3.4 Lung cancer

 

­Last updated: April 2020
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; 2020. Available from  http://www.tobaccoinaustralia.org.au/chapter-3-health-effects/3-4-lung-cance

 

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 loss of 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 2019, there were an estimated 12,817 newly-diagnosed cases and 9,021 deaths from lung cancer.3  Five-year survival in the period 2011– 2015 was only 17.4%.3 For males in Australia, lung cancer is the most common cause of cancer death, with an estimated 5,179 men dying in 2019. In 2019, the estimated risk of death from lung cancer before the age of 85 is 1 in 20 for males. Lung cancer is also the most common cause of cancer death for females in Australia, with an estimated 3,855 deaths in 2019. 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 1 in 30.3

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 2015.4

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.5

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 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.6

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 195411 and 195612, then after 10,13 20,14 4015 and 50 years follow-up.16 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 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.16

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.17 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.18, 19

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

3.4.3.1 Intensity and duration of cigarette smoking

The risk of lung cancer increases with the number of cigarettes smoked and the duration of smoking.18, 20 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.21, 22 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.23 The duration of smoking also had a greater effect on lung cancer mortality than the intensity in a study of US men.24 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.25

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.23, 26 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.27

3.4.3.2 Smoking cessation

Smoking cessation modifies the risk of lung cancer diagnosis and mortality (see also Section 7.1.2.2). For people who stop smoking, the lung cancer incidence rate stops increasing steeply and remains almost constant.28 Mortality from lung cancer follows a similar pattern.29 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, 20

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.28

3.4.3.3 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 1980.30 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.30, 31 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 1991.32

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.32 For women, the relative risk of mortality from lung adenocarcinoma rose from 1.5% (1959 study) to 8.1% (1982 study).32

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.33 Birth cohort patterns suggest that changes in the design and composition of cigarettes may be drivers of the increase in lung adenocarcinoma incidence.30, 33 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.30

3.4.3.4 Gender 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.20, 34 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.35

There is increasing evidence that the biology of lung cancer differs between the genders, however the research in this area has been limited.34 Although adenocarcinoma is currently the most common histological type of lung cancer in both genders, women have proportionally more adenocarcinoma and less squamous cell carcinoma than men.31, 34, 35 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.35 This observation indicates that a biological difference exists in the course of lung cancer disease between the genders.

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.34, 36, 37 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.38 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.39 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.

3.4.3.5 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.31 Emphysema (a form of chronic obstructive pulmonary disease), which is itself a smoking-associated condition, may increase the risk of lung cancer.40

The role of alcohol in causing lung cancer is incompletely 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.41, 42 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.43 This was supported by a pooled analysis of data from seven prospective cohort studies.44 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).43

There are ethnic differences in susceptibility to lung cancer caused by smoking.20 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.45-47 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.48

Indigenous people in Australia are disproportionately affected by lung cancer (see also Section 8.7). Indigenous Australian are 2.1 times more likely to be diagnosed with lung cancer and 1.8 times more likely to die from this disease than non-indigenous Australians. For the period of 2011–2015, Indigenous Australians had 11% chance of surviving 5 years after diagnosis, compared to 16% for non-indigenous people. The age-standardised incidence and mortality have increased during the period from 1998–2015 for Indigenous Australians. The Australian Institute of Heath and Welfare predict 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.49

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.50, 51

In the US, more than 80% of patients continue to smoke after being diagnosed with lung cancer.52 A meta-analysis published in 2010 has provided preliminary evidence that such patients have a worse prognosis than those who quit.53 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.53

Women appear to have a better response to therapy for lung cancer, irrespective of the stage of disease, or whether they were treated by surgery, chemotherapy, radiotherapy or a combination of modalities.34, 40 Some studies indicate that better responses occur in specific histological subsets, such as non-small cell disease or adenocarcinomas.36

3.4.5 Temporal trends in lung cancer rates

The impact of tobacco-control efforts and falling smoking rates on smoking-associated illness 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.

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 2017.54

Three studies from the US have found an association between tobacco-control efforts and lung cancer rates. The first was based on data from California, where an enhanced tobacco-control program was initiated in 1988. This program used increased taxes and comprehensive strategies to change social norms. 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.55 The second analysis, comparing data from the 51 US states, found that an index reflecting the intensity of state tobacco-control efforts was significantly correlated with both lung cancer incidence and mortality in young adults.56 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.57 Analyses of data in the UK,58 US59 and Australia31, 60 have found lung cancer incidence and mortality also trend in line with smoking patterns and the lag between smoking initiation and disease occurrence.

In the US, 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 US men from lung cancer between 1991 and 2003.59

The benefits of smoking cessation for men are now being reflected in Australian national statistics. For example, in Australia, 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 2015.61 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 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.61

Similar trends have been seen in lung cancer death rates. For males, the age-standardised lung cancer mortality fell from 80 (per 100,000 men) to 47 in 2007, then to 40 in 2014.62 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 2014.62

The observations described above infer that 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.60 Researchers anticipate that smoking cessation by women will soon be reflected in disease statistics.63


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References

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