Last updated: June 2021
Suggested citation: Hurley, S, Winnall, WR, Greenhalgh, EM & Winstanley, MH. 3.4 Lung cancer. In Greenhalgh, EM, Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2021. Available from http://www.tobaccoinaustralia.org.au/chapter-3-health-effects/3-4-lung-cancer
The two lungs are located on either side of the heart, near the backbone. The function of the lungs is to transport oxygen from the air to the blood, and carbon dioxide from the blood to the atmosphere. These two gases are ‘exchanged’ across the thin-walled alveolar cells lining the air-sacs of the lungs.
The two main types of lung cancer are non-small-cell lung carcinoma and small-cell lung carcinoma. The subcategories of non-small-cell lung carcinoma are adenocarcinoma, squamous cell carcinoma and large-cell undifferentiated carcinoma.
Lung cancer is now the most common type of cancer in the world. In 2018, there were an estimated 2,093,876 new cases globally and 1,761,007 deaths from lung cancer (including tracheal and bronchus cancers).1 Globally, lung cancer was the third-ranking cause of smoking-attributable years of healthy life lost (disability-adjusted life-years; DALY) for men in 2005–2015, after ischemic heart disease and cerebrovascular disease. For women, lung cancer was the second-ranking cause of smoking-attributable DALY in 2005–2015, after chronic obstructive pulmonary disease.2
In Australia, lung cancer is currently the fifth most common cancer diagnosed each year. In 2020, there were an estimated 13,258 newly-diagnosed cases and 8,641 deaths from lung cancer.3 Five-year survival in the period 2012– 2016 was only 19%.3 For males in Australia, lung cancer is the most common cause of cancer death, with an estimated 4,991 men dying in 2020. In 2019, the estimated risk of death from lung cancer before the age of 85 is one in 20 for males. Lung cancer is also the most common cause of cancer death for females in Australia, with an estimated 3,650 deaths in 2020. Females in Australia have a lower risk of dying than males. Their estimated risk of death from lung cancer before the age of 85 is one in 30.4
In 2015, lung cancer was the fifth leading contributor to total burden in Australia, accounting for 3.2% of total DALY lost due to illness or accidents. For men, it was the 5th leading contributor and for women the 10th. Lung cancer was the second most common cause of fatal burden within Australia in 2015.5
3.4.1 Establishing smoking as a major cause of lung cancer
The evidence that tobacco smoking causes lung cancer is unequivocal. Cigarette smoking causes most cases of lung cancer. In fact, in populations with prolonged cigarette use, up to 90% of lung cancer cases are attributable to smoking.6
Lung cancer was one of the first diseases to be causally linked with smoking. The story of the research that established this link, and the controversies the emerging data created, is told in articles by Colin White7 and Michael Thun;8 in the biography of the late Sir Richard Doll, one of the key researchers of the topic;9 and in the commentary10 published in conjunction with the re-publication of a pivotal 1959 review of the smoking and lung cancer relationship by Cornfield and colleagues.11 The following is a brief summary.
In the early 1900s, lung cancer was a rare disease. By the 1930s and 1940s a notable increase in lung cancer incidence was observed. Evidence came from official mortality statistics, pathologists' reports of autopsy findings and the observations of physicians specialising in lung disease. There was much criticism of the view that the reported increase in lung cancer cases was credible. It was suggested that better diagnosis of the disease, or increased life expectancy, might be the explanation for the increase in cases.
The increase in lung cancer incidence by the 1930s led to a search for the cause. At least seven small studies found an association between smoking and lung cancer, implying smoking as a cause. However, there was much criticism of this view. Other potential causes were suggested, including exposure to pollutants such as traffic exhaust, industrial pollution, smoke from domestic fires and exposure to tars used in road construction.7
By the late 1940s and early 1950s, it became obvious that the increases in lung cancer incidence and deaths were real and important. In 1950, two large case–control studies were published, one by Wynder and Graham in the US, and the other by Doll and Hill in the UK. Both found a large increase in the risk of lung cancer associated with smoking. The British study found that the risk for smokers compared with never smokers was 14-fold higher and the American study found that the risk was seven-fold higher. It is noteworthy that while conducting their research, Doll, Hill and Graham, who were all smokers, were doubtful that smoking was a cause of lung cancer. Their results provoked much controversy and disbelief. Nevertheless, large prospective cohort studies were initiated in Britain (by Doll and Hill) and in the US (Hammond and Horn) to investigate the possible link, in a manner free of the potential bias in retrospective case–control studies. These large studies soon confirmed the relationship between smoking and lung cancer.
Doll and Hill’s study warrants special mention. They sent questionnaires about smoking habits to almost 35,000 male British doctors in 1951, and periodically thereafter. Deaths and causes of death were monitored for almost 99% of these doctors over 50 years and results were published in 195412 and 195613, then after 10,14 20,15 4016 and 50 years follow-up.17 As early as 1956, Doll and Hill had concluded, in relation to lung cancer deaths, that smokers had a higher mortality than non-smokers, heavy smokers had a higher mortality than light smokers, cigarette smokers had a higher mortality than pipe smokers and those who continued to smoke had a higher mortality than those who gave up.13 The 50-year follow-up of the British doctors study found that lung cancer mortality rates were 16-fold higher (averaged across all ages) for cigarette smokers compared with never smokers.17
Numerous cohort studies initiated in the US reported similar findings to Doll and Hill’s British Doctor’s study. Expert bodies eventually agreed that the evidence for smoking as a cause of lung cancer was compelling. That cigarette smoking is a cause of lung cancer in men was the signature finding of the 1964 landmark US Surgeon General’s report, Smoking and Health.18 This report concluded that smoking is a cause of lung cancer in men and a probable cause in women. A subsequent report from 1968 concluded that smoking causes lung cancer in women.19, 20
A plethora of studies have estimated the magnitude of the relative risk of lung cancer for smokers compared to non-smokers. The relative risk depends on the patterns of smoking, smoking intensity and duration, age at initiation, time period and other factors in the population being studied.21 A 9-fold increase in risk for smokers, compared to non-smokers, has been estimated by numerous studies,12, 22-24 however there is considerable variation in this risk, depending on the population studied. A 2021 study from Australia has estimated the increased risk for smokers using data from the 45 and Up Study. This cohort of people from NSW were aged 45 and over, with smoking behaviour reported at baseline between 2006 and 2009. Current smokers had an increased risk of lung cancer, reported until 2013, of 17.66-fold higher than non-smokers (95% CI = 14.65 - 21.29).21
3.4.2 How tobacco smoke causes lung cancer
This issue is discussed in Chapter 3, Section 3.3.
3.4.3 Factors affecting risk
188.8.131.52 Intensity and duration of cigarette smoking
The risk of lung cancer increases with the number of cigarettes smoked and the duration of smoking.19, 25 Cumulative smoking exposure in pack-years (the product of intensity (packs per day) and duration of exposure in years) is often used as a metric in predictions of lung cancer risk. In studies that compare smoking intensity with duration, the latter was found to be the strongest determinant of disease risk and severity.26, 27 Most studies show that smoking at a lower intensity for a longer duration is more deleterious than at a higher intensity over a shorter duration.28 The duration of smoking also had a greater effect on lung cancer mortality than the intensity in a study of US men.29 Consistent with these studies, the annual excess incidence of lung cancer increases approximately 100-fold for men who have smoked for 45 years compared with men who have smoked for 15 years.30
Modelling studies examining the effects of smoking duration and intensity on lung cancer risk have shown that this risk increased linearly with increase in duration, but the effect of smoking intensity on risk is more complex. Below 15–20 cigarettes per day, the risk increased with intensity, suggesting greater risk for a total exposure delivered at higher intensity, for a shorter duration. Above 20 cigarettes per day, the risk decreased with increasing intensity, suggesting greater risk for a total exposure delivered at lower intensity, for a longer duration.28, 31 A study of smoking and lung cancer risk in French women generated a similar conclusion. Duration of smoking in the French study was linearly associated with risk but intensity of smoking had a stronger effect for women who smoked less than 30 cigarettes a day.32
184.108.40.206 Smoking cessation
Smoking cessation modifies the risk of lung cancer diagnosis and mortality (see also Section 220.127.116.11). For people who stop smoking, the lung cancer incidence rate stops increasing steeply and remains almost constant.33 Mortality from lung cancer follows a similar pattern.34 The International Agency for Research on Cancer summarised this effect as follows: ‘Stopping smoking at any age avoids the further increase in lung cancer incurred by continued smoking. The younger the age at cessation, the greater the benefit.19, 25
The relative risks of lung cancer diagnosis do not follow the same pattern as the incidence rates for ex-smokers. The relative risk of lung cancer for ex-smokers, compared to current smokers, falls after cessation because the risk for ex-smokers remains constant whereas it increases for current smokers.33
The relative risks of lung cancer fall for former smokers with the number of years since cessation, compared to those who continue smoking. The relative risk of lung cancer for former smokers takes between 10 and 15 years to be half that of current smokers.35-37
18.104.22.168 Histological type
Smoking increases the risk of all the main histological types of lung cancer. With declining smoking rates in the US, declines in the age-adjusted incidence of small cell carcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas since 1980 are apparent for males. However, for females these rates have remained mostly constant since 1990, reflecting the later peak in smoking rates for women. The exception is adenocarcinoma incidence, which has increased for both genders since 1980.38 The risks for lung cancer for people who have never smoked have remained consistently low over the same time interval.
Adenocarcinoma is now the most common type of lung cancer in smokers.38, 39 The incidence of adenocarcinoma has increased over time. For example, the incidence of adenocarcinoma in Connecticut increased 17-fold in women (from 0.9 to 15.2 cases per 100,000 person-years) and nearly 10-fold in men (from 2.4 to 23.2 cases per 100,000 person-years) from 1950 to 1991.40
Mortality from lung adenocarcinoma has also increased over time. Data from the American Cancer Prevention Study I (initiated in 1959) estimated the relative risk of death from lung adenocarcinoma for male smokers compared with non-smokers at 4.6. These same estimates taken at a later time point indicated an increased incidence. The American Cancer Prevention Study II (initiated in 1982) estimated a relative risk of 19 for male smokers.40 For women, the relative risk of mortality from lung adenocarcinoma rose from 1.5% (1959 study) to 8.1% (1982 study).40
The increasing rates of lung adenocarcinoma associated with smoking suggest a new or substantially enhanced risk of this tumour type has arisen. Changes in diagnosis practices were demonstrated to not be responsible for this difference.41 Birth cohort patterns suggest that changes in the design and composition of cigarettes may be drivers of the increase in lung adenocarcinoma incidence.38, 41 The 2014 Surgeon General’s report highlights the substantial changes that have taken place since the 1950s in the design and composition of cigarettes. Although these changes are not fully understood, they have resulted in different patterns of smoking (such as more intense puffing) and alterations in the chemical composition of cigarette smoke. The conclusion of the 2014 Surgeon General’s report is that the increased risk of lung adenocarcinoma in smokers results from changes in cigarette design and composition since 1950. There is currently insufficient research to specify which changes have caused this increase, but the current evidence implies a role for ventilated filters and increased levels of tobacco-specific nitrosamines.38
22.214.171.124 Sex differences
Although some early studies suggested that women are at greater risk of lung cancer from smoking than men, this is no longer believed to be the case. The weight of evidence suggests that there is little, if any, difference between women and men in their vulnerability to the carcinogenic effects of cigarette smoke.25, 42 An example of this evidence comes from a large prospective US study that followed 4,097 men and 2,237 women aged 50–71 years from 1995 to 2003. For smokers with similar smoking histories, men tended to have slightly higher incidence rates than women, demonstrating that women are no more susceptible than men to the carcinogenic effects of cigarette smoking.43
There is increasing evidence that the biology of lung cancer differs between the sexes, however the research in this area has been limited.42 Although adenocarcinoma is currently the most common histological type of lung cancer in both sexes, women have proportionally more adenocarcinoma and less squamous cell carcinoma than men.39, 42, 43 The aforementioned US study found a 30% higher risk estimate for lung cancer in women who had never smoked compared with men who had never smoked, in a result that approached statistical significance.43 This observation indicates that a biological difference exists in the course of lung cancer disease between the sexes.
A number of plausible mechanisms have been proposed to be responsible for the biological difference between lung cancer suffered by women compared to men. These are categorised as hormonal factors (effects of oestrogen and progesterone), molecular differences, genetic differences, differing levels of infections (such as human papilloma virus and non-tuberculosis mycobacteria) and prior history of radiation exposure during radiotherapy.42, 44, 45 A genetic study found over 800 genes were used differently in the tumour cells of men and women with lung cancer. The sex-specific genes in women with lung cancer were mostly regulators of immune responses, whereas the male-specific genes affected gene use, cell signalling pathways and cell division.46 Data from the Nurses’ Health Study in the US suggest that early onset of menopause and past oral contraceptive use increase lung cancer risk, particularly in smokers.47 In this study, postmenopausal hormone use did not affect lung cancer incidence, but a prospective cohort study in the US state of Washington found that oestrogen plus progesterone replacement therapy was associated with advanced stage at diagnosis.48 Further research will be needed to elucidate the impact of such factors on lung cancer incidence and their interaction, if any, with the influence of smoking.
126.96.36.199 Other factors
Aside from tobacco use and exposure to secondhand smoke, the recognised risk factors for lung cancer include radon gas, exposure to industrial and chemical carcinogens, air pollution, family history of lung cancer and previous lung diseases.39 Emphysema (a form of chronic obstructive pulmonary disease), which is itself a smoking-associated condition, may increase the risk of lung cancer.49
The role of alcohol in causing lung cancer is not completely understood. As smoking is so closely associated with alcohol consumption, it is difficult to determine the effect of alcohol on lung cancer risk, taking into account smoking history. Some studies have suggested that alcohol consumption, particularly binge drinking, increases the risk of lung cancer in smokers but not in non-smokers.50, 51 A dose-specific meta-analysis determined that the evidence for a smoking-adjusted association between alcohol and lung cancer risk is limited to groups with very high alcohol consumption.52 This was supported by a pooled analysis of data from seven prospective cohort studies.53 At lower levels, any associations observed appeared explainable by confounding (the distortion of the association between an exposure and health outcome by a causative third factor; in this case, smoking).52
Diet may play a role in the susceptibility to lung cancer for smokers, according to a European case-control study. The risk of lung cancer for moderate smokers was 41% lower for those with higher adherence to a healthy, Mediterranean-style diet.54 The association of BMI (body mass index) with outcomes from lung cancer is complex. A cohort study has assessed these associations in over 20,000 people with non-small cell lung cancer (NSCLC). Underweight as well as obese female ever-smokers had worse outcomes than those with healthy weight, but only for people of white ethnicity. Asian people, black people and never smokers did not have these BMI associations with NSCLC outcomes.55
There are ethnic differences in susceptibility to lung cancer caused by smoking.25 In the US, the risk of lung cancer has been found to differ between racial/ethnic groups after taking into account the duration and intensity of smoking. Compared to Caucasians, African Americans and native Hawaiian smokers have an increased risk, whereas Latino and Japanese American smokers have a lower risk.56-58 Researchers have hypothesised that racial/ethnic differences in the activity of an enzyme that modifies nicotine may lead to different smoking behaviours, resulting in different levels of tobacco smoke carcinogens from the same number of cigarettes smoked per day. This results in elevated lung cancer risk in groups with greater nicotine metabolism, and reduced risk in those with lesser metabolism. A study of nicotine metabolism in a multiethnic cohort supports this hypothesis.59
Aboriginal and Torres Strait Islander peoples are disproportionately affected by lung cancer (see also Section 8.7). Over the period 2009 to 2013, 85 in 100,000 Indigenous Australians were diagnosed each year with lung cancer (age-standardised rate). There were 57 deaths each year for each 100,000 people over 2011 to 2015. For the period of 2007 to 2014, Aboriginal and Torres Strait Islander peoples had 11% chance of surviving for 5 years after diagnosis. The age-standardised incidence and mortality have increased during the period from 1998 to 2015 for Aboriginal and Torres Strait Islander peoples. The Australian Institute of Health and Welfare predicts that the factors affecting the relatively high lung cancer rates in Indigenous Australians may include smoking rates, alcohol consumption, access to healthcare services and uptake of screening and diagnostic testing.60
3.4.4 Impact of smoking on prognosis
Smoking not only increases the risk of lung cancer but adversely impacts prognosis once lung cancer is diagnosed. In patients with non-small cell lung cancer, the survival rate is lower in those who had smoked for 15 pack-years or more, and also lower in current or former smokers compared to never-smokers.61, 62
In the US, more than 80% of patients continue to smoke after being diagnosed with lung cancer.63 A meta-analysis published in 2010 has provided preliminary evidence that such patients have a worse prognosis than those who quit.64 Most patients in these studies had early stage tumours. For both small cell and non-small cell lung cancer, the risk of death (from any cause) was greater in patients who continued to smoke compared with those who quit at diagnosis. Models developed by the authors suggested that the quitters’ improved prognosis was due to a reduction in cancer progression rather than the cardiovascular benefits of quitting. The meta-analysis results were consistent with this suggestion; the risk of recurrence for both types of lung cancer was higher in continuing smokers.64
3.4.5 Temporal trends in lung cancer rates
The impact of tobacco control programs on reducing smoking prevalence and in turn, tobacco-caused disease (including lung cancer) is important to researchers and policy makers.
Three studies from the US have found an association between tobacco-control policies and lung cancer rates. The first was based on data from California, where an enhanced tobacco-control program that included increased taxes and a range of other strategies was initiated in 1988. Analysis of this program found that over the period of 1988–1997, per capita cigarette consumption declined more rapidly in California compared with the rest of the US. The subsequent decline in lung cancer incidence rates in Californian men was 1.5 times greater than in other states where tobacco control measures were less intensive. In women, lung cancer incidence rates fell by 4.8% in California, but increased by 13.2% in other states.65 The second analysis, comparing data from the 51 US states, found that the intensity of state tobacco control efforts was negatively correlated with both lung cancer incidence and mortality in young adults.66 With longer follow-up, it was shown that annual lung cancer mortality decreased more rapidly in California and by 2013 was 28% lower (62.6 vs. 87.5 per 100,000) than the rest of the United States.67 Analyses of data in the UK,68 US69 and Australia39, 70 have found lung cancer incidence and mortality also follow smoking patterns, with a lag between smoking initiation and disease occurrence.
In the US, the incidence of lung cancer has dropped considerably for males but not for females since 1980. The age-adjusted incidence of lung in males fell from 99.9 (per 100,000 males) in 1980 to 55.4 in 2017; a 45% decrease. In females, the death rate steadily increased from 32.2 (per 100,000 females) in 1980 to 53.8 in 2005, then fell somewhat to 45.05 in 2017.71 The steadily increasing lung cancer death rate began to level off for men in the mid-1970s, peaking in 1991. It is estimated that the reductions in tobacco smoking in the US over the previous half-century had prevented or postponed at least 146,000 deaths in men from lung cancer between 1991 and 2003.69
In Australia, the benefits for men of reductions in smoking prevalence since the 1950s are reflected in national statistics. For example, the aged-standardised lung cancer incidence in males decreased from 85.2 (per 100,000 men) to 60.3 in 2007, then 52.8 in 2015.72 This change constitutes a 38% drop in annual incidence from 1982 to 2015. A similar reduction in incidence has not occurred in females, reflecting the later peak in smoking rates (in the 1970s) by women. The age-standardised lung cancer incidence in Australian women rose from 18.2 (per 100,000 women) to 32.6 in 2007, then 34.6 in 2015. Women therefore saw a 90% rise in incidence from 1982 to 2015. However, by 2015 the incidence in women was still only about two-thirds that of men.72
Similar trends have been seen in lung cancer death rates in Australia. For males, the age-standardised lung cancer mortality fell from 80 (per 100,000 men) to 47 in 2007, then to 40 in 2014.73 This was a 50% decrease in mortality rates from 1982 to 2014. This trend was the opposite in women. Age-standardised lung cancer mortality in women rose from 14 (per 100,000 women) in 1982 to 28 in 2007, then remained at 28 in 2014. Women therefore saw a 100% (two-fold) increase in lung cancer mortality rates from 1982 to 2014.73
The research described above highlights the long-term payoff from strong tobacco control programs, with reductions in lung cancer incidence and mortality rates seen decades after reductions in smoking.70
Relevant news and research
For recent news items and research on this topic, click here. ( Last updated August 2021)
1. Global Cancer Observatory (Globocan). Lung fact sheet. International Agency for Research on Cancer; World Health Organization, 2019. Available from: https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
2. Global Burden of Disease 2015 Tobacco Collaborators. Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015. Lancet, 2017; 389(10082):1885-906. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28390697
3. Cancer Australia. Lung cancer in Australia statistics. Sydney, Australia: Cancer Australia, 2020. Available from: https://lung-cancer.canceraustralia.gov.au/statistics.
4. Australian Institute of Health and Welfare. Cancer in Australia 2019. Cancer series no.119, Cat. no. CAN 123 Canberra: AIHW, 2019. Available from: https://www.aihw.gov.au/getmedia/8c9fcf52-0055-41a0-96d9-f81b0feb98cf/aihw-can-123.pdf.aspx?inline=true.
5. Australian Institute of Health and Welfare. Australian Burden of Disease Study: impact and causes of illness and death in Australia 2015. Australian Burden of Disease, Canberra: AIHW, 2019. Available from: https://www.aihw.gov.au/reports/burden-of-disease/burden-disease-study-illness-death-2015/contents/summary.
6. World Health Organization (WHO). European tobacco use trends report 2019. Copenhagen, Denmark: World Health Organization Regional Office for Europe, 2019. Available from: http://www.euro.who.int/en/health-topics/disease-prevention/tobacco/publications/2019/european-tobacco-use-trends-report-2019-2019.
7. White C. Research on smoking and lung cancer: a landmark in the history of chronic diseases. Yale Journal of Biology and Medicine, 1990; 63(1):29–46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/2192501
8. Thun MJ. When truth is unwelcome: the first reports on smoking and lung cancer. Bulletin of the World Health Organization, 2005; 83(2):144–5.
9. Keating C, Smoking kills. The revolutionary life of Richard Doll. Oxford: Signal Books; 2009.
10. Vandenbroucke JP. Commentary: 'Smoking and lung cancer'--the embryogenesis of modern epidemiology. International Journal of Epidemiology, 2009; 38(5):1193-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19773412
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12. Doll R and Hill AB. The mortality of doctors in relation to their smoking habits: a preliminary report. British Medical Journal, 1954; 1(4877):1451–5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2085438/
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14. Doll R and Hill AB. Mortality in Relation to Smoking: Ten Years' Observations of British Doctors. British Medical Journal, 1964; 1(5395):1399-410. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14135164
15. Doll R and Peto R. Mortality in relation to smoking: 20 years' observations on male British doctors. British Medical Journal, 1976; 2(6051):1525-36. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1009386
16. Doll R, Peto R, Wheatley K, Gray R, and Sutherland I. Mortality in relation to smoking: 40 years' observations on male British doctors. British Medical Journal, 1994; 309(6959):901-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7755693
17. Doll R, Peto R, Boreham J, and Sutherland I. Mortality in relation to smoking: 50 years' observations on male British doctors. British Medical Journal, 2004; 328(7455):1519. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15213107
18. US Department of Health and Education and Welfare, Smoking and Health: A report of the Advisory Committee to the Surgeon General of Public Health Service. Publication no (PHS) 1103 Washington: US Department of Health, Education and Welfare, Public Health Service, Center for Disease Control; 1964. Available from: https://profiles.nlm.nih.gov/spotlight/nn/catalog/nlm:nlmuid-101584932X202-doc.
19. US Department of Health and Education and Welfare. The health consequences of smoking. 1968 supplement to the 1967 Public Health Service review., DHEW Publication No. 1696 (Supplement) Washington, US: US Department of Health. Education, and Welfare, Public Health Service, 1968. Available from: https://sbpt.org.br/portal/wp-content/uploads/2019/02/1969-SGR-TABACO-MALEF-SAUDE-SUPL-1967.pdf.
20. US Department of Health and Human Services. The health consequences of smoking: a report of the Surgeon General. Atlanta, Georgia: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Available from: http://www.cdc.gov/tobacco/data_statistics/sgr/index.htm.
21. Weber MF, Sarich PEA, Vaneckova P, Wade S, Egger S, et al. Cancer incidence and cancer death in relation to tobacco smoking in a population-based Australian cohort study. International Journal of Cancer, 2021. Available from: https://pubmed.ncbi.nlm.nih.gov/34015143/
22. Doll R and Hill AB. Smoking and carcinoma of the lung; preliminary report. British Medical Journal, 1950; 2(4682):739-48. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14772469
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25. International Agency for Research on Cancer Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Volume 83. Lyon: International Agency for Research on Cancer, 2004. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Tobacco-Smoke-And-Involuntary-Smoking-2004.
26. Remen T, Pintos J, Abrahamowicz M, and Siemiatycki J. Risk of lung cancer in relation to various metrics of smoking history: a case-control study in Montreal. BMC Cancer, 2018; 18(1):1275. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30567516
27. Hastie DI, Liverani S, Azizi L, Richardson S, and Stucker I. A semi-parametric approach to estimate risk functions associated with multi-dimensional exposure profiles: application to smoking and lung cancer. BMC Medical Research Methodology, 2013; 13:129. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24152389
28. Lubin JH and Caporaso NE. Cigarette smoking and lung cancer: modeling total exposure and intensity. Cancer Epidemiology, Biomarkers and Prevention, 2006; 15(3):517-23. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16537710
29. Flanders WD, Lally CA, Zhu BP, Henley SJ, and Thun MJ. Lung cancer mortality in relation to age, duration of smoking, and daily cigarette consumption: results from Cancer Prevention Study II. Cancer Research, 2003; 63(19):6556-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14559851
30. Doll R and Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidemiol Community Health (1978), 1978; 32(4):303-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/744822
31. Lubin JH, Caporaso N, Wichmann HE, Schaffrath-Rosario A, and Alavanja MC. Cigarette smoking and lung cancer: modeling effect modification of total exposure and intensity. Epidemiology, 2007; 18(5):639-48. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17700253
32. Papadopoulos A, Guida F, Cenee S, Cyr D, Schmaus A, et al. Cigarette smoking and lung cancer in women: results of the French ICARE case-control study. Lung Cancer, 2011; 74(3):369-77. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21620510
33. Peto J. That lung cancer incidence falls in ex-smokers: misconceptions 2. British Journal of Cancer, 2011; 104(3):389. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21285969
34. Halpern MT, Gillespie BW, and Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. Journal of the National Cancer Institute, 1993; 85(6):457-64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8445673
35. Pinsky PF, Zhu CS, and Kramer BS. Lung cancer risk by years since quitting in 30+ pack year smokers. Journal of Medical Screening, 2015; 22(3):151-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25926339
36. Calle EE, Rodriguez C, Jacobs EJ, Almon ML, Chao A, et al. The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer, 2002; 94(2):500-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11900235
37. US Department of Health and Human Services. Smoking cessation. A report of the Surgeon General. Atlanta, GA U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Centre for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health 2020. Available from: https://www.cdc.gov/tobacco/data_statistics/sgr/2020-smoking-cessation/.
38. US Department of Health and Human Services. The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. Available from: http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf.
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