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' in the alveoli (the thin-walled cells containing air) of the lungs.
There are four main types of lung cancer: squamous cell carcinoma, small-cell undifferentiated carcinoma, adenocarcinoma and large-cell carcinoma.
Lung cancer is now the most common type of cancer in the world. In 2008, the number of new cases that occurred was estimated to be 1.1 million with just under 949 000 deaths occurring in the same year. 1 The number of lung cancer deaths worldwide attributable to smoking has been estimated to be 0.85 million, making lung cancer the third-ranking cause of smoking-attributable deaths, after cardiovascular disease and chronic obstructive pulmonary disease.2
In Australia, lung cancer is the fifth most common cancer diagnosed; there were an estimated 11,280 new cases and 8,410 deaths in 2012.3 Five-year survival in the period 2006 – 2010 was only 13% for males and 17% for females.3 In Australian males, lung cancer is the most common cause of cancer death and is the third leading contributor to burden of disease, accounting for 4.5% of total disability-adjusted life-years (DALYs) lost due to illness or accident.4 In Australian women, lung cancer is the second most common cause of cancer death, after breast cancer.5
3.4.1 Risk associated with smoking
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 cases of lung cancer are attributable to smoking.
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 White6 and Michael Thun;7 in the biography of the late Sir Richard Doll, one of the key researchers of the topic;8 and in the commentary9 published in conjunction with the re-publication of a pivotal 1959 review of the smoking and lung cancer relationship by Cornfield and colleagues.10
The following is a brief summary. In the early 1900s, lung cancer was a rare disease. By the 1930s and 1940s an increase in lung cancer incidence was becoming obvious, and at least seven small studies found an association between smoking and lung cancer. However, it was thought that better diagnosis of the disease, or increased life expectancy, might be the explanation for the increase in lung cancer and these early studies were not widely accepted internationally, or perhaps even read.
In the late 1940s and early 1950s, it became obvious that the increase in lung cancer and lung cancer deaths was 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, but nevertheless large prospective studies were initiated in Britain (by Doll and Hill) and in the US 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 195411 and 195612 and after 10,13, 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.12
The cohort studies initiated in the US reported similar findings, and expert bodies eventually found the evidence that smoking causes lung cancer compelling. The US Surgeon General, for example, concluded in 1964 that smoking causes lung cancer in men, and in 1968 concluded that smoking causes lung cancer in women.18
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
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
220.127.116.11 Intensity and duration
The risk of lung cancer increases with the number of cigarettes smoked and the duration of smoking.1,18 The latter is the strongest determinant. A modelling study of the excess odds ratio for lung cancer per pack-year of smoking found a greater risk for a total exposure delivered for a longer duration than for an equivalent exposure delivered at higher intensity (shorter duration). So the earlier the age a person starts smoking and the longer they continue, the greater the risk.19 For example, 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. In contrast, American Cancer Prevention Study II found that the lung cancer mortality rate for women who had smoked for 21–30 years was about 35% higher in those who reported smoking more than 20 cigarettes per day compared with those who reported smoking 20 cigarettes per day.1
18.104.22.168 Smoking cessation
Stopping smoking decreases the risk of lung cancer. In fact, Julian Peto has pointed out that when a smoker quits, the lung cancer mortality rate stops increasing steeply and remains almost constant.20 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.'1
22.214.171.124 Histological type
Smoking increases the risk of all histological types of lung cancer, but the association between adenocarcinoma and smoking has become stronger over time and it is now the most common type of lung cancer in smokers.21,22 For example, in the American Cancer Prevention Study I (initiated in 1959) the relative risk of death from lung adenocarcinoma for male smokers compared with non-smokers was 4.6, whereas in the American Cancer Prevention Study II (initiated in 1982) the comparable risk was 19.23 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 (e.g., more intense puffing) and alterations in the chemical composition of cigarette smoke, and have caused the increased risk of lung adenocarcinoma from smoking. There is currently not enough research to specify which changes have caused this increase, but the evidence suggests that ventilated filters and increased levels of tobacco-specific nitrosamines are partially responsible.24
126.96.36.199 Gender differences
Some studies have suggested that women who smoke are at greater risk for developing lung cancer than men who smoke. The weight of evidence now suggests that there is little, if any, difference between women and men in their vulnerability to the carcinogenic effects of cigarette smoke.1,25 For example, a US study that followed almost 300 000 men and almost 200 000 women aged 50–71 years from 1995 to 2003 found no statistically significant difference between sexes in the incidence of lung cancer for those who smoked more than two packs of cigarettes per day.26
However, there is mounting evidence that the biology of lung cancer differs between the sexes.25 The US study mentioned above found a 30% higher incidence of lung cancer in women who had never smoked compared with men who had never smoked, and this difference was almost statistically significant.26 Although adenocarcinoma is currently the most common histological type of lung cancer in both men and women, women have proportionally more adenocarcinoma and less squamous cell carcinoma.22,25 Female hormones and reproductive factors may influence lung carcinogenesis.25, 27 Data from the Nurses' Health Study in the US suggest that early onset of menopause and past oral contraceptive use increase lung cancer risk.28 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 increased lung cancer risk.29 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.
188.8.131.52 Other factors
The role of alcohol in lung cancer is controversial. Some studies have suggested that alcohol consumption, particularly binge drinking, increases the risk of lung cancer in smokers but not in non-smokers.30, 31 Another study found that moderate red wine consumption decreases lung cancer risk.32 Further studies are needed to clarify this association.
Emphysema (a form of chronic obstructive pulmonary disease), which is itself a smoking-associated condition, may increase the risk of lung cancer.33
There are ethnic differences in susceptibility to lung cancer caused by smoking.1 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.31,32 Researchers have hypothesised that ethnic/racial differences in the activity of an enzyme that metabolises nicotine may lead to different smoking behaviour, resulting in different levels of tobacco smoke carcinogens for the same number of cigarettes smoked per day, in turn resulting in elevated lung cancer risk in groups with greater nicotine metabolism, and reduced risk in those with lower metabolism. A study of nicotine metabolism in a multiethnic cohort supports this hypothesis.33
3.4.4 Impact of smoking on prognosis
Smoking not only increases the risk of lung cancer, but appears to adversely impact prognosis once lung cancer is diagnosed. In patients with non-small cell lung cancer, the survival rate has been found to be lower in patients who had smoked for more pack-years.37, 38
In the US, more than 80% of patients continue to smoke after being diagnosed with lung cancer.36 A meta-analysis published in 2010 has provided preliminary evidence that such patients have a worse prognosis than those who quit.39 Most patients in the 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.40 Most patients in the 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. 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.40
Women appear to have a better response to therapy for lung cancer, irrespective of stage of disease, histological type and whether they are being treated with surgery, chemotherapy, radiotherapy or a combination of these modalities.25
3.4.5 Temporal trends in lung cancer rates
The impact of tobacco-control efforts and falling smoking rates on smoking-associated illnesses is clearly of interest to researchers, public health program funders and the wider community. In this context, interest has focused on lung cancer, because most lung cancer is caused by smoking, and because reliable national mortality statistics are widely available. Two analyses of data in the US have found links between tobacco-control efforts and lung cancer rates. The first was based on data from California, where an enhanced tobacco-control program, involving increased taxes and comprehensive strategies to change social norms, was initiated in 1988. The analysis found that over the period 1988–1997 per capita cigarette consumption declined more rapidly in California compared with the rest of the US and that the decline in lung cancer incidence rates in 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.41 The second analysis compared data from the 51 US states found that an index reflecting the intensity of tobacco-control efforts in a state was correlated with both lung cancer incidence and mortality in young adults.42
Analyses of data in the UK,43 US44 and Australia45 have found lung cancer incidence and mortality trends in line with smoking patterns and the lag between smoking initiation and disease occurrence. The benefits of smoking cessation in men are now being reflected in national statistics. For example, in Australia, lung cancer incidence in men decreased by 32% between 1982 and 2007, but increased by 72% in women over the same period. However, by 2007 incidence in women was still only about half that in men.46 Similar trends have been seen in lung cancer death rates. In men, mortality fell by 1.9% per year between 1993 and 1998, but increased by 0.3% per annum, on average, in women.5
In the US, the steadily increasing lung cancer death rate began to level off for men in the mid-1970s, peaked in 1991 and had decreased by 20% by 2003. In women, the death rate steadily increased until 1991, after which it began to level off, although still increasing by 9.6% between 1991 and 2003. Thun and Jemal estimated from these data that the reductions in tobacco smoking in the US over the previous half-century had prevented at least 146 000 deaths from lung cancer.44
So, the payoff from tobacco control has only just begun, with lung cancer mortality in men peaking 20–25 years after the peak in smoking rates.45 Researchers anticipate that smoking cessation by women will soon be reflected in disease statistics.47
Relevant news and research
For recent news items and research on this topic, click here.(Last updated July 2019)
1. 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://monographs.iarc.fr/ENG/Monographs/vol85/mono85.pdf
2. Ezzati M and Lopez AD. Estimates of global mortality attributable to smoking in 2000. The Lancet 2003;362(9387):847–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13678970
3. Australian Institute of Health and Welfare and Australasian Association of Cancer Registries. Cancer in Australia: an overview, 2010. Cancer series no. 60. AIHW cat. no. CAN 56. Canberra: AIHW, 2010. Available from: http://www.aihw.gov.au/publication-detail/?id=6442472459&tab=2
4. Australian Institute of Health and Welfare. Cancer survival and prevalence in Australia: cancers diagnosed from 1982 to 2004. Cancer series no. 42. AIHW cat. no CAN 38. Canberra: AIHW, 2008. Available from: http://www.aihw.gov.au/publication-detail/?id=6442468141&libID=6442468139
5. Australian Institute of Health and Welfare. Cancer survival and prevalence in Australia: cancers diagnosed from 1982 to 2004. Cancer series no. 42. AIHW cat. no CAN 38, Canberra: AIHW, 2008. Available from: http://www.aihw.gov.au/publication-detail/?id=6442468141&libID=6442468139
6. 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
7. 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.
8. Keating C, Smoking kills. The revolutionary life of Richard Doll. Oxford: Signal Books; 2009.
9. Vandenbroucke J. 'Smoking and lung cancer'--the embryogenesis of modern epidemiology [Commentary]. International Journal of Epidemiology, 2009; 38(5):1193–6. Available from: http://ije.oxfordjournals.org/content/38/5/1193.full.pdf
10. Cornfield J, Haenszel W, Hammond E, Lilienfeld A, Shimkin M, et al. Smoking and lung cancer: recent evidence and a discussion of some questions. International Journal of Epidemiology, 2009; 38(5):1175–91. Available from: http://ije.oxfordjournals.org/content/38/5/1175.full.pdf
11. 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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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: http://www.ncbi.nlm.nih.gov/pubmed/1009386
16. Doll R, Peto R, Wheatly L, Gray R, and Sutherland I. Mortality in relation to smoking: 40 years' observations on male British doctors. British Medical Journal (Clinical Research Ed.), 1994; 309(6959):901–11. Available from: http://www.bmj.com/cgi/content/full/309/6959/901
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; 328:1519–1527.
18. 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
19. 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: http://www.ncbi.nlm.nih.gov/pubmed/17700253
20. Peto J. That lung cancer incidence falls in ex-smokers: misconceptions 2. British Journal of Cancer, 2011; 104(3):389. Available from: http://www.nature.com/bjc/journal/v104/n3/full/6606080a.html
21. U.S. 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, Printed with corrections, January 2014. Available from: http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf
22. Australian Institute of Health and Welfare (AIHW) and Cancer Australia. Lung cancer in Australia: an overview. Cancer series no. 64. Cat. no. CAN 58., Canberra 2011. Available from: http://www.aihw.gov.au/publication-detail/?id=10737420419
23. Thun MJ, Lally CA, Flannery JT, Calle EE, Flanders WD, et al. Cigarette smoking and changes in the histopathology of lung cancer. Journal of the National Cancer Institute, 1997; 89(21):1580–6. Available from: http://jnci.oxfordjournals.org/cgi/content/abstract/89/21/1580
24. US Department of Health and Human Services. The health consequences of smoking - 50 years of progress. Atlanta, GA: US 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/
25. Patel J. Lung cancer: a biologically different disease in women? Women's Health (London, England), 2009; 5(6):685–91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19863471
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28. Baik C, Strauss G, Speizer F, and Feskanich D. Reproductive factors, hormone use, and risk for lung cancer in postmenopausal women, the Nurses' Health Study. Cancer Epidemiology, Biomarkers & Prevention, 2010; 19(10):2525–33. Available from: http://cebp.aacrjournals.org/content/19/10/2525.long
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30. Toriola A, Kurl S, Laukkanen J, and Kauhanen J. Does binge drinking increase the risk of lung cancer: results from the Findrink study. European Journal of Public Health, 2009; 19(4):389–93. Available from: http://eurpub.oxfordjournals.org/content/19/4/389.long
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33. Li Y, Swensen S, Karabekmez L, Marks R, Stoddard S, et al. Effect of emphysema on lung cancer risk in smokers: a computed tomography-based assessment. Cancer Prevention Research, 2011; 4(1):43–50. Available from: http://cancerpreventionresearch.aacrjournals.org/content/4/1/43.long
34. Le Marchand L, Wilkens LR, and Kolonel LN. Ethnic differences in the lung cancer risk associated with smoking. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 1992; 1(2):103-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1306091
35. Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. New England Journal of Medicine, 2006; 354(4):333-42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16436765
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47. Shibuya K, Inoue M, and Lopez AD. Statistical modeling and projections of lung cancer mortality in 4 industrialized countries. Journal international du cancer, 2005; 117(3):476-85. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ijc.21078/abstract