancer in women and men, comparing current smokers to non-smokers. Multiple-adjusted includes anything that adjusted for more than just age. These covariates are listed in table 1 . Figures may contain less than 29 studies because we report age-adjusted and multiple-adjusted results separately. Some studies only contributed age-adjusted results whereas others only provided multiple-adjusted results. However, the count of unique studies that contributed to at least one of these analyses is 29. APCSC, Asia Pacific Cohort Studies Collaboration; ARIC, Atherosclerosis Risk in Communities study; CPS, Cancer Prevention Study; EHS, Elderly Health Services; EPIC, European Prospective Investigation into Cancer; JACC, Japan Collaborative Cohort Study; JPHC, Japan Public Health Centre Study; NHANES III, National Health And Nutrition Examination Survey III; NHIS, National Health Interview Survey; NIH-AARP, National Institutes of Health American Association of Retrired Persons Diet and Health Study; SHHEC, Scottish Heart Health Extended Cohort Study; TPCS, Three-Prefecture Cohort Study.

Multiple-adjusted women-to-men ratio of relative risks (RRR) for incident lung cancer, comparing current smokers to non-smokers. Multiple-adjusted includes anything that adjusted for more than just age. These covariates are listed in table 1 . Figures may contain less than 29 studies because we report age-adjusted and multiple-adjusted results separately. Some studies only contributed age-adjusted results whereas others only provided multiple-adjusted results. However, the count of unique studies that contributed to at least one of these analyses is 29. APCSC, Asia Pacific Cohort Studies Collaboration; ARIC, Atherosclerosis Risk in Communities study; CPS, Cancer Prevention Study; EHS, Elderly Health Services; EPIC, European Prospective Investigation into Cancer; JACC, Japan Collaborative Cohort Study; JPHC, Japan Public Health Centre Study; NHANES III, National Health And Nutrition Examination Survey III; NHIS, National Health Interview Survey; NIH-AARP, National Institutes of Health American Association of Retired Persons Diet and Health Study; SHHEC, Scottish Heart Health Extended Cohort Study; TPCS, Three-Prefecture Cohort Study.

Sex-specific pooled relative risks (RR) and ratio of relative risks (RRR) for lung cancer associated with smoking

The sex difference in the risk of smoking-related lung cancer in our main analysis did not differ in subgroup analyses stratified by the women-to-men ratio of current smokers (p=0.90), women-to-men ratio of lung cancer incidence in the studies (p=0.64), year of study baseline (p=0.66), study endpoint (p=0.21) or study region (p=0.73) ( table 3 ). The sex difference in the risk of smoking-related lung cancer in our main analysis also did not differ by follow-up time (p=0.83) or study quality (p=0.69). The RRR was 0.93 (95% CI 0.72 to 1.20) for studies from Asia and 0.87 (95% CI 0.66 to 1.14) for studies from USA, Europe or ANZ.

Maximally adjusted pooled women to men ratio of relative risks (RRR) for lung cancer associated with smoking, in subgroup analyses

The risk of smoking-related lung cancer increased according to the number of cigarettes smoked per day in both sexes ( table 2 ). In women, the RRs were 5.30 (95% CI 3.52 to 7.97), 10.67 (95% CI 7.43 to 15.33) and 17.09 (95% CI 12.11 to 24.11) across subgroups of <10, 10 to 20 and >20 cigarettes per day versus non-smoking, respectively. Corresponding RRs in men were 4.97 (95% CI 2.74 to 9.03), 8.93 (95% CI 4.90 to 16.28) and 14.61 (95% CI 8.33 to 25.59), respectively. The RRRs in these subgroups were 0.99 (95% CI 0.65 to 1.52), 1.11 (95% CI 0.75 to 1.64) and 0.94 (95% CI 0.69 to 1.30), respectively.

Risk of lung cancer in former smokers versus never smokers

Data from 89 cohorts, including 6 006 725 individuals and 38 244 cases of lung cancer, reported on the risk of lung cancer in former smokers compared with never smokers. The age-adjusted RR of lung cancer associated with former smoking was 2.82 (95% CI 2.25 to 3.54) in women and 3.01 (95% CI 2.23 to 4.08) in men ( table 2 and online supplementary efigure 4 ); the age-adjusted RRR was 0.88 (95% CI 0.69 to 1.14) (I 2 =64%; p<0.001) ( table 2 and online supplementary efigure 5 ). The corresponding multiple-adjusted RRs were 3.14 (95% CI 2.45 to 4.03) in women and 3.13 (95% CI 2.06 to 4.76) in men ( table 2 and online supplementary efigure 6 ). There was no statistical evidence that the effects of smoking cessation on risk of lung cancer differed between the sexes; the multiple-adjusted RRR was 0.89 (95% CI 0.69 to 1.13) (I 2 =69%; p<0.001) ( table 2 and online supplementary efigure 7 ). There was no evidence that the RRR differed across various subgroup analyses ( table 3 ).

In this systematic review and meta-analysis, comprising data from more than 7 million participants, 99 cohort studies and over 50 000 incident cases of lung cancer, there was no evidence for a difference in the risk of smoking-related lung cancer in women compared with men. This was true across a range of subgroup and sensitivity analyses. However, as smoking prevalence and intensity were higher in men compared with women in most studies included in this analysis, there may yet be an unrealised sex difference in the risk of smoking-related lung cancer that will only become fully manifest as the smoking epidemic reaches full maturity in women. 2

The sevenfold higher RRs of lung cancer associated with smoking found in the present meta-analysis are considerably smaller than the 20-fold increased risks reported in the Million Women’s Study 13 and the British Doctors Study. 14 Both of these studies had the advantage of capturing smoking-related risks in populations that had smoked for long enough for the effects to become fully manifest, highlighting the importance of taking into consideration the stage of the tobacco epidemic in each sex. The lack of any appreciable sex difference in the RRs of lung cancer is surprising given men’s greater cumulative exposure to smoking, in most populations, compared with women. In addition, men have a greater exposure to other risk factors for lung cancer including occupational carcinogens. 15 Men also smoke more cigars and pipes, 3 take longer puffs of longer duration and leave shorter butts compared with women. 4 Hence, it may be reasonable to surmise that the RR estimates of smoking-related lung cancer in women may eventually exceed those of men, once cumulative exposure to smoking in women is comparable to that in men. In a previous meta-analysis, using similar methodology, we found that smoking conferred a 25% greater RR of coronary heart disease (CHD) in women than in men. Two possible explanations for why a similar pattern is not observed for lung cancer are that, first, the lag-time between smoking and CHD is considerably shorter than for lung cancer, 16 and second the pathways by which smoking increases risk are different between CHD and lung cancer.

Although not assessed in this analysis, evidence suggests that there are sex differences in the pattern of lung cancer among never smokers, with a higher prevalence of lung cancer among never-smoking women than never-smoking men. 17 18 A US study among 500000 people found a 30% higher incidence of lung cancer in women never smokers compared with men never smokers. 19 An Australian study found the proportion of patients with lung cancer who had never smoked was approximately 18% in women and 3% of men. 20 The reasons for this sex difference are not clear, but women may have increased exposure to environmental tobacco smoke 21 or other environmental carcinogens such as indoor air pollution 22 or sex-related differences in the metabolism of environmental carcinogens. The possibility of greater exposure to environmental tobacco smoke and other environmental carcinogens in women compared with men could have resulted in a greater underestimation of the association between smoking and lung cancer in women than men. This, in turn, could have impacted the sex difference in risk of smoking-related lung cancer reported in this study.

Our study has several strengths including restriction to cohort studies which provide more robust evidence of the associations compared with case–control studies. Differences between case–control and cohort studies may also explain why a previous meta-analysis of case–control studies (which included only three cohort studies) showed a higher RR of lung cancer in men compared with women. 10 Other strengths to our study include an update of findings to include studies published after 1999, 11 with supplementation of published literature with IPD from three established population databases. We have also performed a range of prespecified sensitivity analyses and several subgroup analyses which were not performed in previous meta-analyses. Our results were consistent across regions and irrespective of the women-to-men smoking ratio, suggesting that underestimation of the association of smoking and lung cancer in women due to sex differences in smoking prevalence and under-reporting of smoking is unlikely. This is especially relevant for parts of Asia where the prevalence of smoking in women is typically <10% and where smoking among women remains relatively socially unacceptable. As the up-take of smoking continues among women in countries where significant sex differences in smoking prevalence exist, the sex-specific risks of lung cancer due to smoking may become further apparent. This is also true for Western countries where differences in prevalence between women and men have reduced substantially over time, with prevalence of smoking in younger cohorts of women and men approaching unity. 23 The limitations of this study include heterogeneity across studies in study design, study population, verification of smoking status and outcome ascertainment. Assessment of smoking status differed across studies and was generally self-reported, which may have introduced measurement error. 24 Notably, compared with men, women are more likely to under-report smoking status, and under-reporting is especially prevalent in countries where smoking among women is not culturally acceptable. 25 The lack of standardisation across studies in how smoking status was obtained, including how smoking dose and duration were measured is also a major limitation. In addition, there was insufficient data available to examine whether there were sex differences in the impact of age at smoking initiation and smoking duration on the risk of lung cancer. The reference group of non-smokers in our analysis of current smoking was composed of former and never smokers which may inflate the risks of smoking-related lung cancer risk among non-smokers. However, we have also examined former smoking compared with never smoking and demonstrated no appreciable sex differences in the risks of smoking-related lung cancer in this group, which provides some evidence that the inclusion of former smokers in the reference category is unlikely to have biased the sex difference in our main analysis. We quantified sex differences in the risk of lung cancer associated with smoking based on RRs rather than absolute risks. This might introduce a statistical artefact, in which the generally higher absolute risk for lung cancer in men, and the same risk difference subsequent to smoking in each sex, would translate to a greater RR in women than men. However, our previous meta-analyses on risk factors for cardiovascular diseases demonstrated that sex differences in RRs are not inevitable, 26 despite differences in absolute risks. Compared with absolute risks, RRs are more stable across populations with different background risks, which makes them suitable for meta-analyses. In addition, RRs are reported much more commonly than absolute risks. In our review, no studies reported adjusted absolute risks, with standard errors, that allow for meta-analyses. We, therefore, believe that use of RRs in the present analysis is appropriate. In addition, while we have aimed to assess study quality using the widely accepted and used NOS, the value and contribution of quality assessment scales such as this to systematic reviews and meta-analyses continues to be debated. 27–29 Finally, there are differences between men and women in histological subtypes of lung cancer. Adenocarcinoma is more common in women and squamous cell carcinoma is more common in men. 30 Smoking is more strongly associated with squamous cell carcinoma than adenocarcinoma. 30 Few studies reported the sex-specific association of smoking with histological subtypes of cancer, which precluded the examination of sex differences in the association of smoking-related lung cancer subtypes and this remains an important limitation of our review. 30 Further studies of the smoking-related risks of lung cancer in women and men are required as the smoking epidemic reaches its full maturity in women. Given the later up-take of smoking in women, studies which allow sufficient lag time for lung cancer to develop are essential. In addition, reducing under-reporting of smoking in women, using standardised and robust methods for the ascertainment of smoking status and smoking behaviours and more extensive measurement and adjustment for confounders which differ by sex (such as exposure to environmental tobacco smoke) is also important for future work, as well as examination of histological subtypes of lung cancer which was not possible in this review.

In conclusion, this meta-analysis, summarising all available literature to date, shows that the effect of smoking on risk of lung cancer is similar in women and men. However, these data may yet underestimate the true RR of smoking-related lung cancer in women, given later uptake and lower intensity of smoking in women. Although strides have been made in reducing smoking rates particularly in high-income countries, continuing efforts to measure the effects of smoking on disease outcomes are required, as the smoking epidemic has not yet reached its global peak, particularly among women. In addition, tobacco control programmes that dissuade both sexes from smoking but which also encourage individuals to quit remain a priority.

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LMO’K and GT contributed equally.

Contributors LMOK, GT, SAEP, RRH and MW designed the study. LMOK and GT performed systematic searches, retrieved literature and performed data extraction. SAEP performed the analysis of the data. LMOK and GT wrote the first draft of the article. RRH, MW and PM contributed important intellectual content and critical expertise and revisions to the manuscript.

Funding The MRC Integrative Epidemiology Unit at the University of Bristol is supported by the University of Bristol and the Medical Research Council [MC_UU_12013/2, MC_UU_12013/3, MC_UU_12013/4, MC_UU_12013/6, MC_UU_12013/9]. LMOK is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). GT is funded by a Cancer Research UK Postdoctoral Fellowship (C56067/A21330). SAEP is supported by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1).

Competing interests None declared.

Patient consent Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Technical appendix, statistical code and dataset (of published data only) available from authors on request.

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Woman's sudden blindness in 1 eye revealed hidden lung cancer

Doctors say it's very unusual to develop a visual impairment as the first symptom of lung cancer.

In an extremely rare case, a woman's sudden blindness in one eye turned out to be the first symptom of undiagnosed lung cancer that had spread throughout her body. 

The woman first sought medical attention after losing vision in her right eye and experiencing occasional flashes of light in her left eye for around 20 days. She was 32 years old at the time and otherwise healthy, with no other symptoms and no history of smoking. 

During an initial eye exam at the hospital, doctors determined her eyes looked healthy. They were not painful or red and the eye's key structures appeared intact — the lens was clear, and the pupil and iris, or colored part of the eye, didn't show noticeable abnormalities. 

However, upon closer inspection, doctors saw that there was a large, whitish-yellowish mass growing in the back of her right eye. Fluid had also accumulated under her retina, the light-sensitive part of the eye, causing it to detach. There was a similar, smaller lesion in her left eye, but its retina was still intact.  

Related: Healthy tissue may predict lung cancer return better than tumors

To determine what caused these masses to appear, doctors checked the woman's blood. They found that she had no signs of an active viral infection or blood disorder, as her red blood cell and immune cell counts were normal. She was didn't have an human immunodeficiency virus (HIV) infection or an autoimmune disease , both of which can make people more vulnerable to vision loss and changes . 

Finally, a chest X-ray and whole-body scan revealed the culprit — a mass of cancerous tissue growing in the lower part of the woman's right lung. This tumor had spread to multiple other organs, including part of the eyes called the choroid . 

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Cancer that develops in one part of the body then spreads to another is called metastatic cancer . Most of the time when cancer spreads to the eyes, the migrating tumors lodge themselves into the choroid. However, this rarely occurs in lung cancers, which only migrate to the eyes in around 0.1% to 7% of cases. 

It's even rarer for patients to experience visual impairment as the first sign of underlying lung cancer. So far, there have only been around 60 such cases described in the medical literature . The woman's case is even more unusual because she didn't smoke, and cigarette smoking is linked to a large proportion of lung cancer cases .  

The doctors who treated the woman believe her case could be the first example of a non-smoking woman of her age developing visual impairment as the first symptom of lung cancer. The woman likely had a distinct subset of lung cancer that can spread without causing telltale symptoms of metastasis, the doctors wrote in a report of her case, published April 17 in the journal Radiology Case Reports . 

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After her cancer was spotted, the woman was referred to an oncologist for treatment; the case report did not note how she's faring now. 

More research is needed to ensure that this seemingly specific type of lung cancer is promptly diagnosed and treated in other people, the doctors wrote in the report. 

This article is for informational purposes only and is not meant to offer medical advice.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun ? Send us your questions about how the human body works to [email protected] with the subject line "Health Desk Q," and you may see your question answered on the website!

Emily is a health news writer based in London, United Kingdom. She holds a bachelor's degree in biology from Durham University and a master's degree in clinical and therapeutic neuroscience from Oxford University. She has worked in science communication, medical writing and as a local news reporter while undertaking journalism training. In 2018, she was named one of MHP Communications' 30 journalists to watch under 30. ( [email protected] ) 

Healthy tissue may predict lung cancer return better than tumors

Millions more people need lung cancer screening, ACS says

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• Correction - January 01, 2013

• Robert N Proctor
• Correspondence to Dr Robert N Proctor, History Department, Stanford University, Stanford, California 94305, USA; rproctor{at}stanford.edu

Lung cancer was once a very rare disease, so rare that doctors took special notice when confronted with a case, thinking it a once-in-a-lifetime oddity. Mechanisation and mass marketing towards the end of the 19th century popularised the cigarette habit, however, causing a global lung cancer epidemic. Cigarettes were recognised as the cause of the epidemic in the 1940s and 1950s, with the confluence of studies from epidemiology, animal experiments, cellular pathology and chemical analytics. Cigarette manufacturers disputed this evidence, as part of an orchestrated conspiracy to salvage cigarette sales. Propagandising the public proved successful, judging from secret tobacco industry measurements of the impact of denialist propaganda. As late as 1960 only one-third of all US doctors believed that the case against cigarettes had been established. The cigarette is the deadliest artefact in the history of human civilisation. Cigarettes cause about 1 lung cancer death per 3 or 4 million smoked, which explains why the scale of the epidemic is so large today. Cigarettes cause about 1.5 million deaths from lung cancer per year, a number that will rise to nearly 2 million per year by the 2020s or 2030s, even if consumption rates decline in the interim. Part of the ease of cigarette manufacturing stems from the ubiquity of high-speed cigarette making machines, which crank out 20 000 cigarettes per min. Cigarette makers make about a penny in profit for every cigarette sold, which means that the value of a life to a cigarette maker is about US$10 000.

• History of industry duplicity
• history of tobacco
• history of science
• history of medicine

https://doi.org/10.1136/tobaccocontrol-2011-050338

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Lung cancer has become a formidable disease, killing about 1.5 million people per year globally, extrapolating from a 2008 International Agency for Research on Cancer (IARC) risk assessment. 1 The tragedy is magnified by the fact that the overwhelming majority of these deaths, around 95%, are entirely preventable. Lung cancer today is primarily caused by the inhalation of smoke from cigarettes, which is also why the disease was quite rare prior to the 20th century. Lung cancer was not even recognised medically until the 18th century, and as recently as 1900 only about 140 cases were known in the published medical literature. The malady must have been occasionally misdiagnosed as tuberculosis (phthisis) or pneumonia or some other lung malaise, but we also know from detailed autopsy records in Germany that the disease cannot have been very common. Findings of primary lung tumours in the autopsied bodies of German research clinics rose dramatically in the second half of the 19th century, and even more dramatically in the first decade of the 20th. Isaac Adler summarised this evidence in 1912, in the world's first monograph on lung cancer, noting that the incidence of malignant neoplasms of the lung seemed to show ‘a decided increase’. Adler mentioned the ‘abuse of tobacco and alcohol’ as one possible cause, while also commenting that the subject was ‘not yet ready for final judgment’. 2

Tobacco was apparently not even suspected as a cause of lung tumours until the final decade of the 19th century. In 1898, a medical student by the name of Hermann Rottmann in Würzburg proposed that tobacco dust—not smoke—might be causing the elevated incidence of lung tumours among German tobacco workers. Rottmann's mistake was not corrected until 1912, when Adler proposed that smoking might be to blame for the growing incidence of pulmonary tumours. Lung cancer was still a very rare disease; so rare, in fact, that medical professors when confronted with a case sometimes told their students they might never see another. 3 By the 1920s, however, surgeons were encountering the malady with increasing frequency, and started puzzling over what might be responsible. Smoking was commonly blamed, along with asphalt dust from newly tarred roads, industrial air pollution and latent effects from exposure to poison gas in the First World War or the global influenza pandemic of 1918–1919. These and a number of other theories were put forward as possible explanations for the rise of lung cancer, until evidence from multiple sources of enquiry made it clear that tobacco was by far and away the leading culprit.

Converging lines of evidence

In the middle decades of the 20th century, four distinct lines of evidence converged to establish cigarette smoking as the leading cause of lung cancer. These are outlined below.

Population studies

These were among the first and most convincing forms of evidence. Scholars started noting the parallel rise in cigarette consumption and lung cancer, and by the 1930s had begun to investigate this relationship using the methods of case-control epidemiology. Franz Hermann Müller at Cologne Hospital in 1939 published the first such study, comparing 86 lung cancer ‘cases’ and a similar number of cancer-free controls. 4 Müller was able to show that people with lung cancer were far more likely than non-cancer controls to have smoked, a fact confirmed by Eberhard Schairer and Eric Schöniger at the University of Jena in an even more ambitious study from 1943. 5 These German results were subsequently verified and amplified by UK and American scholars: in 1950 alone, five separate epidemiological studies were published, including papers by Ernst Wynder and Evarts Graham in the USA and Richard Doll and A Bradford Hill in England. All confirmed this growing suspicion, that smokers of cigarettes were far more likely to contract lung cancer than non-smokers. Further confirmation came shortly thereafter from a series of prospective ‘cohort’ studies, conducted to eliminate the possibility of recall bias. The theory here was that by following two separate and initially healthy groups over time, one smoking and one non-smoking, matched by age, sex, occupation and other relevant traits, you could find out whether smoking was a factor in the genesis of lung disease. The results were unequivocal: Doll and Hill in 1954 concluded that smokers of 35 or more cigarettes per day increased their odds of dying from lung cancer by a factor of 40. 6 Hammond and Horn, working with the American Cancer Society on another large cohort study, concluded that same year that the link had been proven ‘beyond a reasonable doubt’. 7 8

Animal experimentation

This was a second key line of evidence. ‘Tobacco juice’ had been shown to cause cancer on laboratory animals since the first decade of the century, 9 and a number of scholars had confirmed these results. The most active in this realm was the intrepid Angel H Roffo, founding director of Argentina's Institute of Experimental Medicine for the Study and Treatment of Cancer, who in 1931 showed that smoke condensed from the destructive distillation of tobacco could cause tumours when smeared on the hairless skins of rabbits. 10 Roffo in the 1930s and early 1940s published dozens of articles (mainly in German and Spanish) implicating smoking in the genesis of cancer, prompting enthusiastic endorsement from the German public health establishment but also ridicule from the cigarette industry. German tobacco manufacturers even established an entire journal— Chronica Nicotiana —and a scientific ‘academy’, the Academia Nicotiana Internationalis , to buttress the fortunes of tobacco, then under siege from public health activists. 11

In 1953, a great deal of attention was given to an experiment by Ernst Wynder, Evarts Graham and Adele Croninger, showing that tumours could be generated by painting cigarette smoke tars onto the shaved backs of mice. 12 Life magazine devoted several pages to the story, and Time cited Graham's conclusion that the case against tobacco had now been proved ‘beyond any doubt’. 13 Public confidence in tobacco was shaken, and stock prices of American cigarette manufacturers plummeted. Tobacco manufacturers saw this new ‘health scare’ as a mortal threat to their livelihood, and decided to organise a response. On December 14, 1953, at the Plaza Hotel in Manhattan, CEOs of the six largest tobacco manufacturers in the USA (all but Liggett) met to plan a response. The outcome was a far-reaching plan to refute the accumulating evidence, using adverts, ‘white papers’, press releases and corporate schmoozing with popular science writers and journalists. Support for (industry-friendly) science was a vital part of this enterprise: cigarette manufacturers called for ‘more research’ to resolve a purported ‘controversy’, and set out to reassure the public that the companies were taking charge. That campaign was by and large a success, judging from the fact that per capita consumption rebounded from its dip in 1953. Cigarette consumption in the USA would in fact continue to grow throughout the 1960s and 1970s, peaking at about 630 billion sticks in 1982 before starting to decline.

Cellular pathology

A third line of evidence for the cigarette–cancer link came from cellular pathology. Pathologists in the 1930s had started noticing the capacity of cigarette smoke to cause ciliastasis—the deadening of the tiny whip or hair-like structures lining the upper airway passages, structures known to be responsible for wafting particulate contaminants out of the lungs. 14 Suspicions started to grow that ciliastasis could cause cigarette smoke to become trapped in the lungs, causing cancer. Pathologists also started exploring whether damage from smoking could be discerned at the level of the cell. Anderson C Hilding in 1956 confirmed that smokers were experiencing pulmonary ciliastasis, but also that cilia were being deadened at precisely those parts of the lung where cancers were most likely to develop. 15 Oscar Auerbach about this same time showed (from autopsy studies) that precancerous changes could be detected in the cells of smokers—even in those who had died from other causes. 16

Cancer-causing chemicals in cigarette smoke

A fourth line of evidence stemmed from the discovery of cancer-causing chemicals in cigarette smoke. Polycyclic aromatic hydrocarbons had been identified as carcinogenic constituents of coal tar in the 1930s, and the question then arose: might there not be similar compounds in cigarette smoke? Angel Roffo in Argentina was the first to identify polycyclic aromatic hydrocarbons in cigarette smoke from their distinctive spectrographic signatures, and for a time at least his was the most authoritative voice in this realm. 17 Roffo's work was taken seriously even by consultants working for the industry. In 1947, in an internal report to the Lorillard company, makers of Old Gold cigarettes, John B Fishel of Ohio State University acknowledged the presence of ‘carcinogenic benzopyrene in tobacco tars’, citing Roffo as an authority. 18 Tobacco industry laboratories conducted their own investigations: Brown and Williamson researchers identified benzpyrene in cigarette smoke in 1952, and by the end of the decade cigarette manufacturers had characterised several dozen carcinogens in cigarette smoke, including arsenic, chromium, nickel and a veritable zoo of polycyclic aromatic hydrocarbons (chrysene, methylcholanthrene, dibenzanthracene, dibenzacridene, etc). As Philip Morris research director Helmut Wakeham put it in 1961, carcinogens were found in ‘practically every class of compounds in cigarette smoke’. 19 20

The confluence of these diverse forms of evidence—from epidemiology, animal experiments, clinical observation and chemical analysis, combined with diminishing evidence for alternative explanations, prompted health and medical authorities throughout the world to publicly acknowledge a cigarette–cancer link. The American Cancer Society's National Board of Directors in 1954 announced ‘without dissent’ that ‘the presently available evidence indicates an association between smoking, particularly cigarette smoking, and lung cancer’. The Public Health Cancer Association that same year advised stopping smoking as a way to prevent cancer, and cancer authorities in Norway, Sweden, Finland, Denmark and The Netherlands came to similar conclusions. UK cancer authorities came on board, as did the Joint Tuberculosis Society of Great Britain and Canada's National Department of Health and Welfare. 21 Sceptics were converted, and medical attention shifted from the question of ‘whether’ to the question of ‘how’—and what to do about it.

Researchers in the tobacco industry also became convinced of a cigarette–cancer link—though this was never admitted publicly. Claude Teague in his confidential 1953 ‘Survey of Cancer Research’, written for upper management at RJ Reynolds, makers of Camel cigarettes, concluded that the parallel rise in cigarette use and cancer had led to the suspicion that tobacco was ‘an important etiologic factor in the induction of primary cancer of the lung’. Teague observed that clinical data were confirming the relationship, and concluded that the large body of animal experimental work ‘would seem to indicate the presence of carcinogens’. 22

Teague was not the only tobacco insider conceding a hazard. Harris Parmele, Lorillard's director of research, in 1946 had commented privately on how ‘Certain scientists and medical authorities have claimed for many years that the use of tobacco contributes to cancer development in susceptible people. Just enough evidence has been presented to justify the possibility of such a presumption’. 23 The American Tobacco Company in the summer of 1953 took the extraordinary step of sponsoring a series of secret animal tests in the laboratories of the Ecusta Paper Corporation, makers of much of the world’s cigarette paper, with the goal of finding out whether it was the tobacco leaf or the cigarette paper that was causing all this cancer. Their conclusion, distributed only privately, was that tobacco—and not the paper—was the culprit. 21

Tobacco industry insiders by the mid 1950s clearly knew their product was dangerous. In December of 1953, when Hill and Knowlton was exploring how to respond to the uproar surrounding the publication of carcinogens in cigarette smoke, one tobacco company research director commented in a confidential interview: ‘Boy! Wouldn't it be wonderful if our company was first to produce a cancer-free cigarette. What we could do to competition!’ Another remarked on how fortunate it was ‘for us’ (ie, for cigarette manufacturers) that smokers were engaging in ‘a habit they can't break’. 24 The mid-1950s cancer consensus was clearly (albeit privately) shared by the companies; and the reality of addiction was also starting to be conceded—at least in internal industry documents.

UK cigarette makers also commented on the lung cancer consensus. Three leading scientists from British American Tobacco (BAT) visited the USA in 1958, for example, and found that with only one exception all of those consulted—including dozens of experts inside and outside the industry—believed that a cancer connection had been proved. 25 Alan Rodgman at Reynolds 4 years later confessed that while evidence in favour of the cancer link was ‘overwhelming’, the evidence against was ‘scant’. 26 Helmut Wakeham at Philip Morris about this same time drew up a list of dozens of carcinogens in cigarette smoke. 20 None of this was made public; indeed the tobacco industry throughout this time and for decades thereafter—until the end of the millennium—refused to admit any evidence of harms from smoking. No one can say precisely how many lives were lost as a result, but if the decline in per capita consumption that began with the US Surgeon General's report in 1964 had begun instead in 1954, when the conspiracy to challenge the science was launched, millions of lives would have been saved. 27

The 1964 Surgeon General's report, which recognised smoking as a cause of lung cancer in men, is often regarded as a turning point in the recognition of health harms from smoking. But the Surgeon General's report was actually a kind of scientific anticlimax: from an evidentiary point of view the case against smoking had been closed by the end of the 1950s, and it was only the truculence and obstinacy of cigarette manufacturers that forced a blue-ribbon review by the federal government. Charles S Cameron, Medical and Scientific Director of the American Cancer Society, put the matter nicely in a 1956 overview for the Atlantic Monthly , noting that if the same level of evidence had been arrayed against, say, spinach, no one would have objected to the banning of that plant from the national diet. 28

Popular knowledge—and ignorance

History is, among other things, the study of origins and outcomes—how things come to be and disappear. The presumption is often of a certain contingency: how things turn out is often the outcome of struggles among competing agents. We've reviewed here the rise of scholarly knowledge of cigarette carcinogenicity, but it is also important to realise that popular knowledge, too, has a history. Scholars don't pay enough attention to what non-scholars think about the world, the proper study of which is agnotology. 29 What is the history of popular knowledge of the tobacco lung cancer link? What efforts have been made to generate ignorance?

One source of information for the history of ignorance is the polling data amassed by professional opinion research agencies and their tobacco industry counterparts. In 1954, for example, George Gallup sampled a broad swath of the US public to ask: ‘do you think cigarette smoking is one of the causes of lung cancer, or not?’ 41% answered ‘yes’, with the remainder answering either ‘no’ or ‘undecided’. 30 Even large numbers of doctors remained unconvinced. In 1960, in a poll organised by the American Cancer Society, only a third of all US doctors agreed that cigarette smoking should be considered ‘a major cause of lung cancer’. This same poll revealed that 43% of all American doctors were still smoking cigarettes on a regular basis, with occasional users accounting for another 5%. 31 With half of all doctors smoking, it should come as no surprise that most Americans remained unconvinced of life-threatening harms from the habit.

The tobacco industry was not innocent in this persistence of ignorance. Cigarette makers spent countless sums to deny and distract from the cigarette–cancer link, in some instances actually quantifying the impact of their denialist propaganda. In 1973, for example, the Tobacco Institute hired AHF-Basico Market Research Co. and Audience Studies, Inc., to measure the impact of its 1972 propaganda film, ‘Smoking and Health: The Need to Know’, shown to hundreds of thousands throughout the country, including high school students. Prior to screening, viewers were asked a series of questions about whether the Surgeon General ‘could be wrong about the dangers of smoking’; the same questions were then asked after the screening. Anne Duffin at the Tobacco Institute was happy to report that the film had reduced by 17.8% the number of people agreeing that ‘Cigarette smoking cause[s] lung cancer’ (from 74.9% to 57.1%). The film had also produced ‘significant shifts’ in attitudes favourable to the industry in other areas, including whether recent reports had ‘overemphasized the dangers of smoking’. 32

Global denialist campaigns have borne similar fruit. In the 1980s, UK tobacco researchers commented on how Philip Morris was piloting a ‘global strategy’ to deny the reality of secondhand smoke hazards, spending vast sums of money ‘to keep the controversy alive’. 33 Hundreds of millions of Chinese remain poorly informed about the hazards of smoking, and as recently as 2011, scholars from the International Tobacco Control Policy Evaluation Project in The Netherlands published a survey showing that only 61 per cent of Dutch adults agreed that cigarette smoke endangered non-smokers. 34

The global toll

The cigarette is the deadliest artefact in the history of human civilisation. 21 Consumption rates are falling in most of the richer countries, but smoking rates remain high or even increasing in many parts of the globe. In China, cigarette consumption has risen from about 500 billion 1980 to over four times that in 2010, and it is not yet clear whether consumption has peaked. China is now manufacturing about 2.4 trillion cigarettes per year, close to 40% of the global total. Consumption has been facilitated by the introduction of ultra high speed cigarette making machines: Hongta's Yuxi Cigarette Factory, for example, produces over 90 billion cigarettes per year, using 52 high-speed Molins cigarette making machines. Modern cigarette making machines of the sort made by the Hauni Corporation in Hamburg or GD (Generate Differences) in Bologna crank out cigarettes at rates up to 20 000 per min, which helps account for the dramatic drop in manufacturing costs over the last century or so. Cigarette factories today produce death at a faster rate—and cheaper—than any previous form of industrial manufacture. If cigarettes cause 1 lung cancer for every 3 or 4 million smoked, 35 this means that a factory such as Hongta's in Yuxi is responsible for generating 25 000 or 30 000 deaths per year from lung cancer. And about twice that number from other diseases. There are about 400 industrial-scale cigarette factories in the world, 36 each of which causes thousands of preventable deaths per year (see box 1 and table 1 ).

What is a human life worth to a cigarette manufacturer?

Cigarettes cause about one death per million smoked 35 with a latency of about 25 years, which is why the 6 trillion smoked in 1990 will cause about 6 million deaths in 2015. That's one death every 5 seconds. One-third or one-quarter of those deaths will be from lung cancer; about one every 15 or 20 s.

This relationship is fairly consistent in different parts of the world, given the homogeneity of cigarettes and how similarly they are smoked. It also means we can generate some interesting equivalences. Cigarettes typically come in 20 sticks per pack, with 200 sticks per carton, 10 000 sticks per master case and 10 million sticks per container. A 12 m (40 ft) container of the sort shipped overseas or trucked by highway houses 10 million cigarettes, which means that each container will cause about 10 deaths.

We can also think about this in terms of the rate at which cigarettes are smoked. A total of 6 trillion cigarettes are smoked every year, and if each cigarette is about 60 mm (counting only the part that is smoked), this means that 360 trillion mm of cigarettes are smoked per year. Converting this, 360 trillion mm is 360 billion m, or 360 million km. Imagined as one long rod, this means that cigarettes are smoked at a rate of 360 million km per year, which is more than 10 km/s. Cigarettes are smoked at a rate equal to the speed at which satellites orbit the earth.

We can also think about the deaths caused per unit weight of stuffing. Cigarettes contain about two-thirds of a gram of tobacco, which means that if it takes 3 million cigarettes to cause one lung cancer, it takes about 2 million g—or 2 metric tonnes—to cause one lung cancer. A typical tobacco farm yields about 2 tonnes per hectare, so a 10-hectare field will cause about 10 lung cancer deaths/year. And 20 additional deaths from heart attacks, gangrene of the feet, cancers of the bladder and oral cavity, etc.

Finally, we can also think about this in terms of the value of a life as assumed by tobacco manufacturers. Cigarette companies make about a penny in profit for every cigarette sold, or about US$10 000 for every million cigarettes purchased. Since there is one death for every million cigarettes sold (or smoked), a tobacco manufacturer will make about US$10 000 for every death caused by their products. Otherwise put: a cigarette manufacturer will not forgo US$10 000 in profit, even if this means the death of one of their customers. The value of a human life to a cigarette manufacturer is therefore about US$10 000.

• View inline

Factories of death (selected)

There are still many myths surrounding smoking—that the dangers have long been ‘common knowledge’, for example, or that legitimate scholarly doubt about the reality of hazards postdates the Surgeon General's report of 1964. 37–39 Yet another myth, though, is that the tobacco ‘problem’ has by and large been ‘solved’. Tobacco is commonly referred to in the past tense—as when critics of the fast food industry talk about solving dietary problems ‘the way the tobacco problem was solved’. The fact is that cigarette use persists, and on a massive scale. Global cigarette use seems to have peaked at about 6 trillion cigarettes sometime after the turn of the new millennium, but the deadly effects of this epidemic will still be felt for decades—even if global use continues to decline. Only about 100 million people died from smoking in the 20th century, whereas several times that are likely to die in the present century, even if current rates of smoking fall dramatically. 35 Most of the tobacco epidemic remains in the future, with the total global toll likely to approach 2 million lung cancer deaths per year in the 2020s or 2030s.

No causes are themselves uncaused, however, which means that when we think about what causes lung cancer or even smoking, we should think not just in terms of how individuals ‘decide’ to start smoking, but rather in terms of larger, more weblike threads of causation. We have to look at the cigarette epidemic—and therefore lung cancer—as facilitated by long causal chains of a sociopolitical, technical, molecular and agricultural nature. If cigarettes cause cancer, then so do the machines that roll cigarettes and the companies that supply the ‘filters’, ‘flavourants’ and paper. We have to realise that adverts can be carcinogens, along with the convenience stores and pharmacies that sell cigarettes. The executives who work for cigarette companies cause cancer, as do the artists who design cigarette packs and the PR and advertising firms that manage such accounts. Farmers who grow tobacco are part of this network, as are the politicians who take money from ‘Big Tobacco’, and those chemists and breeders who favour the nicotine molecule. So too must we include those many hundreds of experts who testify for the industry in court. 21 We need to better understand such webs or networks if we are to be more creative in finding ways to reduce the toll from this, the world's deadliest malignancy.

What this paper adds

This paper reviews the converging lines of evidence that led to the recognition that smoking is the major cause of lung cancer.

It also shows that the non-scholarly public was slower than scholars and medical professionals to recognise tobacco harms.

The point is made that part of that lag can be traced to campaigns mounted by the industry to manufacture doubt.

The point is also made that global tobacco use would be declining were it not for China, which now accounts for about 40 percent of all cigarettes sold (and smoked).

Deaths caused by some of the world's largest tobacco factories are calculated, and the value of a human life for a cigarette manufacturer is shown to be about $10 000.

• ↵ IARC Globocan 2008 . Cancer Fact Sheet: Lung Cancer Mortality Worldwide in 2008 . http://globocan.iarc.fr/factsheets/cancers/lung.asp
• Schairer E ,
• Schöniger E
• Hammond EC ,
• Graham EA ,
• Croninger AB
• ↵ Beyond Any Doubt. Time 1953 : 60 – 3 .
• Auerbach O ,
• Forman JB ,
• ↵ Brown & Williamson . “Report of Progress—Technical Research Department” (B&W) . 1952 : 8 . http://legacy.library.ucsf.edu/tid/aql66b00
• ↵ Parmele HB to Riafner A . Lorillard , 1946 . http://legacy.library.ucsf.edu/tid/tgt34c00/pdf
• Bentley HR ,
• Felton DGI ,
• Proctor RN ,
• Schiebinger L
• ↵ Duffin A to Kloepfer W. Audience testing of “Smoking & Health: The Need to Know.” 1973 . http://legacy.library.ucsf.edu/tid/uqn92f00
• ↵ ITC Project . ITC Netherlands Survey. Report on Smokers' Awareness of the Health Risks of Smoking and Exposure to Second-hand Smoke . Ontario, Canada : University of Waterloo , 2011 .
• Kyriakoudes L

Competing interests The author has served as an expert witness in litigation against the tobacco industry.

Provenance and peer review Commissioned; externally peer reviewed.

Linked Articles

• Editorial Tobacco control at twenty: reflecting on the past, considering the present and developing the new conversations for the future Ruth E Malone Kenneth E Warner Tobacco Control 2012; 21 74-76 Published Online First: 16 Feb 2012. doi: 10.1136/tobaccocontrol-2012-050447

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Applied Epidemiology: Smoking and Lung Cancer Case Study

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Case-control study for lung cancer and cigarette smoking in Osaka, Japan: comparison with the results from Western Europe

Affiliation.

• 1 Center for Adult Diseases, Osaka.
• PMID: 8014103
• PMCID: PMC5919491
• DOI: 10.1111/j.1349-7006.1994.tb02381.x

In order to clarify the relation between cigarette smoking and lung cancer, a case-control study was conducted. The case series consisted of 1,376 lung cancer patients (1,082 males and 294 females) who were newly diagnosed and admitted to eight hospitals in Osaka during 1986-88. Smoking histories were compared with those of 2,230 controls (1,141 males and 1,089 females) admitted to the same hospitals during the same period without established smoking-related diseases. Odds ratios of current smoker versus nonsmoker were 18.1, 1.9, 21.4, and 3.8 for squamous, adeno, small, and large cell carcinoma, respectively, for males, and 9.7, 1.3, 12.1, 3.7, respectively, for females. Compared to the results from previous studies in Japan, the magnitude of the odds ratios for squamous and small cell carcinoma is approaching the level of Western Europe in the late 1970s. Population attributable risk of exsmokers has also been increasing to the level of Western Europe. Among male current smokers, smoking intensity, such as number of cigarettes per day or fraction smoked per cigarette, seemed to have a slightly greater influence on squamous cell carcinoma than adenocarcinoma, while factors associated with the spread of cigarette smoke, such as inhalation, seemed to have greater influence on adenocarcinoma. The difference in the distribution of these smoking characteristics between Japan and Western Europe could not fully explain the difference in lung cancer incidence and distribution of histologic types between the two areas.

Publication types

• Comparative Study
• Research Support, Non-U.S. Gov't
• Adenocarcinoma / epidemiology
• Carcinoma, Non-Small-Cell Lung / epidemiology
• Carcinoma, Small Cell / epidemiology
• Carcinoma, Squamous Cell / epidemiology
• Case-Control Studies
• Lung Neoplasms / epidemiology*
• Middle Aged
• Smoking / adverse effects*

• Case Report
• Open access
• Published: 22 April 2024

Lung cancer in older patients with granulomatosis with polyangiitis: a report of three cases

• Malgorzata Potentas-Policewicz 1 ,
• Malgorzata Szolkowska 2 ,
• Katarzyna Blasinska 3 ,
• Dariusz Gawryluk 4 ,
• Malgorzata Sobiecka 5 &
• Justyna Fijolek 4  

BMC Pulmonary Medicine volume  24 , Article number:  193 ( 2024 ) Cite this article

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Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous inflammation with necrotizing vasculitis predominantly affecting small to medium vessels. The survival rates have drastically improved; however, GPA can be lethal, with older patients having a worse prognosis and higher mortality than younger patients. Moreover, the incidence of various cancers has been reported to increase in patients with GPA. We aimed to discuss possible associations between GPA and lung cancer and emphasize the associated diagnostic challenges.

Case presentation

We encountered three older patients with chronic GPA who developed lung cancer during long-term follow-up. Two of the patients had a smoking history, with one having silicosis and the other having chronic obstructive pulmonary disease. Furthermore, all of them had radiation exposure from repeated radiography/computed tomography. All the patients had confirmed GPA, and vasculitis relapse was first suspected when new lung lesions were noted during follow-up. However, they had no new clinical symptoms, and serum ANCA titer increased only in one patient. All the patients received standard immunosuppressive treatment but eventually died.

Conclusions

Lung cancer is uncommon in patients with GPA; however, the similarity between the imaging findings of lung cancer and GPA may pose a diagnostic challenge. Clinicians should be particularly vigilant when treating older patients with an increased risk of cancer, as they are often asymptomatic or have poorly apparent clinical features.

Peer Review reports

Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous inflammation with necrotizing vasculitis predominantly affecting small to medium vessels. This condition belongs to the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) family, because circulating ANCAs are detected in most patients [ 1 ]. Despite advances in treatment, GPA can be lethal, with older patients having a worse prognosis and higher mortality than younger patients [ 2 ]. Patients with AAV have a high incidence of cancer, specifically non-melanoma skin cancer, leukemia, and bladder cancer, which may be associated with cyclophosphamide (CYC) use [ 3 ]. Lung cancer is uncommon in patients with GPA; however, the similarity between the imaging findings of lung cancer and GPA may pose a diagnostic challenge and delay diagnosis. Diagnosis may be particularly difficult in patients with confirmed chronic GPA, in whom lung cancer may mimic a relapse of vasculitis. We present three rare cases of lung cancer in older patients with chronic GPA, and discuss the potential association between these two conditions and the associated diagnostic challenges.

Patient 1 was diagnosed with GPA in February 2012 at 69 years of age. He was an ex-smoker, had a history of silica exposure, and had undergone basal cell carcinoma surgery several years previously. GPA was diagnosed based on clinical symptoms and ANCA-positive status. The patient presented with peripheral polyneuropathy, skin lesions, and hematuria. Chest computed tomography (CT) revealed lung nodules without cavitation (Fig.  1 a). Standard immunosuppressive treatment was administered; however, due to incomplete regression of lung lesions after 6 months, the patient underwent a surgical lung biopsy. Histopathological examination revealed silicosis and confirmed diagnosis of GPA. The treatment was completed in December 2013 (Fig.  1 b) (total CYC dose: 31.5 g); however, in January 2014, the patient was readmitted because of a GPA flare-up. At that time, he experienced weakness, dyspnea, and hemoptysis. Chest CT revealed progression of lung nodules, and bronchofiberoscopy revealed multiple bronchial ulcerations. Urinalysis revealed a recurrence of microscopic hematuria, and the ANCA titer was increased. Histological examination of bronchial specimens confirmed the diagnosis of GPA. Rituximab was administered, resulting in clinical improvement and ANCA negativity. The next vasculitis flare-up occurred in April 2015. Rituximab was restarted, and oral methotrexate was administered as maintenance therapy. The patient was followed up every 6 months, and in August 2017 (when the patient was aged 74 years), CT revealed a new nodule in the right upper lobe (Fig.  1 c). A second GPA relapse was suspected; however, ANCAs were not detected, and the patient was asymptomatic. The next CT, performed 3 months later, revealed that the nodule had grown (Fig.  1 d). Bronchofiberoscopy results (cultures and cytology examination) were negative, and the patient underwent thoracotomy. Due to significant impairment of lung function, the wedge resection of the nodule was performed. Histological examination revealed squamous cell carcinoma (stage T2aN0R0L0V0) (Fig.  1 e). The patient received radiotherapy (6000 cGy/t). Despite this, he died 14 months later because of cancer progression.

Patient 1. Chest CT, lung window, axial plane; histological examination. a Baseline study. Nodules in the left lung, the larger lesion located in segment 1 + 2 of the upper lobe (black asterisk). The subsequent examination after one year ( b ) shows partial regression of lesions. Another chest CT during the follow -up ( c ) revealed a new nodule in the right upper lobe which enlarged at 3-month observation (black arrow) ( d ). e Microscopic image of poorly-differentiated squamous cell carcinoma in resection specimen (A—hematoxylin and eosin stain, magnification × 200; B—cytokeratin AE1AE3 immunohistochemical reaction, magnification × 200)

Patient 2 was diagnosed with GPA in March 2006 at 61 years of age. He had a smoking history, and had been diagnosed with chronic obstructive pulmonary disease (COPD) 5 years previously. GPA was diagnosed based on clinical symptoms and ANCA-positive status, and confirmed via nasal mucosal biopsy. The patient presented with sino-nasal symptoms and kidney involvement. Chest CT revealed multiple lung nodules, some of which exhibited cavitation (Fig.  2 a). The patient received standard immunosuppressive therapy from March 2006 to May 2007 and showed improvement (Fig.  2 b); however, in November 2008, he was readmitted because of a GPA flare-up, presenting with diffuse alveolar hemorrhage. Standard immunosuppressive treatment (total CYC dose: 54 g) was restarted and continued until September 2010, resulting in symptom resolution, improvement in lung lesions, and ANCA titer reduction. In May 2015 (when the patient was aged 70 years), CT performed during a follow-up visit revealed a single new tumor with cavitation in the left lung (Fig.  2 c). The patient had no symptoms, and laboratory test results showed a significant increase in ANCA titer. This pattern of findings was different from that of GPA, and histological examination of the material obtained via bronchofiberoscopy revealed squamous cell carcinoma (stage pT2aN0M0R0L0V0). The patient underwent a left upper lobectomy (Fig.  2 d shows the microscopic image of resected specimen). However, he died of cancer progression 4 years later.

Patient 2. Chest CT, lung window, axial plane; histological examination. a Baseline study showed the cavitated lesion in segment 6 of the right lower lobe (white arrow) which decreased in the next examination ( b ). A follow-up examination 5 years later showed a new lesion with cavitation in the left upper lobe (white arrow) ( c ). d Microscopic image of keratinizing squamous cell carcinoma. Resection specimen (hematoxylin and eosin stain, magnification × 200)

Patient 3 was diagnosed with GPA in February 2005 at 71 years of age. She had never smoked, but had diabetes, hypertension, and bronchial asthma. The disease was limited to the lungs (chest CT revealed multiple lung nodules) (Fig.  3 a) and was confirmed based on histological examination findings and the patient’s ANCA-positive status. The patient was treated with standard immunosuppressive drugs (total CYC dose: 58.5 g) until March 2007, and showed clinical and radiological improvements. In February 2014 (when the patient was aged 80 years), a chest CT revealed a single new tumor in the right lung (Fig.  3 b). Relapse of GPA was considered; however, ANCA test results were negative, and the patient had no new symptoms. Biopsy revealed lung adenocarcinoma (clinical stage T2aN0M0) (Fig.  3 c). Due to the clinical burden and lung function limitations (persistent airway obstruction and desaturation in a 6-min walk test), the patient was ineligible for surgical treatment. She received palliative care and died 1 year later.

Patient 3. Chest CT, lung window, axial plane; histological examination. a Baseline CT revealed multiple nodules in both lungs (white arrows). b A follow-up CT scan after 7 years showed new solid lesion in the right lung (black asterisk). c Microscopic image of adenocarcinoma in cell block (hematoxylin and eosin stain, magnification × 200)

Discussion and conclusions

This report presents three older patients with GPA who developed lung cancer during long-term follow-up. These cases highlighted several important issues: 1) patients with GPA should undergo long-term monitoring, even if they are in remission; 2) histological examination should be performed in patients with GPA who develop new lung lesions, especially in the absence of other organ involvement and signs of vasculitis; and 3) in patients with GPA, particularly older patients, oncological vigilance should be maintained. Moreover, these cases prompted us to consider the possible association between GPA and lung cancer, and to emphasize the associated diagnostic challenges.

Although many studies reported an increased incidence of cancers in AAV compared to the general population [ 3 , 4 , 5 , 6 , 7 ], data on lung cancer in patients with GPA are limited. Chemouny et al. [ 8 ] described five patients with AAV who had lung cancer developing concurrently or within 2 years. Most of these patients (4/5) were elderly and ANCA positive and all of them had renal involvement. Three patients were diagnosed with squamous cell carcinoma, and two with adenocarcinoma. Masiak et al. [ 9 ] reported the case of a 63-year-old man who developed small-cell lung cancer 12 years after GPA diagnosis. The patient had chronic GPA and during the course of the disease, relapses were observed with progression and cavitation of the infiltrates in the lungs. The patient was hospitalized because of headaches, general weakness, decrease in exercise capacity, and a tear of the eye, which combined with the presence of the new infiltrate in the lung, was suggestive of the next relapse of vasculitis, but finally small-cell lung cancer was diagnosed. In turn,Toriyama et al. [ 10 ] presented a case of lung cancer that developed during long-term CYC treatment for GPA, while Andino et al. [ 11 ] described a 50-year-old male with chronic renal failure secondary to GPA, who 23 years after the diagnosis of vasculitis (and 12 years after the completion of treatment) developed multifocal lung adenocarcinoma with pleural effusion. Herein, we described three patients with GPA who developed lung cancer 5–9 years after being diagnosed with vasculitis. All three patients were aged above 60 years when GPA was diagnosed, and all lung cancers were detected when GPA was in clinical remission. Increases in lung cancer incidence in patients with GPA have been reported [ 6 , 7 , 8 ]; however, only a single Korean study demonstrated a significant increase in the adjusted hazard ratio (HR) of lung cancer (HR = 1.92, 95% confidence interval, 1.20–3.07) [ 12 ]. In contrast, a retrospective analysis of the French Vasculitis Study registry found that lung cancer was the most frequent cause of death due to malignancy in patients with systemic necrotizing vasculitides [ 13 ]. Therefore, patients with GPA must be monitored over the long term, even during remission, as our cases strongly highlight.

The classical presentation of GPA includes upper respiratory tract, lung, and kidney symptoms [ 14 ]. Lung findings are non-specific; however, the most common CT features include nodules and masses, often with cavitation [ 15 ]. These features require differentiation, mainly from those of infections and primary and secondary lung malignancies. Diagnosis is particularly challenging when lesions are limited to the lungs [ 16 ]; moreover, because both GPA and lung cancer have similar clinical features, symptom masking may occur [ 9 ]. Finally, lung cancer may coexist with GPA [ 17 ]; this should be considered when diagnosing patients with AAV and pulmonary lesions. Our patients had confirmed GPA, and a relapse of vasculitis was first suspected when new lung lesions were noted during follow-up. However, they had no new clinical symptoms, and serum ANCA titer increased only in patient 2. Additionally, patient 1. developed numerous nodular lesions owing to silicosis, which further complicated clinical interpretation of that patient’s CT scans. Owing to diagnostic uncertainty, all our patients underwent a biopsy, which allowed us to establish the correct diagnosis. Our cases strongly highlight that long-term remission of vasculitis does not eliminate the need for vigilance when assessing new lung lesions in patients with GPA. Such patients should be further investigated and not automatically diagnosed with vasculitis relapse. Biopsy and histological examinations should be considered, as they are essential for proper differential diagnosis.

The association between GPA and lung cancer has yet to be fully established. Systemic autoimmune rheumatic diseases are associated with an increased risk of cancer, with the overall cancer risk for most patients being the highest in the first year of follow-up and decreasing thereafter [ 18 ]. In contrast, in our patients, lung cancer developed late in the observation period (5, 9, and 9 years after vasculitis diagnosis respectively). Several mechanisms may contribute to increased cancer risk in patients with autoimmune rheumatic diseases, including chronic inflammation and damage from the disease, cytotoxic therapies, and inability to clear oncogenic infections [ 19 ]. To the best of our knowledge, detailed studies on lung cancer formation in patients with vasculitis have not been conducted. As lung parenchymal inflammation is a symptom of GPA, the possible contribution of chronic inflammation to cancer development cannot be ruled out. The impact of CYC has also been considered. In fact, an increased incidence of non-melanoma skin cancers, bladder cancer and myeloid leukemia was demonstrated among patients exposed to cumulative CYC doses > 36 g [ 7 ]; however, lung injury after CYC treatment is rare (< 1%) and mainly manifests as early-onset pneumonitis or late-onset lung fibrosis [ 20 ]. In the study analysing solid malignancies among patients with Wegener’s granulomatosis treated with etanercept (WGET), patients who developed solid malignancies were more likely to be enrolled into the trial with a disease relapse (85% versus 54%, p = 0.04), and had longer disease duration (6.4 ± 3.9 years versus 3.3 ± 4.8 years, p = 0.001), while there were no differences in the assigned treatment, age, gender, or extent of disease [ 21 ]. On the other hand, the report of case of GPA that lung cancer has developed during the long-term treatment with CYC also exists. In that patient, cumulative dose of CYC was about 200 g and the duration was 12 years, which could be the risk of carcinogenesis [ 10 ]. Notably, rituximab treatment is not associated with an increased malignancy risk compared with the general population and could therefore be a safe alternative to CYC in the treatment of AAV [ 22 ]. Other factors that may be considered include environmental factors such as cigarette smoking, radiation, and occupational lung carcinogens, with the common risk factors for both diseases can be exposure to silica and infectious agents [ 8 , 23 ]. There is a hypothesis that there is a common pathway between AAV and malignancy, namely, that patients with vasculitis have an intrinsically higher risk of developing malignancies based on a state of acquired immunological dysfunction underlying both diseases [ 12 , 24 ]. The observed ANCA titer variations related to lung cancer evolution may be also indicative of a link between both diseases, decreasing or becoming undetectable after cancer treatment and increasing with cancer relapse [ 8 ]. Of the three our patients, two had a smoking history, with one of them having silicosis and the other having COPD. Furthermore, all patients were exposed to radiation because they repeatedly underwent radiography/CT. However, only in one patient (patient 2) the ANCA titer was increased at the time of lung cancer diagnosis, while in other ANCA was not detected. Another factor is older age of the patients. Recent data have shown that the incidence of cancer strongly increases after the age of 50 years; this has been thought to result from reduced immune system function, leading to inefficient purging of dysfunctional cells and an increase in the number of altered cells (including pre-neoplastic cells) [ 25 ]. According to data from NCI’s Surveillance, Epidemiology, and End Results Program, the median age of cancer diagnosis is 66 years, with the median age for lung cancer being 71 years [ 26 ]. Interestingly, our preliminary analysis of the data of 300 patients with GPA observed since 1978 (data not published) revealed that none of the younger patients were diagnosed with lung cancer, whereas among the older patients (accounting for approximately 15% of all the groups), three developed lung cancer; the cases of these three patients have been reported herein, with the patients being 74, 70, and 80 years old at the time of cancer diagnosis. In conclusion, older age is an important risk factor for lung cancer, and oncological vigilance should be strongly maintained in patients with GPA, especially older patients, who develop new lung symptoms.

In summary, we present three cases of older patients with GPA who developed lung cancer during long-term follow-up. These cases demonstrate that patients with GPA should be monitored even when vasculitis is in remission. This strategy enables early detection and appropriate treatment of cancer. Additionally, we highlight the diagnostic challenges in patients with GPA who develop new lung lesions, emphasizing that although relapse is considered first, clinicians must suspect other potential causes, such as malignancy. In such cases, biopsy and histological examination are pivotal for appropriate differential diagnosis. Finally, clinicians should be particularly vigilant when managing older patients with GPA, who face a higher risk of cancer than younger patients. Our cases raise the question of a potential link between vasculitis and lung cancer and highlight the clinical conditions recurrently observed together; however, they do not allow conclusions regarding the significance of their association or pathophysiological link, and further studies on a larger number of patients are needed. Nonetheless, physicians should be aware of this potential association and consider it when treating patients with AAV who have new pulmonary lesions.

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article.

Abbreviations

Antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibody

Chronic obstructive pulmonary disease

Computed tomography

Cyclophosphamide

• Granulomatosis with polyangiitis

Hazard ratio

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Malgorzata Potentas-Policewicz

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M.P.P. drafted the manuscript. J.F. designed, drafted and supervised the manuscript. K.B. interpreted and described radiological studies. M.Sz. performed histological examinations and described histological patterns. D.G. and M.S. analyzed data and contributed to writing the manuscript. All authors have read and approved the final version of the manuscript.

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Potentas-Policewicz, M., Szolkowska, M., Blasinska, K. et al. Lung cancer in older patients with granulomatosis with polyangiitis: a report of three cases. BMC Pulm Med 24 , 193 (2024). https://doi.org/10.1186/s12890-024-03024-7

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Cigarettes in Canada get a new look to help deter smoking

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Jeff Danby was the recipient of the Windsor Wildcats women's hockey team award for courage and determination Tuesday night at the 17th annual WESPY Awards.

Lawyers for alleged serial killer to argue he is not criminally responsible

Defence lawyers told court they will argue alleged serial killer Jeremy Skibicki is not criminally responsible for the deaths of four Indigenous women by way of a mental disorder.

High traffic at bustling Winnipeg Costco prompts calls for traffic light

A motion before Winnipeg’s public works committee could make it easier for shoppers who stocked up on bulk packs of toilet paper and chicken breast to exit one of the city’s bustling Costco locations.

NEW | Interprovincial drug bust led by Winnipeg police turns up millions in drugs, cash, luxury goods

More than a dozen people are facing charges, the majority Winnipeggers, after an interprovincial drug bust that turned up millions of dollars in cash, drugs, guns, jewelry and luxury vehicles.

Moe 'will respond' to CRA, insists Saskatchewan has 'paid in full' amid carbon tax audit

Saskatchewan Premier Scott Moe says his government 'will respond' to the Canada Revenue Agency when it concludes its audit of the province, but that his position is Saskatchewan doesn't owe Ottawa any money.

Here's how one of Sask.'s largest power plants was knocked out for 73 days, and what it took to fix it

A group of SaskPower workers recently received special recognition at the legislature – for their efforts in repairing one of Saskatchewan's largest power plants after it was knocked offline for months following a serious flood last summer.

These driving offences now come with an automatic impoundment, licence suspension in Sask.

Drivers in Saskatchewan will now lose their licence for a week and their vehicle for a month if they are caught committing certain high-speed and dangerous offences on the road.

'Tire fire of a deal' still raising burning questions in Sask. legislature

Saskatchewan's scrap tire industry was top of mind again in Regina Tuesday as politicians and advocates continued to probe into how an American company became the province’s only recycler.

'Not an easy task': Police begin 'meticulous' search at Saskatoon landfill in Mackenzie Trottier case

Police officers and cadaver dogs have begun searching the Saskatoon landfill for answers in the Mackenzie Lee Trottier case.

Managers must tell new hires about risk of violence at work under new Sask. employment rules

Saskatchewan employers will be required to tell new hires if they face a risk of violence in the workplace and to take actions against it starting on May 17.

Police arrest woman who praised Hamas attack at Vancouver protest

Authorities have arrested a 44-year-old woman who praised last October's attack on Israel during a rally in downtown Vancouver.

Person seriously injured while in Vancouver police custody, IIO notified more than 2 months later

B.C.'s police watchdog is looking into an incident that led to one person being seriously injured while in Vancouver police custody, but says it was weeks before it was notified.

B.C. tribunal decides first case involving non-consensual sharing of intimate images

In a first-of-its-kind case, a B.C. tribunal has ruled on a dispute involving the non-consensual sharing of intimate images, awarding damages and issuing orders that the photos be destroyed and taken offline.

Vancouver Island

Gaza protesters at University of Victoria say encampment will stay until demands are met

A pro-Palestinian protest camp has formed at the University of Victoria in solidarity with the people of Gaza and with similar encampments that have sprung up on university and college campuses in opposition to the Israel-Hamas war.

B.C. to provide $155.7 million to recruit and retain specialized health workers

The British Columbia government is spending more money to recruit and retain health-science workers, especially those in rural and remote communities.

'Floatel' won't be allowed to house LNG workers near Squamish, B.C.

Plans to use a renovated cruise ship to house more than 600 workers as they build a liquefied natural gas facility near Squamish, B.C., have been voted down by the local council.

B.C. breweries take home awards at World Beer Cup

Out of more than 9,000 entries from over 2,000 breweries in 50 countries, a handful of B.C. brews landed on the podium at the World Beer Cup this week.

B.C. man rescues starving dachshund trapped in carrier: BC SPCA

An emaciated dachshund is now recovering thanks to a Good Samaritan who found the pup near a biking trail in Kelowna, according to the BC SPCA.

Search crews called in after missing Kelowna senior's truck found

Search and rescue crews have been called in after a vehicle belonging to a missing senior was located near a rural intersection outside of Kelowna Tuesday.

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